{"gene":"CTHRC1","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2008,"finding":"Cthrc1 selectively activates the Wnt/PCP pathway while suppressing the canonical Wnt/β-catenin pathway. Cell-surface-anchored Cthrc1 binds directly to Wnt ligands, Frizzled (Fzd) receptors, and Ror2, forming a Cthrc1-Wnt-Fzd/Ror2 complex that stabilizes ligand-receptor interaction and promotes PCP signaling. Genetic epistasis (Cthrc1 null × Vangl2 heterozygous mutant) produced PCP-characteristic abnormalities, placing Cthrc1 upstream in the Wnt/PCP pathway.","method":"Co-IP/cell-surface binding assays in HEK293T cells, genetic epistasis with Vangl2 and Ror2 mutant mice, reporter assays for PCP vs. canonical pathway","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal binding assays, pathway reporter assays, and multi-allele genetic epistasis in two independent mouse models","pmids":["18606138"],"is_preprint":false},{"year":2007,"finding":"Cthrc1 is a cell-type-specific inhibitor of TGF-β/Smad2/3 signaling in smooth muscle cells. Transgenic overexpression of Cthrc1 reduced phospho-Smad2/3 immunoreactivity and procollagen levels in smooth muscle cells, inhibited TGF-β-sensitive reporter constructs, and reduced neointimal lesion formation and adventitial collagen deposition after carotid ligation; this effect was absent in endothelial cells.","method":"Transgenic mouse overexpression, immunohistochemistry for phospho-Smad2/3, TGF-β reporter assay, carotid ligation model, primary and PAC1 smooth muscle cell culture","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vitro and in vivo approaches in one rigorous study","pmids":["17322174"],"is_preprint":false},{"year":2006,"finding":"CTHRC1 is a 30 kDa secreted, N-glycosylated protein that inhibits collagen matrix synthesis. It contains a signal sequence consistent with extracellular localization and is expressed at epithelial-mesenchymal interfaces, developing skeleton, and sites overlapping with TGF-β family members.","method":"In situ hybridization, immunohistochemistry, in vitro collagen matrix inhibition assay","journal":"Gene expression patterns : GEP","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vitro functional assay plus detailed expression mapping, single lab","pmids":["16678498"],"is_preprint":false},{"year":2008,"finding":"Cthrc1 is a positive regulator of osteoblastic bone formation. Cthrc1-null mice showed reduced osteoblast number and bone formation without change in osteoclast number; transgenic osteoblast-specific overexpression increased bone mass and osteoblast number. Cthrc1 stimulated osteoprogenitor differentiation, mineralization, and proliferation (BrdU) in vitro. Cthrc1 is a downstream target of BMP2 in osteochondroprogenitor cells.","method":"Cthrc1-null and transgenic mice, micro-CT, bone histomorphometry, CFU assays, BrdU incorporation, gene expression of ALP/Col1a1/Osteocalcin","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic models (KO and transgenic) with multiple quantitative bone readouts replicated in vivo and in vitro","pmids":["18779865"],"is_preprint":false},{"year":2008,"finding":"In differentiated smooth muscle cells, full-length Cthrc1 is retained intracellularly despite its signal peptide. Upon arterial injury, Cthrc1 expression increases and plasmin cleaves a propeptide from the N-terminus, generating a truncated form with enhanced inhibitory activity on procollagen synthesis.","method":"Domain-specific antibodies, immunofluorescence, immunoblotting, plasmin cleavage assay, immunohistochemistry of neointima","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical cleavage assay plus localization studies, single lab","pmids":["18467647"],"is_preprint":false},{"year":2013,"finding":"CTHRC1 is secreted by mature bone-resorbing osteoclasts and acts as a coupling factor that stimulates stromal cells to promote osteogenesis. Osteoclast-specific deletion of Cthrc1 caused osteopenia due to reduced bone formation and impaired bone mass recovery after RANKL-induced resorption. Cthrc1 expression was induced in osteoclasts placed on dentin/hydroxyapatite and by increasing extracellular calcium.","method":"Osteoclast-specific conditional knockout mice, RANKL injection model, bone histomorphometry, micro-CT, cell-type-specific deletion vs. osteoblast-specific deletion","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional KO with clear in vivo coupling phenotype, orthogonal stimulation assays","pmids":["23908115"],"is_preprint":false},{"year":2013,"finding":"N-glycosylation of CTHRC1 stabilizes the protein by reducing its turnover in oral squamous cell carcinoma cells; partial inhibition of DPAGT1 (a regulator of N-glycosylation) increased CTHRC1 protein turnover and reduced its levels. Canonical Wnt/β-catenin signaling also promotes β-catenin/TCF transcriptional activity at the CTHRC1 promoter to elevate CTHRC1 levels. CTHRC1 localizes to cells at the leading edge of a wound front and drives oral cancer cell migration.","method":"DPAGT1 knockdown, protein stability/turnover assay, luciferase reporter for β-catenin/TCF activity, immunolocalization of CTHRC1 at wound front","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (knockdown, reporter, localization), single lab","pmids":["23703614"],"is_preprint":false},{"year":2014,"finding":"miR-9 inhibits Schwann cell migration by directly targeting CTHRC1 mRNA, which in turn inactivates downstream Rac1 GTPase. In vitro, anti-miR-9 promotes Schwann cell migration via CTHRC1/Rac1 signaling; Rac1 inhibitor blocked the pro-migratory effect of anti-miR-9.","method":"miR-9 overexpression/knockdown, luciferase target validation, Rac1 inhibitor rescue, in vivo nerve regeneration model","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target validation with rescue experiment using Rac1 inhibitor, single lab","pmids":["24413174"],"is_preprint":false},{"year":2014,"finding":"CTHRC1 promotes colorectal cancer cell invasion via ERK-dependent upregulation of MMP9. Overexpression of CTHRC1 in SW480 and HT-29 cells increased invasiveness with elevated ERK activation and MMP9; knockdown of CTHRC1 attenuated ERK activation and invasivity.","method":"Gain- and loss-of-function in cancer cell lines, invasion assay, ERK/MMP9 western blot","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation with pathway mechanistic follow-up, single lab","pmids":["24504172"],"is_preprint":false},{"year":2012,"finding":"Cthrc1 has characteristics of a circulating hormone. In pigs, Cthrc1 is stored in pituitary colloid-filled follicles and around chromophobe cells; in C57BL/6J mice, expression is in the paraventricular and supraoptic hypothalamic nuclei. Radiolabeled Cthrc1 has a circulatory half-life of ~2.5 hours with highest binding in the liver. Cthrc1-null mice develop hepatic steatosis and altered glycogen storage, phenotypes consistent with loss of a metabolic hormone.","method":"Cthrc1-null mouse (homologous recombination), 125I-labeled CTHRC1 pharmacokinetics, immunohistochemistry with monoclonal antibodies, histological analysis of liver","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct radiolabeled hormone kinetics plus null mouse phenotype, multiple tissues, single lab","pmids":["23056600"],"is_preprint":false},{"year":2012,"finding":"Cthrc1 is a negative regulator of peripheral myelination in Schwann cells. Cthrc1 overexpression in transgenic mice delays myelin formation by maintaining Schwann cells in a proliferative state; RNAi knockdown in culture promotes myelination. Cthrc1 enhances Schwann cell proliferation but prevents the onset of myelination.","method":"RNAi knockdown in Schwann cell culture, transgenic overexpression mouse, time-course analysis of myelin formation","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation in vitro and in vivo, single lab","pmids":["22379615"],"is_preprint":false},{"year":2015,"finding":"CTHRC1 facilitates HBV replication by activating the PKCα/ERK/JNK/c-Jun signaling cascade, which represses the IFN/JAK/STAT pathway. CTHRC1 downregulates type I IFN activity, reduces IFN-stimulated gene production, decreases STAT1/2 phosphorylation, and increases ubiquitination and phosphorylation of IFNAR α/β receptors.","method":"CTHRC1 overexpression/knockdown in HBV-transfected cells and BALB/c mice, western blot for PKCα/ERK/JNK/c-Jun and STAT1/2 phosphorylation, IFNAR ubiquitination assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling endpoints with in vivo validation, single lab","pmids":["26180054"],"is_preprint":false},{"year":2017,"finding":"CTHRC1 inhibits osteoclast differentiation via inhibition of NFκB-dependent signaling, specifically by preventing IκBα degradation and inhibiting ERK1/2 activation. Cthrc1 is expressed by osteocytes and osteoblasts (not osteoclasts), and extrinsically derived CTHRC1 is required to inhibit osteoclastogenic differentiation of bone marrow-derived monocytes and functional bone resorption. In a collagen antibody-induced arthritis model, Cthrc1-null mice showed more severe inflammation and joint destruction.","method":"Cthrc1-null mice, bone marrow monocyte differentiation assay with exogenous rCTHRC1, western blot for IκBα and p-ERK1/2, collagen antibody-induced arthritis model, specific monoclonal antibodies for cell-type expression","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct mechanistic signaling (IκBα/ERK) corroborated by cell-specific expression mapping, functional rescue, and in vivo arthritis model","pmids":["28115279"],"is_preprint":false},{"year":2018,"finding":"WAIF1/5T4 (encoded by Tpbg) is a cell-surface CTHRC1 binding protein in marrow stromal cells. CTHRC1 binding to WAIF1 activates a PKCδ/MEK/ERK osteoblastogenic signaling pathway. Osteoblast lineage-specific deletion of Tpbg reduced RANKL expression, impaired bone formation and resorption, and impaired bone mass recovery after RANKL-induced resorption, reproducing the phenotype of osteoclast-specific Cthrc1 deficiency.","method":"Protein binding identification, WAIF1 knockdown in marrow stromal cells, PKCδ/ERK western blot, osteoblast lineage-specific Tpbg knockout, RANKL injection model","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified binding partner, defined downstream kinase pathway, conditional KO phenotype recapitulates osteoclast-specific Cthrc1 KO","pmids":["29624737"],"is_preprint":false},{"year":2019,"finding":"CTHRC1 secreted by hepatic stellate cells (HSCs) promotes HSC activation (quiescent-to-activated transition) and enhances migratory and contractile capacities by activating TGF-β signaling. CTHRC1 also competitively binds to the Wnt non-canonical receptor, promoting contractility but not activation. CTHRC1 monoclonal antibody suppressed CCl4/TAA-induced liver fibrosis in vivo; CTHRC1-/- mice showed attenuated fibrosis.","method":"CTHRC1-/- mice with CCl4/TAA fibrosis model, anti-CTHRC1 monoclonal antibody treatment, HSC activation/migration/contractility assays, TGF-β signaling western blot, competitive Wnt receptor binding assay","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse plus antibody intervention plus in vitro mechanistic assays in one study","pmids":["30639416"],"is_preprint":false},{"year":2021,"finding":"CTHRC1 promotes liver metastasis of colorectal cancer by binding directly to TGF-β receptor II (TGFβRII) and TGF-β receptor III (TGFβRIII), stabilizing the TGF-β receptor complex and activating TGF-β signaling to induce M2 macrophage polarization. Macrophage depletion by liposomal clodronate largely abolished the pro-metastatic effect of CTHRC1.","method":"Co-immunoprecipitation of CTHRC1 with TGFβRII and TGFβRIII, macrophage depletion with liposomal clodronate, in vivo hepatic metastasis mouse model, TGF-β signaling assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct receptor binding by Co-IP, mechanistic macrophage depletion rescue, in vivo model","pmids":["33986509"],"is_preprint":false},{"year":2015,"finding":"Cthrc1 regulates body composition by inhibiting adipocyte differentiation and suppressing PPARγ and CREB reporter activity. Preadipocytes from Cthrc1-null mice exhibited enhanced adipogenic differentiation in vitro. Cthrc1-null mice had reduced lean mass, increased fat mass, and reduced voluntary physical activity.","method":"Cthrc1-null mice, in vitro adipogenesis assay, PPARγ/CREB reporter assay, metabolic/activity monitoring","journal":"Obesity (Silver Spring, Md.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse plus direct in vitro reporter and differentiation assays, single lab","pmids":["26148471"],"is_preprint":false},{"year":2017,"finding":"CTHRC1 promotes ESCC cell proliferation, migration, and invasion by activating FRA-1 (FOSL1) through the MAPK/MEK/ERK cascade, leading to cyclin D1 upregulation and cell proliferation, and FRA-1-induced Snail1-mediated MMP14 expression to facilitate invasion and metastasis.","method":"RNAi knockdown and overexpression in ESCC cell lines, RNA-seq, western blot for MEK/ERK/FRA-1/cyclin D1/Snail1/MMP14, xenograft model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq with pathway validation by western blot and functional assays, single lab","pmids":["28645305"],"is_preprint":false},{"year":2016,"finding":"CTHRC1 promotes angiogenesis by upregulating angiopoietin-2 (Ang-2) through ERK-dependent activation of AP-1 in endothelial cells, leading to recruitment of Tie2-expressing monocytes (TEMs) to tumors. A CTHRC1-neutralizing antibody abrogated Ang-2 expression in ECs and reduced tumor burden and TEM infiltration in a xenograft model.","method":"Recombinant CTHRC1 treatment of endothelial cells, ERK/AP-1 western blot, Ang-2 expression assay, TEM recruitment in xenograft mouse model, neutralizing antibody treatment","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic signaling assays plus in vivo neutralizing antibody experiment, single lab","pmids":["27686285"],"is_preprint":false},{"year":2017,"finding":"CTHRC1 promotes ovarian cancer metastasis by activating integrin β3/FAK signaling. FAK is phosphorylated on Tyr397 via integrin β3, and this is required for CTHRC1-mediated migratory, invasive, and in vivo peritoneal metastatic ability. Co-immunoprecipitation identified integrin β3 as part of the CTHRC1-activated complex.","method":"Phospho-antibody microarray, Co-immunoprecipitation, FAK Tyr397 phosphorylation assay, in vivo i.p. xenograft model, CTHRC1 overexpression/knockdown","journal":"Journal of ovarian research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying binding partner, functional rescue in vivo, single lab","pmids":["29021002"],"is_preprint":false},{"year":2017,"finding":"CTHRC1 inhibits TGF-β/Smad signaling and modulates YAP subcellular localization in fibroblasts. Cthrc1 overexpression decreased pSmad2/3 nuclear transfer and collagen I in both normal and keloid fibroblasts. In normal fibroblasts, Cthrc1 promoted YAP nuclear translocation (activation), whereas in keloid fibroblasts it suppressed YAP nuclear translocation, suggesting cell-context-dependent effects on YAP localization.","method":"Lentivirus-mediated Cthrc1 overexpression, western blot and immunofluorescence for pSmad2/3 and YAP localization, collagen I measurement","journal":"Current medical science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression approach, no endogenous knockdown or rescue experiment","pmids":["30341526"],"is_preprint":false},{"year":2017,"finding":"CTHRC1 activates HIF-1α/CXCR4 signaling in gastric cancer cells: CTHRC1 overexpression increased CXCR4 expression via HIF-1α upregulation, promoting cell migration and invasion. Silencing CXCR4 or HIF-1α abolished the pro-migratory and pro-invasive effects of CTHRC1.","method":"CTHRC1 overexpression/silencing, HIF-1α and CXCR4 western blot, CXCR4 silencing rescue, migration/invasion assays","journal":"Biomedicine & pharmacotherapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional pathway validation by knockdown rescue, single lab, no receptor binding or in vivo confirmation","pmids":["31855733"],"is_preprint":false},{"year":2021,"finding":"GPR180 is required to manifest CTHRC1 action in brown/beige adipocytes. GPR180 is not a GPCR but a component of the TGFβ signaling pathway that regulates TGFβ receptor complex activity through SMAD3 phosphorylation. CTHRC1/GPR180 signaling integrates into TGFβ signaling as an alternative axis to control glucose and energy metabolism.","method":"Genetic and pharmacological tools to manipulate GPR180, SMAD3 phosphorylation assays, metabolic phenotyping in vivo","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor identification with downstream signaling validation, multiple approaches, single lab","pmids":["34880217"],"is_preprint":false},{"year":2023,"finding":"CTHRC1 expression in cardiac myofibroblasts is regulated by the actin-binding protein drebrin via myocardin-related transcription factor (MRTF)-serum response factor (SRF) signaling. Drebrin promotes actin cytoskeleton formation which activates MRTF-SRF to drive Cthrc1 transcription in myofibroblasts during cardiac and hepatic fibrosis.","method":"Single-cell analysis, immunocytochemistry for actin cytoskeleton, RNA-Seq, MRTF-SRF pathway reporter, drebrin knockdown/overexpression in cardiac myofibroblasts and hepatic stellate cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic transcriptional pathway identified using multiple orthogonal methods, single lab","pmids":["36690273"],"is_preprint":false},{"year":2023,"finding":"Cardiac fibroblast-derived CTHRC1 expression is induced by canonical TGFβ1-Smad2/3 signaling axis. CTHRC1 improves post-MI wound healing and prevents cardiac rupture via activation of non-canonical WNT5A-PCP signaling pathway. Cthrc1 deficiency in mice aggravated cardiac dysfunction and increased mortality from cardiac rupture after MI; effects were partly reversed by rCTHRC1 or rWNT5A protein.","method":"Cthrc1 knockout mice with MI model, TGFβ1-Smad2/3 pathway western blot, rCTHRC1 and rWNT5A rescue, collagen/MMP measurements","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined phenotype, pathway rescue with recombinant proteins, single lab","pmids":["36923925"],"is_preprint":false},{"year":2020,"finding":"Cleaved (N-terminally truncated) CTHRC1 significantly promotes glycolysis in endothelial cells, whereas full-length CTHRC1 is less effective. Propeptide cleavage is attenuated by protease inhibitors in vitro. Key glycolytic enzymes are upregulated in endothelial cells treated with cleaved CTHRC1. Cthrc1-null mice have significantly lower respiratory exchange ratio in vivo, consistent with reduced glycolytic activity.","method":"In vitro protease cleavage assay with protease inhibitors, endothelial cell metabolic respirometry (Seahorse), gene expression of glycolytic enzymes, Cthrc1-null mouse respirometry","journal":"Vascular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro cleavage mechanistic assay with functional readout, corroborated by in vivo metabolic phenotype, single lab","pmids":["38040222"],"is_preprint":false},{"year":2018,"finding":"CTHRC1 mediates IL-1β-induced chondrocyte apoptosis via JNK1/2 signaling. Overexpression of CTHRC1 mimics IL-1β-induced JNK1/2 activation, increased Bax/caspase-3/PARP-1 and decreased Bcl-2; knockdown of CTHRC1 or JNK1/2 inhibitor SP600125 inhibited IL-1β-induced apoptosis and JNK1/2 activation.","method":"CTHRC1 overexpression/shRNA knockdown in rat chondrocytes, SP600125 JNK inhibitor rescue, western blot for apoptosis markers and p-JNK1/2, flow cytometry apoptosis assay","journal":"International journal of molecular medicine","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — bidirectional manipulation with inhibitor rescue, single lab, in vitro only","pmids":["29393342"],"is_preprint":false},{"year":2019,"finding":"CTHRC1 promotes M2-like macrophage polarization in endometrial cancer via upregulation of CX3CR1 (Fractalkine receptor) in macrophages, and promotes myometrial invasion through interaction with the Integrin β3-Akt signaling pathway. Recombinant CTHRC1 promoted tumor migration and invasion via enhanced macrophage recruitment in vitro.","method":"Recombinant CTHRC1 treatment, integrin β3-Akt western blot, CX3CR1 expression assay, macrophage recruitment in vitro","journal":"Clinical & experimental metastasis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — mechanistic pathway identification without Co-IP or in vivo knockdown rescue, single lab","pmids":["31119444"],"is_preprint":false},{"year":2021,"finding":"NEDD4L suppresses pulmonary fibrosis by promoting β-catenin ubiquitination and downregulating the CTHRC1/HIF-1α axis. NEDD4L overexpression reduced CTHRC1 and HIF-1α expression and attenuated lung fibroblast activity; NEDD4L silencing activated CTHRC1/HIF-1α signaling and aggravated fibrosis in vivo.","method":"NEDD4L overexpression/silencing in lung fibroblasts, β-catenin ubiquitination assay, CTHRC1/HIF-1α western blot, bleomycin fibrosis mouse model","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — identifies CTHRC1 as downstream of NEDD4L/β-catenin axis but does not directly demonstrate mechanism of CTHRC1 action, single lab","pmids":["34512149"],"is_preprint":false},{"year":2024,"finding":"CTHRC1 promotes tendon stem/progenitor cell (TSPC) proliferation, migration, and tenogenic differentiation by binding to EGFR and activating the MAPK signaling pathway. Inhibiting EGFR reversed the tendon-healing effect of CTHRC1. Proteomics on CTHRC1-stimulated TSPCs confirmed MAPK pathway activation.","method":"Multi-proteomic analysis, recombinant CTHRC1 treatment of TSPCs, EGFR inhibitor rescue, CTHRC1 KO and overexpression mouse models, in vitro and in vivo tendon healing assays","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — receptor interaction identified by proteomics, EGFR inhibitor rescue, bidirectional in vivo models, single lab","pmids":["39540237"],"is_preprint":false},{"year":2025,"finding":"CTHRC1+ CAFs enhance glycolytic activity of cancer cells by activating TGF-β/Smad3 signaling pathway. Excess lactate from glycolysis upregulates CTHRC1 expression in CAFs through histone lactylation (H3K18la), creating a CTHRC1/glycolysis/H3K18la positive feedback loop that sustains EGFR-TKI resistance in lung cancer.","method":"scRNA-seq of lung cancer patients, TGF-β/Smad3 pathway western blot, histone lactylation (H3K18la) chromatin analysis, lactate supplementation/inhibition experiments","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic pathway with epigenetic feedback loop demonstrated by multiple orthogonal methods, single lab","pmids":["40011576"],"is_preprint":false},{"year":2024,"finding":"Exosomal CTHRC1 from cancer-associated fibroblasts promotes endometrial cancer cell migration via ITGB3/FAK signaling: CTHRC1 immunoprecipitates with ITGB3 and leads to FAK phosphorylation on Tyr397. FAK inhibitor (Defactinib) blocked the pro-migratory effect of exosomal CTHRC1.","method":"Co-immunoprecipitation of CTHRC1 with ITGB3, FAK Tyr397 phosphorylation assay, Defactinib inhibitor rescue, exosome isolation, in vivo xenograft model","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of binding partner, kinase phosphorylation site identified, pharmacological rescue in vivo, single lab","pmids":["39229506"],"is_preprint":false},{"year":2025,"finding":"Senescent CAF-secreted CTHRC1 promotes cancer stemness and metastasis in HCC via the Notch1 signaling pathway. CTHRC1 expression in senescent CAFs is transcriptionally regulated by SOX4. Chromatin immunoprecipitation verified SOX4 binding to the CTHRC1 promoter region.","method":"scRNA-seq, ChIP assay for SOX4 at CTHRC1 promoter, Notch1 pathway western blot, in vitro and in vivo functional assays","journal":"Cell communication and signaling : CCS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP validation of transcriptional regulation plus Notch signaling pathway mechanistic data, single lab","pmids":["40855439"],"is_preprint":false}],"current_model":"CTHRC1 is a secreted, N-glycosylated glycoprotein that acts as a context-dependent signaling cofactor: it selectively activates the Wnt/PCP pathway by stabilizing Wnt-Frizzled-Ror2 receptor complexes; inhibits TGF-β/Smad2/3 signaling in smooth muscle cells; is secreted by osteoclasts to couple bone resorption to osteoblastic formation via WAIF1/PKCδ/ERK signaling; promotes osteoblast differentiation and inhibits osteoclastogenesis through NFκB/IκBα suppression; requires plasmin-mediated propeptide cleavage for full extracellular activity (including promotion of glycolysis); inhibits peripheral myelination; and in cancer contexts drives invasion and metastasis through ERK/MMP9, integrin β3/FAK, TGFβR complex stabilization, HIF-1α/CXCR4, EGFR/MAPK, and PKCα/ERK/JNK axes, as well as promoting M2 macrophage polarization via STAT6 and TGF-β signaling."},"narrative":{"mechanistic_narrative":"CTHRC1 is a secreted, N-glycosylated glycoprotein that functions as a context-dependent extracellular signaling cofactor coordinating Wnt, TGF-β, and matrix-remodeling programs across tissue development, fibrosis, bone homeostasis, and cancer [PMID:18606138, PMID:16678498, PMID:33986509]. As a cell-surface-anchored protein it selectively activates the non-canonical Wnt/PCP pathway by binding Wnt ligands, Frizzled receptors, and Ror2 to stabilize the ligand-receptor complex while suppressing canonical Wnt/β-catenin signaling [PMID:18606138]. In parallel, CTHRC1 modulates TGF-β/Smad2/3 signaling in a cell-type-specific manner—inhibiting Smad2/3 activation and collagen synthesis in smooth muscle cells and fibroblasts [PMID:17322174, PMID:16678498], yet stabilizing TGF-β receptor complexes (TGFβRII/TGFβRIII) to potentiate signaling in cancer and stellate cell contexts [PMID:30639416, PMID:33986509]. Its full extracellular activity requires plasmin-mediated cleavage of an N-terminal propeptide, generating a truncated form with enhanced collagen-inhibitory and pro-glycolytic activity [PMID:18467647, PMID:38040222]. In bone, CTHRC1 couples resorption to formation: it is secreted by mature osteoclasts to stimulate osteoblastogenesis through the cell-surface receptor WAIF1/Tpbg via a PKCδ/MEK/ERK cascade, promotes osteoblastic bone formation, and inhibits osteoclastogenesis by preventing IκBα degradation and ERK1/2 activation [PMID:18779865, PMID:23908115, PMID:28115279, PMID:29624737]. CTHRC1 also acts through additional receptors including GPR180 in adipocytes and EGFR in tendon progenitors [PMID:34880217, PMID:39540237]. In cancer, CTHRC1 drives invasion, metastasis, angiogenesis, and an immunosuppressive microenvironment via ERK/MMP9, integrin β3/FAK, and TGF-β-dependent M2 macrophage polarization [PMID:24504172, PMID:33986509, PMID:27686285, PMID:29021002]. Genetic loss in mice produces metabolic phenotypes—hepatic steatosis, altered glycogen and body composition—consistent with a circulating, hormone-like function [PMID:23056600, PMID:26148471].","teleology":[{"year":2006,"claim":"Established CTHRC1 as a secreted, N-glycosylated protein whose biochemical activity is inhibition of collagen matrix synthesis, defining it as a matrix-modulating extracellular factor.","evidence":"In situ hybridization, immunohistochemistry, and in vitro collagen matrix inhibition assay across epithelial-mesenchymal interfaces and developing skeleton","pmids":["16678498"],"confidence":"Medium","gaps":["No receptor or signaling pathway identified","Mechanism of collagen inhibition not resolved"]},{"year":2007,"claim":"Showed CTHRC1 is a cell-type-specific inhibitor of TGF-β/Smad2/3 signaling, linking its matrix effects to a defined signaling axis in vascular remodeling.","evidence":"Transgenic overexpression, phospho-Smad2/3 IHC, TGF-β reporter, and carotid ligation model in smooth muscle vs. endothelial cells","pmids":["17322174"],"confidence":"High","gaps":["Molecular basis of cell-type specificity unknown","Does not explain later pro-TGF-β effects in other contexts"]},{"year":2008,"claim":"Defined CTHRC1's selective activation of Wnt/PCP signaling through direct receptor complex assembly, establishing it as an upstream PCP pathway component rather than a canonical Wnt regulator.","evidence":"Co-IP/cell-surface binding in HEK293T, reporter assays, and genetic epistasis with Vangl2 and Ror2 mutant mice","pmids":["18606138"],"confidence":"High","gaps":["Stoichiometry and structural basis of the Cthrc1-Wnt-Fzd/Ror2 complex unresolved","How PCP activation is reconciled with TGF-β inhibition not addressed"]},{"year":2008,"claim":"Identified CTHRC1 as a positive regulator of osteoblastic bone formation downstream of BMP2, extending its role to skeletal anabolism.","evidence":"Cthrc1-null and osteoblast-specific transgenic mice with micro-CT, histomorphometry, CFU and BrdU assays","pmids":["18779865"],"confidence":"High","gaps":["Receptor mediating osteoblast effects not yet identified","Cellular source of bone CTHRC1 unresolved at this stage"]},{"year":2008,"claim":"Demonstrated that proteolytic processing controls CTHRC1 activity—plasmin cleaves an N-terminal propeptide upon injury to generate a more active truncated form, revealing post-translational regulation of its function.","evidence":"Domain-specific antibodies, immunofluorescence, immunoblotting, and plasmin cleavage assay in differentiated smooth muscle cells","pmids":["18467647"],"confidence":"Medium","gaps":["Cleavage site not mapped at residue level","Whether cleavage governs all CTHRC1 activities unknown"]},{"year":2012,"claim":"Proposed CTHRC1 as a circulating hormone-like factor regulating systemic metabolism, broadening its biology beyond local matrix and signaling roles.","evidence":"Cthrc1-null mice, 125I-CTHRC1 pharmacokinetics with hepatic binding, hypothalamic/pituitary IHC, and liver steatosis phenotype","pmids":["23056600"],"confidence":"Medium","gaps":["No cognate metabolic receptor identified here","Direct hormonal target tissue unconfirmed"]},{"year":2012,"claim":"Established CTHRC1 as a negative regulator of peripheral myelination acting by maintaining Schwann cell proliferation, defining a developmental role in the nervous system.","evidence":"RNAi knockdown in Schwann cell culture and transgenic overexpression mice with myelin time-course analysis","pmids":["22379615"],"confidence":"Medium","gaps":["Receptor/pathway in Schwann cells not defined here","Link to PCP or TGF-β signaling unexplored"]},{"year":2013,"claim":"Revealed osteoclast-derived CTHRC1 as a resorption-to-formation coupling factor, identifying the cellular source that drives the bone-anabolic phenotype.","evidence":"Osteoclast-specific conditional knockout mice, RANKL injection model, and calcium/dentin induction assays","pmids":["23908115"],"confidence":"High","gaps":["Stromal receptor for the coupling signal not yet identified","Apparent discrepancy with later osteocyte/osteoblast source reports"]},{"year":2013,"claim":"Linked CTHRC1 stability and expression to N-glycosylation and canonical Wnt/β-catenin transcriptional control, and to cancer cell migration at the wound front.","evidence":"DPAGT1 knockdown turnover assays, β-catenin/TCF luciferase reporter, and wound-front immunolocalization in oral squamous carcinoma cells","pmids":["23703614"],"confidence":"Medium","gaps":["Glycosylation sites controlling stability not mapped","Single cancer cell context"]},{"year":2014,"claim":"Established CTHRC1 as a pro-invasive effector in cancer through ERK-dependent MMP9 induction, opening the cancer-progression dimension of its biology.","evidence":"Gain/loss-of-function in colorectal cancer lines with invasion assays and ERK/MMP9 western blots","pmids":["24504172"],"confidence":"Medium","gaps":["Surface receptor coupling CTHRC1 to ERK not identified","No in vivo metastasis confirmation"]},{"year":2014,"claim":"Placed CTHRC1 in a miR-9/Rac1 axis controlling Schwann cell migration, providing upstream regulatory and downstream effector context for its motility functions.","evidence":"miR-9 modulation, luciferase target validation, and Rac1-inhibitor rescue in nerve regeneration","pmids":["24413174"],"confidence":"Medium","gaps":["Direct mechanism linking CTHRC1 to Rac1 activation not defined","Single-lab finding"]},{"year":2015,"claim":"Extended CTHRC1's metabolic role by showing it inhibits adipocyte differentiation and regulates body composition via PPARγ/CREB suppression.","evidence":"Cthrc1-null mice with in vitro adipogenesis and PPARγ/CREB reporter assays plus metabolic monitoring","pmids":["26148471"],"confidence":"Medium","gaps":["Receptor mediating adipocyte effects unknown","Mechanistic link to PPARγ unresolved"]},{"year":2015,"claim":"Showed CTHRC1 can suppress innate antiviral immunity via a PKCα/ERK/JNK/c-Jun cascade that represses IFN/JAK/STAT signaling, implicating it in infection biology.","evidence":"Overexpression/knockdown in HBV-transfected cells and mice with STAT1/2 phosphorylation and IFNAR ubiquitination assays","pmids":["26180054"],"confidence":"Medium","gaps":["How secreted CTHRC1 triggers intracellular PKCα remains unclear","Receptor not identified"]},{"year":2017,"claim":"Resolved that CTHRC1 inhibits osteoclastogenesis through NF-κB suppression (blocking IκBα degradation) and ERK inhibition, and reassigned its skeletal source to osteocytes/osteoblasts.","evidence":"Cthrc1-null mice, exogenous rCTHRC1 monocyte differentiation, IκBα/p-ERK western blots, and collagen antibody-induced arthritis model","pmids":["28115279"],"confidence":"High","gaps":["Reconciliation of cell-source assignments across studies incomplete","Receptor on monocytes not defined"]},{"year":2018,"claim":"Identified WAIF1/Tpbg as a cell-surface CTHRC1 receptor transducing a PKCδ/MEK/ERK osteoblastogenic signal, supplying the missing receptor in bone coupling.","evidence":"Binding-partner identification, WAIF1 knockdown, PKCδ/ERK western blots, and osteoblast lineage-specific Tpbg knockout phenocopying osteoclast-specific Cthrc1 deletion","pmids":["29624737"],"confidence":"High","gaps":["Whether WAIF1 mediates CTHRC1 effects outside bone unknown","Structural basis of CTHRC1-WAIF1 binding unresolved"]},{"year":2019,"claim":"Demonstrated CTHRC1 drives fibrosis by activating TGF-β signaling in hepatic stellate cells while separately engaging non-canonical Wnt for contractility, and validated it as an antibody-targetable fibrosis driver.","evidence":"CTHRC1-/- mice and anti-CTHRC1 antibody in CCl4/TAA fibrosis with HSC activation, TGF-β western blots, and competitive Wnt receptor binding","pmids":["30639416"],"confidence":"High","gaps":["Molecular switch determining TGF-β activation vs. inhibition across cell types unresolved","Wnt receptor identity in HSCs not specified"]},{"year":2021,"claim":"Established a direct mechanism for CTHRC1 potentiation of TGF-β signaling—binding and stabilizing TGFβRII/TGFβRIII—linking it to M2 macrophage-driven metastasis.","evidence":"Co-IP of CTHRC1 with TGFβRII/TGFβRIII, clodronate macrophage depletion, and hepatic metastasis mouse model","pmids":["33986509"],"confidence":"High","gaps":["Structural basis of receptor complex stabilization not defined","Why this contrasts with TGF-β inhibition in SMCs unresolved"]},{"year":2021,"claim":"Identified GPR180 as a CTHRC1-required component of TGF-β signaling in brown/beige adipocytes, providing a receptor link for its metabolic actions.","evidence":"Genetic/pharmacological GPR180 manipulation, SMAD3 phosphorylation assays, and metabolic phenotyping","pmids":["34880217"],"confidence":"Medium","gaps":["Direct CTHRC1-GPR180 binding not shown here","Relationship to WAIF1 and TGFβR receptors unclear"]},{"year":2024,"claim":"Identified EGFR as a CTHRC1 receptor activating MAPK signaling in tendon progenitor cells, expanding the receptor repertoire and a regenerative role.","evidence":"Multi-proteomics, recombinant CTHRC1 with EGFR-inhibitor rescue, and bidirectional in vivo tendon-healing mouse models","pmids":["39540237"],"confidence":"Medium","gaps":["Direct CTHRC1-EGFR binding interface not mapped","Whether EGFR engagement operates in other tissues unknown"]},{"year":2023,"claim":"Defined transcriptional control of CTHRC1 in fibrosis through drebrin/actin-driven MRTF-SRF and TGFβ1-Smad2/3 signaling, with a downstream WNT5A/PCP protective role after myocardial infarction.","evidence":"Single-cell analysis, MRTF-SRF reporter, drebrin manipulation, Cthrc1-KO MI mouse model, and rCTHRC1/rWNT5A rescue","pmids":["36690273","36923925"],"confidence":"Medium","gaps":["Integration of multiple upstream transcriptional inputs unresolved","Tissue-specificity of WNT5A/PCP output not fully defined"]},{"year":2025,"claim":"Showed CTHRC1+ cancer-associated fibroblasts sustain glycolysis and therapy resistance via a TGF-β/Smad3 and histone-lactylation feedback loop, and that senescent CAF-derived CTHRC1 drives stemness via Notch1 under SOX4 control.","evidence":"scRNA-seq, TGF-β/Smad3 and Notch1 western blots, H3K18la chromatin analysis, ChIP for SOX4 at the CTHRC1 promoter, and lactate modulation","pmids":["40011576","40855439"],"confidence":"Medium","gaps":["Receptor mediating CAF-derived CTHRC1 effects on cancer cells not identified here","Single-lab mechanistic loops"]},{"year":null,"claim":"The unifying molecular determinant of CTHRC1's context-dependent switch—between Wnt/PCP activation, TGF-β inhibition, and TGF-β potentiation—and the rules governing which of its multiple receptors (WAIF1, GPR180, EGFR, TGFβRII/III, integrin β3, Fzd/Ror2) it engages in a given tissue remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of CTHRC1 bound to any receptor","No unified framework reconciling opposing TGF-β effects","Receptor selectivity determinants across cell types unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,15]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,13,22,29]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,13,15]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2,5,15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,13]},{"term_id":"GO:0031012","term_label":"extracellular matrix","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal 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Cell-surface-anchored Cthrc1 binds directly to Wnt ligands, Frizzled (Fzd) receptors, and Ror2, forming a Cthrc1-Wnt-Fzd/Ror2 complex that stabilizes ligand-receptor interaction and promotes PCP signaling. Genetic epistasis (Cthrc1 null × Vangl2 heterozygous mutant) produced PCP-characteristic abnormalities, placing Cthrc1 upstream in the Wnt/PCP pathway.\",\n      \"method\": \"Co-IP/cell-surface binding assays in HEK293T cells, genetic epistasis with Vangl2 and Ror2 mutant mice, reporter assays for PCP vs. canonical pathway\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal binding assays, pathway reporter assays, and multi-allele genetic epistasis in two independent mouse models\",\n      \"pmids\": [\"18606138\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cthrc1 is a cell-type-specific inhibitor of TGF-β/Smad2/3 signaling in smooth muscle cells. Transgenic overexpression of Cthrc1 reduced phospho-Smad2/3 immunoreactivity and procollagen levels in smooth muscle cells, inhibited TGF-β-sensitive reporter constructs, and reduced neointimal lesion formation and adventitial collagen deposition after carotid ligation; this effect was absent in endothelial cells.\",\n      \"method\": \"Transgenic mouse overexpression, immunohistochemistry for phospho-Smad2/3, TGF-β reporter assay, carotid ligation model, primary and PAC1 smooth muscle cell culture\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vitro and in vivo approaches in one rigorous study\",\n      \"pmids\": [\"17322174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"CTHRC1 is a 30 kDa secreted, N-glycosylated protein that inhibits collagen matrix synthesis. It contains a signal sequence consistent with extracellular localization and is expressed at epithelial-mesenchymal interfaces, developing skeleton, and sites overlapping with TGF-β family members.\",\n      \"method\": \"In situ hybridization, immunohistochemistry, in vitro collagen matrix inhibition assay\",\n      \"journal\": \"Gene expression patterns : GEP\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vitro functional assay plus detailed expression mapping, single lab\",\n      \"pmids\": [\"16678498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cthrc1 is a positive regulator of osteoblastic bone formation. Cthrc1-null mice showed reduced osteoblast number and bone formation without change in osteoclast number; transgenic osteoblast-specific overexpression increased bone mass and osteoblast number. Cthrc1 stimulated osteoprogenitor differentiation, mineralization, and proliferation (BrdU) in vitro. Cthrc1 is a downstream target of BMP2 in osteochondroprogenitor cells.\",\n      \"method\": \"Cthrc1-null and transgenic mice, micro-CT, bone histomorphometry, CFU assays, BrdU incorporation, gene expression of ALP/Col1a1/Osteocalcin\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic models (KO and transgenic) with multiple quantitative bone readouts replicated in vivo and in vitro\",\n      \"pmids\": [\"18779865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In differentiated smooth muscle cells, full-length Cthrc1 is retained intracellularly despite its signal peptide. Upon arterial injury, Cthrc1 expression increases and plasmin cleaves a propeptide from the N-terminus, generating a truncated form with enhanced inhibitory activity on procollagen synthesis.\",\n      \"method\": \"Domain-specific antibodies, immunofluorescence, immunoblotting, plasmin cleavage assay, immunohistochemistry of neointima\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical cleavage assay plus localization studies, single lab\",\n      \"pmids\": [\"18467647\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"CTHRC1 is secreted by mature bone-resorbing osteoclasts and acts as a coupling factor that stimulates stromal cells to promote osteogenesis. Osteoclast-specific deletion of Cthrc1 caused osteopenia due to reduced bone formation and impaired bone mass recovery after RANKL-induced resorption. Cthrc1 expression was induced in osteoclasts placed on dentin/hydroxyapatite and by increasing extracellular calcium.\",\n      \"method\": \"Osteoclast-specific conditional knockout mice, RANKL injection model, bone histomorphometry, micro-CT, cell-type-specific deletion vs. osteoblast-specific deletion\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional KO with clear in vivo coupling phenotype, orthogonal stimulation assays\",\n      \"pmids\": [\"23908115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"N-glycosylation of CTHRC1 stabilizes the protein by reducing its turnover in oral squamous cell carcinoma cells; partial inhibition of DPAGT1 (a regulator of N-glycosylation) increased CTHRC1 protein turnover and reduced its levels. Canonical Wnt/β-catenin signaling also promotes β-catenin/TCF transcriptional activity at the CTHRC1 promoter to elevate CTHRC1 levels. CTHRC1 localizes to cells at the leading edge of a wound front and drives oral cancer cell migration.\",\n      \"method\": \"DPAGT1 knockdown, protein stability/turnover assay, luciferase reporter for β-catenin/TCF activity, immunolocalization of CTHRC1 at wound front\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (knockdown, reporter, localization), single lab\",\n      \"pmids\": [\"23703614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-9 inhibits Schwann cell migration by directly targeting CTHRC1 mRNA, which in turn inactivates downstream Rac1 GTPase. In vitro, anti-miR-9 promotes Schwann cell migration via CTHRC1/Rac1 signaling; Rac1 inhibitor blocked the pro-migratory effect of anti-miR-9.\",\n      \"method\": \"miR-9 overexpression/knockdown, luciferase target validation, Rac1 inhibitor rescue, in vivo nerve regeneration model\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target validation with rescue experiment using Rac1 inhibitor, single lab\",\n      \"pmids\": [\"24413174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"CTHRC1 promotes colorectal cancer cell invasion via ERK-dependent upregulation of MMP9. Overexpression of CTHRC1 in SW480 and HT-29 cells increased invasiveness with elevated ERK activation and MMP9; knockdown of CTHRC1 attenuated ERK activation and invasivity.\",\n      \"method\": \"Gain- and loss-of-function in cancer cell lines, invasion assay, ERK/MMP9 western blot\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation with pathway mechanistic follow-up, single lab\",\n      \"pmids\": [\"24504172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cthrc1 has characteristics of a circulating hormone. In pigs, Cthrc1 is stored in pituitary colloid-filled follicles and around chromophobe cells; in C57BL/6J mice, expression is in the paraventricular and supraoptic hypothalamic nuclei. Radiolabeled Cthrc1 has a circulatory half-life of ~2.5 hours with highest binding in the liver. Cthrc1-null mice develop hepatic steatosis and altered glycogen storage, phenotypes consistent with loss of a metabolic hormone.\",\n      \"method\": \"Cthrc1-null mouse (homologous recombination), 125I-labeled CTHRC1 pharmacokinetics, immunohistochemistry with monoclonal antibodies, histological analysis of liver\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct radiolabeled hormone kinetics plus null mouse phenotype, multiple tissues, single lab\",\n      \"pmids\": [\"23056600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cthrc1 is a negative regulator of peripheral myelination in Schwann cells. Cthrc1 overexpression in transgenic mice delays myelin formation by maintaining Schwann cells in a proliferative state; RNAi knockdown in culture promotes myelination. Cthrc1 enhances Schwann cell proliferation but prevents the onset of myelination.\",\n      \"method\": \"RNAi knockdown in Schwann cell culture, transgenic overexpression mouse, time-course analysis of myelin formation\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation in vitro and in vivo, single lab\",\n      \"pmids\": [\"22379615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CTHRC1 facilitates HBV replication by activating the PKCα/ERK/JNK/c-Jun signaling cascade, which represses the IFN/JAK/STAT pathway. CTHRC1 downregulates type I IFN activity, reduces IFN-stimulated gene production, decreases STAT1/2 phosphorylation, and increases ubiquitination and phosphorylation of IFNAR α/β receptors.\",\n      \"method\": \"CTHRC1 overexpression/knockdown in HBV-transfected cells and BALB/c mice, western blot for PKCα/ERK/JNK/c-Jun and STAT1/2 phosphorylation, IFNAR ubiquitination assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling endpoints with in vivo validation, single lab\",\n      \"pmids\": [\"26180054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTHRC1 inhibits osteoclast differentiation via inhibition of NFκB-dependent signaling, specifically by preventing IκBα degradation and inhibiting ERK1/2 activation. Cthrc1 is expressed by osteocytes and osteoblasts (not osteoclasts), and extrinsically derived CTHRC1 is required to inhibit osteoclastogenic differentiation of bone marrow-derived monocytes and functional bone resorption. In a collagen antibody-induced arthritis model, Cthrc1-null mice showed more severe inflammation and joint destruction.\",\n      \"method\": \"Cthrc1-null mice, bone marrow monocyte differentiation assay with exogenous rCTHRC1, western blot for IκBα and p-ERK1/2, collagen antibody-induced arthritis model, specific monoclonal antibodies for cell-type expression\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct mechanistic signaling (IκBα/ERK) corroborated by cell-specific expression mapping, functional rescue, and in vivo arthritis model\",\n      \"pmids\": [\"28115279\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"WAIF1/5T4 (encoded by Tpbg) is a cell-surface CTHRC1 binding protein in marrow stromal cells. CTHRC1 binding to WAIF1 activates a PKCδ/MEK/ERK osteoblastogenic signaling pathway. Osteoblast lineage-specific deletion of Tpbg reduced RANKL expression, impaired bone formation and resorption, and impaired bone mass recovery after RANKL-induced resorption, reproducing the phenotype of osteoclast-specific Cthrc1 deficiency.\",\n      \"method\": \"Protein binding identification, WAIF1 knockdown in marrow stromal cells, PKCδ/ERK western blot, osteoblast lineage-specific Tpbg knockout, RANKL injection model\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified binding partner, defined downstream kinase pathway, conditional KO phenotype recapitulates osteoclast-specific Cthrc1 KO\",\n      \"pmids\": [\"29624737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTHRC1 secreted by hepatic stellate cells (HSCs) promotes HSC activation (quiescent-to-activated transition) and enhances migratory and contractile capacities by activating TGF-β signaling. CTHRC1 also competitively binds to the Wnt non-canonical receptor, promoting contractility but not activation. CTHRC1 monoclonal antibody suppressed CCl4/TAA-induced liver fibrosis in vivo; CTHRC1-/- mice showed attenuated fibrosis.\",\n      \"method\": \"CTHRC1-/- mice with CCl4/TAA fibrosis model, anti-CTHRC1 monoclonal antibody treatment, HSC activation/migration/contractility assays, TGF-β signaling western blot, competitive Wnt receptor binding assay\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse plus antibody intervention plus in vitro mechanistic assays in one study\",\n      \"pmids\": [\"30639416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"CTHRC1 promotes liver metastasis of colorectal cancer by binding directly to TGF-β receptor II (TGFβRII) and TGF-β receptor III (TGFβRIII), stabilizing the TGF-β receptor complex and activating TGF-β signaling to induce M2 macrophage polarization. Macrophage depletion by liposomal clodronate largely abolished the pro-metastatic effect of CTHRC1.\",\n      \"method\": \"Co-immunoprecipitation of CTHRC1 with TGFβRII and TGFβRIII, macrophage depletion with liposomal clodronate, in vivo hepatic metastasis mouse model, TGF-β signaling assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct receptor binding by Co-IP, mechanistic macrophage depletion rescue, in vivo model\",\n      \"pmids\": [\"33986509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Cthrc1 regulates body composition by inhibiting adipocyte differentiation and suppressing PPARγ and CREB reporter activity. Preadipocytes from Cthrc1-null mice exhibited enhanced adipogenic differentiation in vitro. Cthrc1-null mice had reduced lean mass, increased fat mass, and reduced voluntary physical activity.\",\n      \"method\": \"Cthrc1-null mice, in vitro adipogenesis assay, PPARγ/CREB reporter assay, metabolic/activity monitoring\",\n      \"journal\": \"Obesity (Silver Spring, Md.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse plus direct in vitro reporter and differentiation assays, single lab\",\n      \"pmids\": [\"26148471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTHRC1 promotes ESCC cell proliferation, migration, and invasion by activating FRA-1 (FOSL1) through the MAPK/MEK/ERK cascade, leading to cyclin D1 upregulation and cell proliferation, and FRA-1-induced Snail1-mediated MMP14 expression to facilitate invasion and metastasis.\",\n      \"method\": \"RNAi knockdown and overexpression in ESCC cell lines, RNA-seq, western blot for MEK/ERK/FRA-1/cyclin D1/Snail1/MMP14, xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq with pathway validation by western blot and functional assays, single lab\",\n      \"pmids\": [\"28645305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CTHRC1 promotes angiogenesis by upregulating angiopoietin-2 (Ang-2) through ERK-dependent activation of AP-1 in endothelial cells, leading to recruitment of Tie2-expressing monocytes (TEMs) to tumors. A CTHRC1-neutralizing antibody abrogated Ang-2 expression in ECs and reduced tumor burden and TEM infiltration in a xenograft model.\",\n      \"method\": \"Recombinant CTHRC1 treatment of endothelial cells, ERK/AP-1 western blot, Ang-2 expression assay, TEM recruitment in xenograft mouse model, neutralizing antibody treatment\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic signaling assays plus in vivo neutralizing antibody experiment, single lab\",\n      \"pmids\": [\"27686285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTHRC1 promotes ovarian cancer metastasis by activating integrin β3/FAK signaling. FAK is phosphorylated on Tyr397 via integrin β3, and this is required for CTHRC1-mediated migratory, invasive, and in vivo peritoneal metastatic ability. Co-immunoprecipitation identified integrin β3 as part of the CTHRC1-activated complex.\",\n      \"method\": \"Phospho-antibody microarray, Co-immunoprecipitation, FAK Tyr397 phosphorylation assay, in vivo i.p. xenograft model, CTHRC1 overexpression/knockdown\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying binding partner, functional rescue in vivo, single lab\",\n      \"pmids\": [\"29021002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTHRC1 inhibits TGF-β/Smad signaling and modulates YAP subcellular localization in fibroblasts. Cthrc1 overexpression decreased pSmad2/3 nuclear transfer and collagen I in both normal and keloid fibroblasts. In normal fibroblasts, Cthrc1 promoted YAP nuclear translocation (activation), whereas in keloid fibroblasts it suppressed YAP nuclear translocation, suggesting cell-context-dependent effects on YAP localization.\",\n      \"method\": \"Lentivirus-mediated Cthrc1 overexpression, western blot and immunofluorescence for pSmad2/3 and YAP localization, collagen I measurement\",\n      \"journal\": \"Current medical science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression approach, no endogenous knockdown or rescue experiment\",\n      \"pmids\": [\"30341526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"CTHRC1 activates HIF-1α/CXCR4 signaling in gastric cancer cells: CTHRC1 overexpression increased CXCR4 expression via HIF-1α upregulation, promoting cell migration and invasion. Silencing CXCR4 or HIF-1α abolished the pro-migratory and pro-invasive effects of CTHRC1.\",\n      \"method\": \"CTHRC1 overexpression/silencing, HIF-1α and CXCR4 western blot, CXCR4 silencing rescue, migration/invasion assays\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional pathway validation by knockdown rescue, single lab, no receptor binding or in vivo confirmation\",\n      \"pmids\": [\"31855733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"GPR180 is required to manifest CTHRC1 action in brown/beige adipocytes. GPR180 is not a GPCR but a component of the TGFβ signaling pathway that regulates TGFβ receptor complex activity through SMAD3 phosphorylation. CTHRC1/GPR180 signaling integrates into TGFβ signaling as an alternative axis to control glucose and energy metabolism.\",\n      \"method\": \"Genetic and pharmacological tools to manipulate GPR180, SMAD3 phosphorylation assays, metabolic phenotyping in vivo\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor identification with downstream signaling validation, multiple approaches, single lab\",\n      \"pmids\": [\"34880217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CTHRC1 expression in cardiac myofibroblasts is regulated by the actin-binding protein drebrin via myocardin-related transcription factor (MRTF)-serum response factor (SRF) signaling. Drebrin promotes actin cytoskeleton formation which activates MRTF-SRF to drive Cthrc1 transcription in myofibroblasts during cardiac and hepatic fibrosis.\",\n      \"method\": \"Single-cell analysis, immunocytochemistry for actin cytoskeleton, RNA-Seq, MRTF-SRF pathway reporter, drebrin knockdown/overexpression in cardiac myofibroblasts and hepatic stellate cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic transcriptional pathway identified using multiple orthogonal methods, single lab\",\n      \"pmids\": [\"36690273\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cardiac fibroblast-derived CTHRC1 expression is induced by canonical TGFβ1-Smad2/3 signaling axis. CTHRC1 improves post-MI wound healing and prevents cardiac rupture via activation of non-canonical WNT5A-PCP signaling pathway. Cthrc1 deficiency in mice aggravated cardiac dysfunction and increased mortality from cardiac rupture after MI; effects were partly reversed by rCTHRC1 or rWNT5A protein.\",\n      \"method\": \"Cthrc1 knockout mice with MI model, TGFβ1-Smad2/3 pathway western blot, rCTHRC1 and rWNT5A rescue, collagen/MMP measurements\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined phenotype, pathway rescue with recombinant proteins, single lab\",\n      \"pmids\": [\"36923925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cleaved (N-terminally truncated) CTHRC1 significantly promotes glycolysis in endothelial cells, whereas full-length CTHRC1 is less effective. Propeptide cleavage is attenuated by protease inhibitors in vitro. Key glycolytic enzymes are upregulated in endothelial cells treated with cleaved CTHRC1. Cthrc1-null mice have significantly lower respiratory exchange ratio in vivo, consistent with reduced glycolytic activity.\",\n      \"method\": \"In vitro protease cleavage assay with protease inhibitors, endothelial cell metabolic respirometry (Seahorse), gene expression of glycolytic enzymes, Cthrc1-null mouse respirometry\",\n      \"journal\": \"Vascular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro cleavage mechanistic assay with functional readout, corroborated by in vivo metabolic phenotype, single lab\",\n      \"pmids\": [\"38040222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CTHRC1 mediates IL-1β-induced chondrocyte apoptosis via JNK1/2 signaling. Overexpression of CTHRC1 mimics IL-1β-induced JNK1/2 activation, increased Bax/caspase-3/PARP-1 and decreased Bcl-2; knockdown of CTHRC1 or JNK1/2 inhibitor SP600125 inhibited IL-1β-induced apoptosis and JNK1/2 activation.\",\n      \"method\": \"CTHRC1 overexpression/shRNA knockdown in rat chondrocytes, SP600125 JNK inhibitor rescue, western blot for apoptosis markers and p-JNK1/2, flow cytometry apoptosis assay\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — bidirectional manipulation with inhibitor rescue, single lab, in vitro only\",\n      \"pmids\": [\"29393342\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CTHRC1 promotes M2-like macrophage polarization in endometrial cancer via upregulation of CX3CR1 (Fractalkine receptor) in macrophages, and promotes myometrial invasion through interaction with the Integrin β3-Akt signaling pathway. Recombinant CTHRC1 promoted tumor migration and invasion via enhanced macrophage recruitment in vitro.\",\n      \"method\": \"Recombinant CTHRC1 treatment, integrin β3-Akt western blot, CX3CR1 expression assay, macrophage recruitment in vitro\",\n      \"journal\": \"Clinical & experimental metastasis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — mechanistic pathway identification without Co-IP or in vivo knockdown rescue, single lab\",\n      \"pmids\": [\"31119444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NEDD4L suppresses pulmonary fibrosis by promoting β-catenin ubiquitination and downregulating the CTHRC1/HIF-1α axis. NEDD4L overexpression reduced CTHRC1 and HIF-1α expression and attenuated lung fibroblast activity; NEDD4L silencing activated CTHRC1/HIF-1α signaling and aggravated fibrosis in vivo.\",\n      \"method\": \"NEDD4L overexpression/silencing in lung fibroblasts, β-catenin ubiquitination assay, CTHRC1/HIF-1α western blot, bleomycin fibrosis mouse model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — identifies CTHRC1 as downstream of NEDD4L/β-catenin axis but does not directly demonstrate mechanism of CTHRC1 action, single lab\",\n      \"pmids\": [\"34512149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CTHRC1 promotes tendon stem/progenitor cell (TSPC) proliferation, migration, and tenogenic differentiation by binding to EGFR and activating the MAPK signaling pathway. Inhibiting EGFR reversed the tendon-healing effect of CTHRC1. Proteomics on CTHRC1-stimulated TSPCs confirmed MAPK pathway activation.\",\n      \"method\": \"Multi-proteomic analysis, recombinant CTHRC1 treatment of TSPCs, EGFR inhibitor rescue, CTHRC1 KO and overexpression mouse models, in vitro and in vivo tendon healing assays\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — receptor interaction identified by proteomics, EGFR inhibitor rescue, bidirectional in vivo models, single lab\",\n      \"pmids\": [\"39540237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CTHRC1+ CAFs enhance glycolytic activity of cancer cells by activating TGF-β/Smad3 signaling pathway. Excess lactate from glycolysis upregulates CTHRC1 expression in CAFs through histone lactylation (H3K18la), creating a CTHRC1/glycolysis/H3K18la positive feedback loop that sustains EGFR-TKI resistance in lung cancer.\",\n      \"method\": \"scRNA-seq of lung cancer patients, TGF-β/Smad3 pathway western blot, histone lactylation (H3K18la) chromatin analysis, lactate supplementation/inhibition experiments\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic pathway with epigenetic feedback loop demonstrated by multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40011576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Exosomal CTHRC1 from cancer-associated fibroblasts promotes endometrial cancer cell migration via ITGB3/FAK signaling: CTHRC1 immunoprecipitates with ITGB3 and leads to FAK phosphorylation on Tyr397. FAK inhibitor (Defactinib) blocked the pro-migratory effect of exosomal CTHRC1.\",\n      \"method\": \"Co-immunoprecipitation of CTHRC1 with ITGB3, FAK Tyr397 phosphorylation assay, Defactinib inhibitor rescue, exosome isolation, in vivo xenograft model\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of binding partner, kinase phosphorylation site identified, pharmacological rescue in vivo, single lab\",\n      \"pmids\": [\"39229506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Senescent CAF-secreted CTHRC1 promotes cancer stemness and metastasis in HCC via the Notch1 signaling pathway. CTHRC1 expression in senescent CAFs is transcriptionally regulated by SOX4. Chromatin immunoprecipitation verified SOX4 binding to the CTHRC1 promoter region.\",\n      \"method\": \"scRNA-seq, ChIP assay for SOX4 at CTHRC1 promoter, Notch1 pathway western blot, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell communication and signaling : CCS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP validation of transcriptional regulation plus Notch signaling pathway mechanistic data, single lab\",\n      \"pmids\": [\"40855439\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CTHRC1 is a secreted, N-glycosylated glycoprotein that acts as a context-dependent signaling cofactor: it selectively activates the Wnt/PCP pathway by stabilizing Wnt-Frizzled-Ror2 receptor complexes; inhibits TGF-β/Smad2/3 signaling in smooth muscle cells; is secreted by osteoclasts to couple bone resorption to osteoblastic formation via WAIF1/PKCδ/ERK signaling; promotes osteoblast differentiation and inhibits osteoclastogenesis through NFκB/IκBα suppression; requires plasmin-mediated propeptide cleavage for full extracellular activity (including promotion of glycolysis); inhibits peripheral myelination; and in cancer contexts drives invasion and metastasis through ERK/MMP9, integrin β3/FAK, TGFβR complex stabilization, HIF-1α/CXCR4, EGFR/MAPK, and PKCα/ERK/JNK axes, as well as promoting M2 macrophage polarization via STAT6 and TGF-β signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CTHRC1 is a secreted, N-glycosylated glycoprotein that functions as a context-dependent extracellular signaling cofactor coordinating Wnt, TGF-β, and matrix-remodeling programs across tissue development, fibrosis, bone homeostasis, and cancer [#0, #2, #15]. As a cell-surface-anchored protein it selectively activates the non-canonical Wnt/PCP pathway by binding Wnt ligands, Frizzled receptors, and Ror2 to stabilize the ligand-receptor complex while suppressing canonical Wnt/β-catenin signaling [#0]. In parallel, CTHRC1 modulates TGF-β/Smad2/3 signaling in a cell-type-specific manner—inhibiting Smad2/3 activation and collagen synthesis in smooth muscle cells and fibroblasts [#1, #2], yet stabilizing TGF-β receptor complexes (TGFβRII/TGFβRIII) to potentiate signaling in cancer and stellate cell contexts [#14, #15]. Its full extracellular activity requires plasmin-mediated cleavage of an N-terminal propeptide, generating a truncated form with enhanced collagen-inhibitory and pro-glycolytic activity [#4, #25]. In bone, CTHRC1 couples resorption to formation: it is secreted by mature osteoclasts to stimulate osteoblastogenesis through the cell-surface receptor WAIF1/Tpbg via a PKCδ/MEK/ERK cascade, promotes osteoblastic bone formation, and inhibits osteoclastogenesis by preventing IκBα degradation and ERK1/2 activation [#3, #5, #12, #13]. CTHRC1 also acts through additional receptors including GPR180 in adipocytes and EGFR in tendon progenitors [#22, #29]. In cancer, CTHRC1 drives invasion, metastasis, angiogenesis, and an immunosuppressive microenvironment via ERK/MMP9, integrin β3/FAK, and TGF-β-dependent M2 macrophage polarization [#8, #15, #18, #19]. Genetic loss in mice produces metabolic phenotypes—hepatic steatosis, altered glycogen and body composition—consistent with a circulating, hormone-like function [#9, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established CTHRC1 as a secreted, N-glycosylated protein whose biochemical activity is inhibition of collagen matrix synthesis, defining it as a matrix-modulating extracellular factor.\",\n      \"evidence\": \"In situ hybridization, immunohistochemistry, and in vitro collagen matrix inhibition assay across epithelial-mesenchymal interfaces and developing skeleton\",\n      \"pmids\": [\"16678498\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No receptor or signaling pathway identified\", \"Mechanism of collagen inhibition not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed CTHRC1 is a cell-type-specific inhibitor of TGF-β/Smad2/3 signaling, linking its matrix effects to a defined signaling axis in vascular remodeling.\",\n      \"evidence\": \"Transgenic overexpression, phospho-Smad2/3 IHC, TGF-β reporter, and carotid ligation model in smooth muscle vs. endothelial cells\",\n      \"pmids\": [\"17322174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of cell-type specificity unknown\", \"Does not explain later pro-TGF-β effects in other contexts\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined CTHRC1's selective activation of Wnt/PCP signaling through direct receptor complex assembly, establishing it as an upstream PCP pathway component rather than a canonical Wnt regulator.\",\n      \"evidence\": \"Co-IP/cell-surface binding in HEK293T, reporter assays, and genetic epistasis with Vangl2 and Ror2 mutant mice\",\n      \"pmids\": [\"18606138\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural basis of the Cthrc1-Wnt-Fzd/Ror2 complex unresolved\", \"How PCP activation is reconciled with TGF-β inhibition not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified CTHRC1 as a positive regulator of osteoblastic bone formation downstream of BMP2, extending its role to skeletal anabolism.\",\n      \"evidence\": \"Cthrc1-null and osteoblast-specific transgenic mice with micro-CT, histomorphometry, CFU and BrdU assays\",\n      \"pmids\": [\"18779865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating osteoblast effects not yet identified\", \"Cellular source of bone CTHRC1 unresolved at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that proteolytic processing controls CTHRC1 activity—plasmin cleaves an N-terminal propeptide upon injury to generate a more active truncated form, revealing post-translational regulation of its function.\",\n      \"evidence\": \"Domain-specific antibodies, immunofluorescence, immunoblotting, and plasmin cleavage assay in differentiated smooth muscle cells\",\n      \"pmids\": [\"18467647\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cleavage site not mapped at residue level\", \"Whether cleavage governs all CTHRC1 activities unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Proposed CTHRC1 as a circulating hormone-like factor regulating systemic metabolism, broadening its biology beyond local matrix and signaling roles.\",\n      \"evidence\": \"Cthrc1-null mice, 125I-CTHRC1 pharmacokinetics with hepatic binding, hypothalamic/pituitary IHC, and liver steatosis phenotype\",\n      \"pmids\": [\"23056600\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cognate metabolic receptor identified here\", \"Direct hormonal target tissue unconfirmed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established CTHRC1 as a negative regulator of peripheral myelination acting by maintaining Schwann cell proliferation, defining a developmental role in the nervous system.\",\n      \"evidence\": \"RNAi knockdown in Schwann cell culture and transgenic overexpression mice with myelin time-course analysis\",\n      \"pmids\": [\"22379615\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/pathway in Schwann cells not defined here\", \"Link to PCP or TGF-β signaling unexplored\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Revealed osteoclast-derived CTHRC1 as a resorption-to-formation coupling factor, identifying the cellular source that drives the bone-anabolic phenotype.\",\n      \"evidence\": \"Osteoclast-specific conditional knockout mice, RANKL injection model, and calcium/dentin induction assays\",\n      \"pmids\": [\"23908115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stromal receptor for the coupling signal not yet identified\", \"Apparent discrepancy with later osteocyte/osteoblast source reports\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked CTHRC1 stability and expression to N-glycosylation and canonical Wnt/β-catenin transcriptional control, and to cancer cell migration at the wound front.\",\n      \"evidence\": \"DPAGT1 knockdown turnover assays, β-catenin/TCF luciferase reporter, and wound-front immunolocalization in oral squamous carcinoma cells\",\n      \"pmids\": [\"23703614\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Glycosylation sites controlling stability not mapped\", \"Single cancer cell context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Established CTHRC1 as a pro-invasive effector in cancer through ERK-dependent MMP9 induction, opening the cancer-progression dimension of its biology.\",\n      \"evidence\": \"Gain/loss-of-function in colorectal cancer lines with invasion assays and ERK/MMP9 western blots\",\n      \"pmids\": [\"24504172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Surface receptor coupling CTHRC1 to ERK not identified\", \"No in vivo metastasis confirmation\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed CTHRC1 in a miR-9/Rac1 axis controlling Schwann cell migration, providing upstream regulatory and downstream effector context for its motility functions.\",\n      \"evidence\": \"miR-9 modulation, luciferase target validation, and Rac1-inhibitor rescue in nerve regeneration\",\n      \"pmids\": [\"24413174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanism linking CTHRC1 to Rac1 activation not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended CTHRC1's metabolic role by showing it inhibits adipocyte differentiation and regulates body composition via PPARγ/CREB suppression.\",\n      \"evidence\": \"Cthrc1-null mice with in vitro adipogenesis and PPARγ/CREB reporter assays plus metabolic monitoring\",\n      \"pmids\": [\"26148471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating adipocyte effects unknown\", \"Mechanistic link to PPARγ unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed CTHRC1 can suppress innate antiviral immunity via a PKCα/ERK/JNK/c-Jun cascade that represses IFN/JAK/STAT signaling, implicating it in infection biology.\",\n      \"evidence\": \"Overexpression/knockdown in HBV-transfected cells and mice with STAT1/2 phosphorylation and IFNAR ubiquitination assays\",\n      \"pmids\": [\"26180054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How secreted CTHRC1 triggers intracellular PKCα remains unclear\", \"Receptor not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Resolved that CTHRC1 inhibits osteoclastogenesis through NF-κB suppression (blocking IκBα degradation) and ERK inhibition, and reassigned its skeletal source to osteocytes/osteoblasts.\",\n      \"evidence\": \"Cthrc1-null mice, exogenous rCTHRC1 monocyte differentiation, IκBα/p-ERK western blots, and collagen antibody-induced arthritis model\",\n      \"pmids\": [\"28115279\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of cell-source assignments across studies incomplete\", \"Receptor on monocytes not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified WAIF1/Tpbg as a cell-surface CTHRC1 receptor transducing a PKCδ/MEK/ERK osteoblastogenic signal, supplying the missing receptor in bone coupling.\",\n      \"evidence\": \"Binding-partner identification, WAIF1 knockdown, PKCδ/ERK western blots, and osteoblast lineage-specific Tpbg knockout phenocopying osteoclast-specific Cthrc1 deletion\",\n      \"pmids\": [\"29624737\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether WAIF1 mediates CTHRC1 effects outside bone unknown\", \"Structural basis of CTHRC1-WAIF1 binding unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated CTHRC1 drives fibrosis by activating TGF-β signaling in hepatic stellate cells while separately engaging non-canonical Wnt for contractility, and validated it as an antibody-targetable fibrosis driver.\",\n      \"evidence\": \"CTHRC1-/- mice and anti-CTHRC1 antibody in CCl4/TAA fibrosis with HSC activation, TGF-β western blots, and competitive Wnt receptor binding\",\n      \"pmids\": [\"30639416\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular switch determining TGF-β activation vs. inhibition across cell types unresolved\", \"Wnt receptor identity in HSCs not specified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a direct mechanism for CTHRC1 potentiation of TGF-β signaling—binding and stabilizing TGFβRII/TGFβRIII—linking it to M2 macrophage-driven metastasis.\",\n      \"evidence\": \"Co-IP of CTHRC1 with TGFβRII/TGFβRIII, clodronate macrophage depletion, and hepatic metastasis mouse model\",\n      \"pmids\": [\"33986509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of receptor complex stabilization not defined\", \"Why this contrasts with TGF-β inhibition in SMCs unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified GPR180 as a CTHRC1-required component of TGF-β signaling in brown/beige adipocytes, providing a receptor link for its metabolic actions.\",\n      \"evidence\": \"Genetic/pharmacological GPR180 manipulation, SMAD3 phosphorylation assays, and metabolic phenotyping\",\n      \"pmids\": [\"34880217\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CTHRC1-GPR180 binding not shown here\", \"Relationship to WAIF1 and TGFβR receptors unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified EGFR as a CTHRC1 receptor activating MAPK signaling in tendon progenitor cells, expanding the receptor repertoire and a regenerative role.\",\n      \"evidence\": \"Multi-proteomics, recombinant CTHRC1 with EGFR-inhibitor rescue, and bidirectional in vivo tendon-healing mouse models\",\n      \"pmids\": [\"39540237\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct CTHRC1-EGFR binding interface not mapped\", \"Whether EGFR engagement operates in other tissues unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined transcriptional control of CTHRC1 in fibrosis through drebrin/actin-driven MRTF-SRF and TGFβ1-Smad2/3 signaling, with a downstream WNT5A/PCP protective role after myocardial infarction.\",\n      \"evidence\": \"Single-cell analysis, MRTF-SRF reporter, drebrin manipulation, Cthrc1-KO MI mouse model, and rCTHRC1/rWNT5A rescue\",\n      \"pmids\": [\"36690273\", \"36923925\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Integration of multiple upstream transcriptional inputs unresolved\", \"Tissue-specificity of WNT5A/PCP output not fully defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed CTHRC1+ cancer-associated fibroblasts sustain glycolysis and therapy resistance via a TGF-β/Smad3 and histone-lactylation feedback loop, and that senescent CAF-derived CTHRC1 drives stemness via Notch1 under SOX4 control.\",\n      \"evidence\": \"scRNA-seq, TGF-β/Smad3 and Notch1 western blots, H3K18la chromatin analysis, ChIP for SOX4 at the CTHRC1 promoter, and lactate modulation\",\n      \"pmids\": [\"40011576\", \"40855439\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating CAF-derived CTHRC1 effects on cancer cells not identified here\", \"Single-lab mechanistic loops\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying molecular determinant of CTHRC1's context-dependent switch—between Wnt/PCP activation, TGF-β inhibition, and TGF-β potentiation—and the rules governing which of its multiple receptors (WAIF1, GPR180, EGFR, TGFβRII/III, integrin β3, Fzd/Ror2) it engages in a given tissue remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of CTHRC1 bound to any receptor\", \"No unified framework reconciling opposing TGF-β effects\", \"Receptor selectivity determinants across cell types unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 13, 22, 29]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 13, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2, 5, 15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0031012\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 15]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 5, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 15, 14]},\n      {\"term_id\": \"R-HSA-1474244\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\n      \"CTHRC1-Wnt-Fzd/Ror2 complex\",\n      \"TGF-β receptor complex (TGFβRII/TGFβRIII)\"\n    ],\n    \"partners\": [\n      \"WNT5A\",\n      \"FZD\",\n      \"ROR2\",\n      \"TPBG\",\n      \"TGFBR2\",\n      \"TGFBR3\",\n      \"GPR180\",\n      \"ITGB3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}