{"gene":"FGF18","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":1998,"finding":"FGF-18 is a secreted, glycosylated protein (207 amino acids) with a typical N-terminal signal sequence. Recombinant rat FGF-18 expressed in insect cells induced neurite outgrowth in PC12 cells, establishing its activity as a signaling molecule.","method":"Recombinant protein expression (baculovirus/insect cells), PC12 neurite outgrowth assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro bioassay with recombinant protein, single lab, single method","pmids":["9660775"],"is_preprint":false},{"year":1998,"finding":"Recombinant murine FGF-18 stimulated proliferation of NIH 3T3 fibroblasts in vitro in a heparan sulfate-dependent manner, and in vivo administration induced proliferation in liver and small intestine, identifying these as primary target tissues.","method":"In vitro proliferation assay (NIH 3T3), in vivo injection into normal mice and liver-specific transgenic overexpression","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro assay plus in vivo transgenic model, single lab, two orthogonal methods","pmids":["9742123"],"is_preprint":false},{"year":2001,"finding":"FGF-18 stimulates proliferation of osteoblasts and chondrocytes via ERK phosphorylation, and additionally via p38 MAPK in chondrocytes. FGF-18 also induces osteoclast formation through RANKL and COX-2 upregulation and stimulates osteoclast resorption activity.","method":"Primary cell cultures (osteoblasts, chondrocytes, osteoclast coculture), ERK/p38 phosphorylation assays, specific kinase inhibitors, dentine resorption pit assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple cell types, kinase inhibitor dissection, multiple orthogonal assays in one study","pmids":["11741978"],"is_preprint":false},{"year":2002,"finding":"Fgf18 knockout mice show delayed suture closure, decreased calvarial osteogenic mesenchymal cell proliferation, delayed terminal osteoblast differentiation, and increased chondrocyte proliferation and differentiation, establishing FGF18 as a positive regulator of osteogenesis and negative regulator of chondrogenesis in vivo.","method":"Gene targeting (Fgf18−/− mice), histological analysis, cell proliferation assays","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockout with defined skeletal phenotype, replicated across multiple skeletal compartments","pmids":["11937494"],"is_preprint":false},{"year":2002,"finding":"FGF-18 binds FGF receptors 3c and 2c but not FGFR-1c (as measured by BIAcore surface plasmon resonance), and has mitogenic activity for astrocytes and microglia but not neurons, identifying it as a neuron-derived glial cell growth factor.","method":"BIAcore surface plasmon resonance binding assay, primary cell culture mitogenic assays (astrocytes, microglia, cortical neurons)","journal":"Brain research. Molecular brain research","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — direct binding assay plus functional cell assays, single lab","pmids":["12399108"],"is_preprint":false},{"year":2003,"finding":"FGF18 is a direct transcriptional target of the β-catenin/TCF4 (Wnt) pathway. Reporter gene and EMSA assays demonstrated that the FGF18 promoter contains functional TCF4-binding motifs. Exogenous FGF18 promoted NIH 3T3 cell growth in an autocrine manner; siRNA knockdown of FGF18 suppressed colon cancer cell growth.","method":"Luciferase reporter assay, electromobility shift assay (EMSA), siRNA knockdown, cell proliferation assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reporter assay + EMSA + functional siRNA, multiple orthogonal methods in one study","pmids":["14559787"],"is_preprint":false},{"year":2004,"finding":"Calcium-dependent signals through calcineurin phosphatase and the transcription factor NFAT4 induce FGF18 expression. FGF18 (or constitutively active FGFR) suppresses noggin gene induction, thereby enhancing BMP-dependent chondrocyte differentiation and chondrogenesis.","method":"Expression of activated calcineurin/NFAT4 constructs, FGF18 treatment of chondrocytes, noggin reporter assays, chondrogenesis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function with defined molecular readout, single lab, multiple methods","pmids":["15252029"],"is_preprint":false},{"year":2004,"finding":"Fgf18-deficient mouse lungs at E18.5 show reduced alveolar space and thicker interstitial mesenchymal compartments with transiently reduced cell proliferation around E17.5, establishing FGF18 as required for embryonic lung alveolar development.","method":"Fgf18−/− knockout mice, histological analysis, cell proliferation assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean knockout with defined lung phenotype, single lab","pmids":["15336546"],"is_preprint":false},{"year":2005,"finding":"FGF18 signals through FGFR3 to promote chondrogenesis in limb bud mesenchymal cells: FGFR3−/− cultures show impaired cartilage nodule formation, impaired mitogenic response to FGF18, decreased type II collagen and proteoglycan production, altered integrin expression, and altered FGFR1/2 expression in response to FGF18.","method":"FGFR3+/+ vs FGFR3−/− limb bud mesenchymal cell cultures, confocal laser-scanning microscopy, FGF18 stimulation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function receptor model with multiple orthogonal readouts, identifies FGF18 as selective FGFR3 ligand in this context","pmids":["15781473"],"is_preprint":false},{"year":2005,"finding":"FGF18 mRNA is highly expressed in hair follicles (anagen inner root sheath and telogen bulge). Subcutaneous administration of FGF18 to mice in telogen induced anagen hair growth, and FGF18 stimulated DNA synthesis in dermal fibroblasts, dermal papilla cells, keratinocytes, and endothelial cells in culture.","method":"In situ hybridization, subcutaneous protein injection in vivo, DNA synthesis assay (BrdU/thymidine incorporation) in cultured cells","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo functional experiment plus in vitro assays, single lab","pmids":["15854025"],"is_preprint":false},{"year":2006,"finding":"FGF18 is required for VEGF expression in hypertrophic chondrocytes and perichondrium, and is sufficient to induce VEGF expression in skeletal explants, coordinating growth plate vascularization with osteoblast/osteoclast recruitment. Loss of FGF18 delays chondrocyte hypertrophy, early chondroprogenitor proliferation, skeletal vascularization, and osteoblast/osteoclast recruitment.","method":"Fgf18−/− knockout analysis, Vegf expression analysis by in situ hybridization, FGF18 skeletal explant stimulation assay","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO plus gain-of-function explant rescue, multiple mechanistic readouts","pmids":["17014841"],"is_preprint":false},{"year":2006,"finding":"FGF18 is a direct target of canonical Wnt signaling through a single TCF/Lef-binding site in its promoter. Runx2 and TCF/Lef cooperate to induce FGF18 expression: Runx2 forms a complex with Lef1 or TCF4 that binds the composite binding site in the fgf18 promoter. Targeted disruption of β-catenin blocks fgf18 expression in vivo.","method":"Promoter reporter assay, EMSA, RNAi knockdown of Runx2, Runx2 forced expression, co-immunoprecipitation of Runx2-Lef1/TCF4 complex, in vivo β-catenin conditional knockout","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (reporter, EMSA, Co-IP, in vivo KO), identifies composite transcriptional mechanism","pmids":["17158875"],"is_preprint":false},{"year":2007,"finding":"The core protein of growth plate perlecan (domain III, cysteine-rich regions) binds FGF-18 directly with Kd ~27.8–145 nM independent of its heparan sulfate or chondroitin sulfate chains (binding not reduced by glycosaminoglycanase digestion but reduced by reduction/alkylation). Perlecan binding reverses the mitogenic effect of FGF-18 on growth plate chondrocytes by 37–74%.","method":"Cationic filtration binding assay, immunoprecipitation, recombinant perlecan domain expression in COS-7 cells, chondroitinase/heparitinase digestion, 3H-thymidine incorporation assay","journal":"Archives of biochemistry and biophysics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct binding with Kd measurement, domain mapping with recombinant proteins, functional consequence assay, multiple orthogonal methods","pmids":["17971291"],"is_preprint":false},{"year":2007,"finding":"The zinc finger protein Glis3 directly binds a Glis3-binding site in the FGF18 promoter and induces FGF18 expression, promoting osteoblast differentiation. RNAi knockdown of Glis3 decreased FGF18 expression, while Glis3 overexpression induced it.","method":"Promoter reporter assay, EMSA, microarray, RNAi, gain-of-function in C3H10T1/2 cells","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA + reporter + RNAi + gain-of-function, single lab","pmids":["17488195"],"is_preprint":false},{"year":2010,"finding":"Cysteine-rich FGF receptor (Cfr/Glg1) physically interacts with FGF18 and genetically cooperates with FGF18 signaling. Cfr-deficient mice exhibit phenotypes similar to Fgf18-deficient mice; Cfr facilitates FGF18-dependent proliferation of Ba/F3 cells expressing FGFR3c. Delta-like protein (Dlk) binds Cfr and interrupts Cfr-FGF18 interaction, acting antagonistically.","method":"Cfr knockout mice, genetic epistasis (Cfr/Fgf18 compound mutants), co-immunoprecipitation (Cfr-FGF18, Cfr-Dlk), Ba/F3 cell proliferation assay","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis + physical interaction (Co-IP) + functional cell assay + identification of competing regulator (Dlk), multiple orthogonal methods","pmids":["20023171"],"is_preprint":false},{"year":2012,"finding":"Epithelial FGF18 expression in the hair stem cell niche during telogen maintains the resting phase of the hair cycle. Conditional knockout of Fgf18 in keratin 5-positive epithelial cells causes dramatically shortened telogen and rapid hair cycling; local FGF18 delivery suppresses hair follicle growth during anagen.","method":"Conditional (K5-Cre) Fgf18 knockout mice, in vivo FGF18 protein delivery, hair cycle analysis","journal":"The Journal of investigative dermatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific conditional KO with defined phenotypic readout plus rescue by protein delivery, replicated by two complementary approaches","pmids":["22297635"],"is_preprint":false},{"year":2013,"finding":"Foxp1 maintains hair follicle stem cell quiescence by directly regulating FGF18 expression. Loss of Foxp1 in skin epithelial cells leads to shortened telogen and precocious stem cell activation; exogenous FGF18 rescues premature stem cell activation in Foxp1-null mice, placing FGF18 as a key downstream target of Foxp1.","method":"Conditional Foxp1 knockout, Foxp1 overexpression, exogenous FGF18 rescue experiment in Foxp1-null mice, hair cycle analysis","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with rescue experiment (FGF18 rescues Foxp1 KO phenotype), multiple orthogonal approaches, identifies pathway order","pmids":["23946441"],"is_preprint":false},{"year":2013,"finding":"FGF18 and FGF8 signal through divergent intracellular pathways in bovine granulosa cells: FGF8 increases ERK1/2 phosphorylation and induces SPRY1/2/4, NR4A1/3, and FOS expression, whereas FGF18 does not activate ERK1/2 or induce these genes. FGF18 activates EGR1, FOSL1, BAMBI, PLK2 but not FOS or XIRP1.","method":"Primary bovine granulosa cell culture, ERK1/2 phosphorylation assay, microarray gene expression analysis, qPCR validation","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — comparative signaling assays with microarray plus protein readout, single lab","pmids":["23707615"],"is_preprint":false},{"year":2015,"finding":"PHLPP1 phosphatase deficiency leads to increased FGF18 expression via a FoxO1-dependent mechanism, and elevated FGF18 drives increased MEK/ERK activity and chondrocyte metabolic activity. Chemical inhibition of FGFR signaling abrogated the elevated ERK1/2 phosphorylation in Phlpp1-null cultures, placing FGF18/FGFR downstream of PHLPP1/FoxO1.","method":"Phlpp1−/− knockout mice and chondrocyte cultures, FGFR chemical inhibitor epistasis, phosphorylation assays (Akt2, PKC, p70S6K, ERK1/2), metabolic activity assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus pharmacological epistasis, single lab","pmids":["25953896"],"is_preprint":false},{"year":2016,"finding":"A Shh-Foxf-Fgf18-Shh circuit operates in palate development: Foxf1 and Foxf2 repress Fgf18 expression in palatal mesenchyme downstream of Shh signaling; elevated FGF18 (in Foxf mutants) inhibits Shh expression in the palatal epithelium. Exogenous FGF18 protein added to cultured palatal explants directly inhibited Shh expression.","method":"Tissue-specific Cre/loxP Foxf1/Foxf2 conditional knockouts in neural crest cells, RNA-seq, whole mount in situ hybridization, palatal explant culture with exogenous FGF18 protein","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple conditional KOs plus direct protein rescue/inhibition experiment in explant culture","pmids":["26745863"],"is_preprint":false},{"year":2016,"finding":"FGF9 and FGF18 redundantly regulate all stages of skeletogenesis; compound loss of Fgf9 and Fgf18 alleles reveals variable potency along the proximodistal limb axis and affects expression of IHH, PTHrP, and RUNX2, placing FGF9/18 signaling upstream of these skeletal regulators.","method":"Combined Fgf9/Fgf18 null allele series, skeletal analysis, gene expression analysis","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic compound genetic analysis across multiple allele combinations, replicates and extends prior KO findings","pmids":["26794256"],"is_preprint":false},{"year":2016,"finding":"FGF9 and FGF18 promote survival and migration of human lung fibroblasts and inhibit TGFβ1-induced myofibroblast differentiation partially through FGFR3 (siRNA knockdown of FGFR3 impaired p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration).","method":"Primary human lung fibroblast cultures, siRNA knockdown of FGFR isoforms, ERK phosphorylation assay, apoptosis assay, migration assay, differentiation markers","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA receptor knockdown with multiple functional readouts, single lab","pmids":["26773067"],"is_preprint":false},{"year":2017,"finding":"FGF18 activates the AKT/GSK3β/β-catenin signaling pathway in breast cancer cells, promoting EMT and cell migration. FGF18 increased Akt-Ser473 and Thr308 phosphorylation and GSK3β-Ser9 phosphorylation; β-catenin bound to target gene promoters was confirmed by ChIP.","method":"Western blotting (phosphorylation assays), wound-healing migration assay, chromatin immunoprecipitation (ChIP), clonogenicity assay","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple signaling assays plus ChIP, single lab","pmids":["30196303"],"is_preprint":false},{"year":2017,"finding":"FGF18 promotes angiogenesis in hepatocellular carcinoma by enhancing Wnt/β-catenin-mediated FGF18 expression via RPS15A; FGF18 binds FGFR3 on endothelial cells to activate AKT and ERK pathways.","method":"HCC cell line co-culture with endothelial cells, RPS15A overexpression/knockdown, in vivo xenograft, western blotting (AKT/ERK phosphorylation)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo plus in vitro experiments with defined signaling readouts, single lab","pmids":["29242604"],"is_preprint":false},{"year":2018,"finding":"FGF18 is required for acetylcholine receptor (AChR) clustering and neuromuscular junction (NMJ) formation. FGF18 is expressed in spinal motor neurons and localized at NMJs. Fgf18−/− embryos show reduced NMJ size, simplified motor endplates, reduced Chrne and Colq expression, and low-amplitude miniature endplate potentials. In C2C12 myotubes, FGF18 enhanced AChR clustering via FGFR and MEK1 signaling.","method":"Fgf18−/− knockout mice, laser capture microdissection, immunofluorescence localization, electrophysiology (mEPP recording), C2C12 cell AChR clustering assay with FGFR/MEK1 inhibitors","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with ultrastructural + electrophysiological + molecular readouts, plus in vitro mechanistic dissection with pharmacological inhibitors","pmids":["29323161"],"is_preprint":false},{"year":2020,"finding":"FGF18-FGFR2 signaling activates the c-Jun–YAP1 axis in gastric cancer: stimulation of FGFR2 with recombinant FGF18 induces F-actin formation, nuclear accumulation of YAP1, and overexpression of YAP1 targets, effects attenuated by FGFR2 depletion or AZD4547. FGF18-FGFR2 upregulates YAP1 through c-Jun, an effector of MAPK signaling.","method":"Recombinant FGF18 stimulation, FGFR2 siRNA knockdown, AZD4547 pharmacological inhibition, RNA-seq, immunofluorescence of YAP1 nuclear translocation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition with defined molecular pathway readouts, single lab","pmids":["32934314"],"is_preprint":false},{"year":2020,"finding":"Sprifermin (rhFGF18) is transiently internalized in chondrocytes through clathrin- and dynamin-independent endocytosis, is intracellularly degraded together with FGFR3, causing receptor desensitization. Receptor activation is not required for sprifermin endocytosis. Removal of sprifermin allows re-sensitization of cells.","method":"Western blot, cell staining for endocytic pathway markers, ERK1/2 activation assay, pharmacological inhibition of clathrin/dynamin pathways","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inhibitor/marker experiments identifying endocytic route, single lab","pmids":["32798495"],"is_preprint":false},{"year":2022,"finding":"TGF-β signaling in neural crest-derived perimysial fibroblasts, cooperating with transcription factor Creb5, activates Fgf18 expression to support pharyngeal muscle development. Exogenous FGF18 partially rescues myogenic cell numbers in Osr2 mutants lacking TGF-β signaling.","method":"Conditional Osr2-Cre TGF-β signaling knockouts, single-cell RNAseq, in vivo exogenous FGF18 rescue, in situ hybridization","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with conditional KO plus in vivo rescue experiment and single-cell transcriptomics, multiple methods","pmids":["36542062"],"is_preprint":false},{"year":2022,"finding":"HDAC7 promotes FGF18 expression via reducing β-catenin acetylation at Lys49 and phosphorylation at Ser45, facilitating nuclear translocation of β-catenin which then activates FGF18 transcription through TCF4 binding. USP10 deubiquitinase interacts with and stabilizes HDAC7.","method":"Co-immunoprecipitation, western blotting for post-translational modifications, lentiviral overexpression/knockdown in vivo and in vitro, gene rescue experiments","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus PTM analysis plus rescue experiments, single lab","pmids":["35277183"],"is_preprint":false},{"year":2023,"finding":"FGF18 secreted by hepatic stellate cells alleviates hepatic ischemia-reperfusion injury through the USP16/KEAP1/Nrf2 pathway: FGF18 reduces USP16 levels, leading to increased ubiquitination of KEAP1 and activation of Nrf2. USP16 interacts with and deubiquitinates KEAP1, and Nrf2 directly binds the USP16 promoter, forming a negative feedback loop.","method":"HSC-specific FGF18 deletion, Co-IP (USP16-KEAP1), ubiquitination assays, ChIP (Nrf2 binding to USP16 promoter), western blotting","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO plus Co-IP plus ubiquitination assay plus ChIP, multiple orthogonal methods, identifies complete pathway","pmids":["37777507"],"is_preprint":false},{"year":2023,"finding":"FGF18 promotes human lung branching morphogenesis by regulating mesenchymal progenitor cells: FGF18 treatment of human fetal lung explants promotes branching, increases epithelial proliferation, maintains SOX2/SOX9 double-positive distal bud progenitors, and increases expression of SOX9, FN1, and COL2A1 in mesenchyme.","method":"Human fetal lung explant culture (air-liquid interface), recombinant FGF18 protein treatment, immunofluorescence, gene expression analysis","journal":"American journal of physiology. Lung cellular and molecular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct gain-of-function in human tissue explants with multiple molecular readouts, single lab","pmids":["36791060"],"is_preprint":false},{"year":2024,"finding":"BUB1 promotes FGF18 expression by interacting with METTL3 to induce m6A methylation of TRAF6 mRNA, thereby activating the NF-κB/FGF18 transcriptional axis in gastric cancer cells.","method":"Co-immunoprecipitation (BUB1-METTL3), MeRIP-qPCR (m6A of TRAF6), RNA-seq, western blotting, siRNA/overexpression in vivo and in vitro","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus m6A sequencing assay plus functional rescue, single lab","pmids":["39025206"],"is_preprint":false},{"year":2025,"finding":"FGF18 facilitates intercellular communication between hepatic stellate cells and myofibroblasts in liver fibrosis by efficiently inducing osteopontin (Spp1/OPN) expression in culture-activated αSMA+ HSCs (but not in quiescent HSCs); OPN in turn upregulates profibrotic genes in quiescent HSCs. FGF18 and TGFβ synergistically increase OPN expression. Myofibroblast-derived Spp1 signals back to HSCs, forming a feedforward fibrotic loop.","method":"In vitro HSC/myofibroblast cultures (activated vs. quiescent), FGF18 and TGFβ stimulation, immunohistochemistry, cell-cell communication analysis of murine liver fibrosis models","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic cell culture experiments plus in vivo fibrosis model analysis, single lab","pmids":["40678531"],"is_preprint":false},{"year":2014,"finding":"FGF18 expressed in the distal limb mesenchyme induces premature expression of myogenic determination genes Myf5 and MyoD in chick limb myoblasts via ERK MAP kinase signaling (not PI3K). Retinoic acid inhibits the myogenic activity of FGF18, and blocking RA signaling allows premature FGF18-induced MyoD expression.","method":"Chick limb bud explant/electroporation assays, pharmacological inhibition of ERK/PI3K, retinoic acid addition/inhibition, in situ hybridization for myogenic genes","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological dissection experiments in embryonic tissue, single lab","pmids":["25446536"],"is_preprint":false}],"current_model":"FGF18 is a secreted glycoprotein that signals primarily through FGFR3 (and also FGFR2c) to regulate skeletal development, hair follicle cycling, lung alveologenesis, NMJ formation, and diverse cancer-related processes by activating ERK, p38 MAPK, AKT/GSK3β/β-catenin, and FGFR-dependent pathways; its transcription is directly controlled by β-catenin/TCF-Runx2 complexes, calcineurin/NFAT4, Foxp1, Glis3, Creb5/TGF-β, and HDAC7/β-catenin, while its extracellular activity is modulated by perlecan domain III binding and by the co-receptor Cfr (which is antagonized by Dlk), and following receptor activation sprifermin/FGF18 undergoes clathrin- and dynamin-independent endocytosis leading to FGFR3 co-degradation and transient cellular desensitization."},"narrative":{"mechanistic_narrative":"FGF18 is a secreted, glycosylated signaling protein that acts as a paracrine and autocrine growth factor coordinating skeletal, epithelial, neuromuscular, and tissue-repair programs [PMID:9660775, PMID:9742123]. It binds selectively to FGFR3c and FGFR2c, but not FGFR1c, and engages these receptors in a heparan sulfate–dependent manner to activate ERK, p38 MAPK, and AKT/GSK3β/β-catenin signaling [PMID:9742123, PMID:12399108, PMID:15781473]. In the skeleton FGF18 is a positive regulator of osteogenesis and a context-dependent regulator of chondrogenesis: knockout mice show delayed suture closure and altered chondrocyte proliferation, and FGF18 drives osteoblast/chondrocyte proliferation through ERK (and p38 in chondrocytes), promotes osteoclast formation via RANKL/COX-2, suppresses noggin to enhance BMP-dependent chondrogenesis, and is required for VEGF-driven growth plate vascularization [PMID:11741978, PMID:11937494, PMID:15252029, PMID:17014841]; it acts redundantly with FGF9 upstream of IHH, PTHrP, and RUNX2 [PMID:26794256]. Beyond bone, FGF18 maintains hair follicle stem cell quiescence and the resting (telogen) phase of the hair cycle [PMID:22297635, PMID:23946441], is required for acetylcholine receptor clustering and neuromuscular junction formation via FGFR/MEK1 signaling [PMID:29323161], promotes lung branching morphogenesis and alveologenesis [PMID:15336546, PMID:36791060], and regulates limb myogenesis through ERK-dependent induction of Myf5/MyoD [PMID:25446536]. FGF18 transcription is a convergence point for multiple regulatory inputs, most prominently canonical Wnt signaling acting through a composite β-catenin/TCF-Runx2 element in its promoter, as well as calcineurin/NFAT4, Glis3, Foxp1, Foxf1/2, and Creb5/TGF-β [PMID:14559787, PMID:15252029, PMID:17158875, PMID:17488195, PMID:23946441, PMID:26745863, PMID:36542062]. Extracellular FGF18 activity is tuned by direct binding to perlecan domain III, which antagonizes its mitogenic effect, and by the co-receptor Cfr/Glg1, whose interaction with FGF18 is blocked by Dlk [PMID:17971291, PMID:20023171]. In cancers FGF18 promotes EMT, migration, and angiogenesis through AKT/GSK3β/β-catenin and FGFR2-driven c-Jun–YAP1 signaling [PMID:30196303, PMID:29242604, PMID:32934314]. Following receptor activation, FGF18 (sprifermin) undergoes clathrin- and dynamin-independent endocytosis and is co-degraded with FGFR3, producing transient receptor desensitization [PMID:32798495].","teleology":[{"year":1998,"claim":"Established FGF18 as a bona fide secreted signaling molecule with mitogenic/differentiation-inducing activity, defining the basic biochemical identity that all later mechanism rests on.","evidence":"Recombinant rat/murine FGF18 in neurite outgrowth and fibroblast proliferation assays plus in vivo overexpression","pmids":["9660775","9742123"],"confidence":"Medium","gaps":["Receptor specificity not yet defined","In vivo target tissues identified phenomenologically without pathway dissection"]},{"year":2002,"claim":"Defined FGF18 receptor selectivity and the core signaling outputs, answering which FGFRs transduce its signal and through which kinases.","evidence":"BIAcore binding to FGFR3c/FGFR2c vs FGFR1c, and ERK/p38 phosphorylation dissection in osteoblasts and chondrocytes with kinase inhibitors","pmids":["12399108","11741978"],"confidence":"High","gaps":["Cell-type-specific receptor usage not resolved","Heparan sulfate dependence quantified only indirectly"]},{"year":2002,"claim":"Demonstrated the in vivo skeletal role, showing FGF18 is a positive osteogenic and negative chondrogenic regulator and resolving its physiological function in bone.","evidence":"Fgf18−/− mice with histology and proliferation assays across calvaria and growth plate","pmids":["11937494"],"confidence":"High","gaps":["Receptor mediating each effect not genetically assigned","Opposite effects on osteoblasts vs chondrocytes mechanistically unexplained"]},{"year":2003,"claim":"Placed FGF18 transcription downstream of canonical Wnt/β-catenin signaling and linked it to autocrine tumor growth, connecting a developmental pathway to cancer.","evidence":"Promoter reporter, EMSA for TCF4 sites, and FGF18 siRNA in colon cancer cells","pmids":["14559787"],"confidence":"High","gaps":["Composite promoter architecture not yet defined","In vivo relevance of Wnt control not tested here"]},{"year":2005,"claim":"Assigned FGFR3 as the functional receptor for FGF18 in chondrogenesis and showed FGF18 controls vascularization, integrating cartilage and bone development.","evidence":"FGFR3−/− limb bud mesenchyme cultures and Fgf18−/− analysis with VEGF in situ and explant rescue","pmids":["15781473","17014841"],"confidence":"High","gaps":["Contribution of FGFR2c not separated","Downstream transcriptional effectors of VEGF induction unknown"]},{"year":2006,"claim":"Resolved the composite transcriptional mechanism by showing Runx2 forms a complex with Lef1/TCF4 on the FGF18 promoter, and that calcineurin/NFAT4 and Glis3 also drive its expression.","evidence":"Reporter, EMSA, Co-IP of Runx2-Lef1/TCF4, in vivo β-catenin conditional KO; NFAT4 and Glis3 gain/loss-of-function","pmids":["17158875","15252029","17488195"],"confidence":"High","gaps":["Combinatorial logic of multiple inputs not integrated","Cell-type specificity of each transcription factor not mapped"]},{"year":2010,"claim":"Identified extracellular modulators of FGF18 activity, showing perlecan domain III directly binds and antagonizes it and that the co-receptor Cfr/Glg1 promotes signaling while Dlk competes Cfr away.","evidence":"Kd binding/domain mapping with recombinant perlecan; Cfr KO epistasis, Co-IP (Cfr-FGF18, Cfr-Dlk), Ba/F3 proliferation","pmids":["17971291","20023171"],"confidence":"High","gaps":["Structural basis of perlecan and Cfr binding unknown","How Cfr couples to FGFR3 mechanistically unresolved"]},{"year":2013,"claim":"Established FGF18 as the effector maintaining hair follicle stem cell quiescence and resolved its upstream control by Foxp1, ordering the niche signaling pathway.","evidence":"Conditional Fgf18 and Foxp1 KO with FGF18 rescue of Foxp1-null phenotype and in vivo protein delivery","pmids":["22297635","23946441"],"confidence":"High","gaps":["Receptor mediating quiescence signal not identified","Downstream effectors of FGF18 in stem cells unknown"]},{"year":2016,"claim":"Extended FGF18 into craniofacial and limb developmental circuits, defining Shh-Foxf-Fgf18 feedback and FGF9/18 redundancy upstream of IHH/PTHrP/RUNX2.","evidence":"Conditional Foxf1/2 KO with explant FGF18 inhibition of Shh; 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Recombinant rat FGF-18 expressed in insect cells induced neurite outgrowth in PC12 cells, establishing its activity as a signaling molecule.\",\n      \"method\": \"Recombinant protein expression (baculovirus/insect cells), PC12 neurite outgrowth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro bioassay with recombinant protein, single lab, single method\",\n      \"pmids\": [\"9660775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Recombinant murine FGF-18 stimulated proliferation of NIH 3T3 fibroblasts in vitro in a heparan sulfate-dependent manner, and in vivo administration induced proliferation in liver and small intestine, identifying these as primary target tissues.\",\n      \"method\": \"In vitro proliferation assay (NIH 3T3), in vivo injection into normal mice and liver-specific transgenic overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro assay plus in vivo transgenic model, single lab, two orthogonal methods\",\n      \"pmids\": [\"9742123\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"FGF-18 stimulates proliferation of osteoblasts and chondrocytes via ERK phosphorylation, and additionally via p38 MAPK in chondrocytes. FGF-18 also induces osteoclast formation through RANKL and COX-2 upregulation and stimulates osteoclast resorption activity.\",\n      \"method\": \"Primary cell cultures (osteoblasts, chondrocytes, osteoclast coculture), ERK/p38 phosphorylation assays, specific kinase inhibitors, dentine resorption pit assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple cell types, kinase inhibitor dissection, multiple orthogonal assays in one study\",\n      \"pmids\": [\"11741978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Fgf18 knockout mice show delayed suture closure, decreased calvarial osteogenic mesenchymal cell proliferation, delayed terminal osteoblast differentiation, and increased chondrocyte proliferation and differentiation, establishing FGF18 as a positive regulator of osteogenesis and negative regulator of chondrogenesis in vivo.\",\n      \"method\": \"Gene targeting (Fgf18−/− mice), histological analysis, cell proliferation assays\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockout with defined skeletal phenotype, replicated across multiple skeletal compartments\",\n      \"pmids\": [\"11937494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FGF-18 binds FGF receptors 3c and 2c but not FGFR-1c (as measured by BIAcore surface plasmon resonance), and has mitogenic activity for astrocytes and microglia but not neurons, identifying it as a neuron-derived glial cell growth factor.\",\n      \"method\": \"BIAcore surface plasmon resonance binding assay, primary cell culture mitogenic assays (astrocytes, microglia, cortical neurons)\",\n      \"journal\": \"Brain research. Molecular brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — direct binding assay plus functional cell assays, single lab\",\n      \"pmids\": [\"12399108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FGF18 is a direct transcriptional target of the β-catenin/TCF4 (Wnt) pathway. Reporter gene and EMSA assays demonstrated that the FGF18 promoter contains functional TCF4-binding motifs. Exogenous FGF18 promoted NIH 3T3 cell growth in an autocrine manner; siRNA knockdown of FGF18 suppressed colon cancer cell growth.\",\n      \"method\": \"Luciferase reporter assay, electromobility shift assay (EMSA), siRNA knockdown, cell proliferation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reporter assay + EMSA + functional siRNA, multiple orthogonal methods in one study\",\n      \"pmids\": [\"14559787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Calcium-dependent signals through calcineurin phosphatase and the transcription factor NFAT4 induce FGF18 expression. FGF18 (or constitutively active FGFR) suppresses noggin gene induction, thereby enhancing BMP-dependent chondrocyte differentiation and chondrogenesis.\",\n      \"method\": \"Expression of activated calcineurin/NFAT4 constructs, FGF18 treatment of chondrocytes, noggin reporter assays, chondrogenesis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function with defined molecular readout, single lab, multiple methods\",\n      \"pmids\": [\"15252029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Fgf18-deficient mouse lungs at E18.5 show reduced alveolar space and thicker interstitial mesenchymal compartments with transiently reduced cell proliferation around E17.5, establishing FGF18 as required for embryonic lung alveolar development.\",\n      \"method\": \"Fgf18−/− knockout mice, histological analysis, cell proliferation assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean knockout with defined lung phenotype, single lab\",\n      \"pmids\": [\"15336546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FGF18 signals through FGFR3 to promote chondrogenesis in limb bud mesenchymal cells: FGFR3−/− cultures show impaired cartilage nodule formation, impaired mitogenic response to FGF18, decreased type II collagen and proteoglycan production, altered integrin expression, and altered FGFR1/2 expression in response to FGF18.\",\n      \"method\": \"FGFR3+/+ vs FGFR3−/− limb bud mesenchymal cell cultures, confocal laser-scanning microscopy, FGF18 stimulation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function receptor model with multiple orthogonal readouts, identifies FGF18 as selective FGFR3 ligand in this context\",\n      \"pmids\": [\"15781473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FGF18 mRNA is highly expressed in hair follicles (anagen inner root sheath and telogen bulge). Subcutaneous administration of FGF18 to mice in telogen induced anagen hair growth, and FGF18 stimulated DNA synthesis in dermal fibroblasts, dermal papilla cells, keratinocytes, and endothelial cells in culture.\",\n      \"method\": \"In situ hybridization, subcutaneous protein injection in vivo, DNA synthesis assay (BrdU/thymidine incorporation) in cultured cells\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo functional experiment plus in vitro assays, single lab\",\n      \"pmids\": [\"15854025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FGF18 is required for VEGF expression in hypertrophic chondrocytes and perichondrium, and is sufficient to induce VEGF expression in skeletal explants, coordinating growth plate vascularization with osteoblast/osteoclast recruitment. Loss of FGF18 delays chondrocyte hypertrophy, early chondroprogenitor proliferation, skeletal vascularization, and osteoblast/osteoclast recruitment.\",\n      \"method\": \"Fgf18−/− knockout analysis, Vegf expression analysis by in situ hybridization, FGF18 skeletal explant stimulation assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus gain-of-function explant rescue, multiple mechanistic readouts\",\n      \"pmids\": [\"17014841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"FGF18 is a direct target of canonical Wnt signaling through a single TCF/Lef-binding site in its promoter. Runx2 and TCF/Lef cooperate to induce FGF18 expression: Runx2 forms a complex with Lef1 or TCF4 that binds the composite binding site in the fgf18 promoter. Targeted disruption of β-catenin blocks fgf18 expression in vivo.\",\n      \"method\": \"Promoter reporter assay, EMSA, RNAi knockdown of Runx2, Runx2 forced expression, co-immunoprecipitation of Runx2-Lef1/TCF4 complex, in vivo β-catenin conditional knockout\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (reporter, EMSA, Co-IP, in vivo KO), identifies composite transcriptional mechanism\",\n      \"pmids\": [\"17158875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The core protein of growth plate perlecan (domain III, cysteine-rich regions) binds FGF-18 directly with Kd ~27.8–145 nM independent of its heparan sulfate or chondroitin sulfate chains (binding not reduced by glycosaminoglycanase digestion but reduced by reduction/alkylation). Perlecan binding reverses the mitogenic effect of FGF-18 on growth plate chondrocytes by 37–74%.\",\n      \"method\": \"Cationic filtration binding assay, immunoprecipitation, recombinant perlecan domain expression in COS-7 cells, chondroitinase/heparitinase digestion, 3H-thymidine incorporation assay\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct binding with Kd measurement, domain mapping with recombinant proteins, functional consequence assay, multiple orthogonal methods\",\n      \"pmids\": [\"17971291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The zinc finger protein Glis3 directly binds a Glis3-binding site in the FGF18 promoter and induces FGF18 expression, promoting osteoblast differentiation. RNAi knockdown of Glis3 decreased FGF18 expression, while Glis3 overexpression induced it.\",\n      \"method\": \"Promoter reporter assay, EMSA, microarray, RNAi, gain-of-function in C3H10T1/2 cells\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA + reporter + RNAi + gain-of-function, single lab\",\n      \"pmids\": [\"17488195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Cysteine-rich FGF receptor (Cfr/Glg1) physically interacts with FGF18 and genetically cooperates with FGF18 signaling. Cfr-deficient mice exhibit phenotypes similar to Fgf18-deficient mice; Cfr facilitates FGF18-dependent proliferation of Ba/F3 cells expressing FGFR3c. Delta-like protein (Dlk) binds Cfr and interrupts Cfr-FGF18 interaction, acting antagonistically.\",\n      \"method\": \"Cfr knockout mice, genetic epistasis (Cfr/Fgf18 compound mutants), co-immunoprecipitation (Cfr-FGF18, Cfr-Dlk), Ba/F3 cell proliferation assay\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis + physical interaction (Co-IP) + functional cell assay + identification of competing regulator (Dlk), multiple orthogonal methods\",\n      \"pmids\": [\"20023171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Epithelial FGF18 expression in the hair stem cell niche during telogen maintains the resting phase of the hair cycle. Conditional knockout of Fgf18 in keratin 5-positive epithelial cells causes dramatically shortened telogen and rapid hair cycling; local FGF18 delivery suppresses hair follicle growth during anagen.\",\n      \"method\": \"Conditional (K5-Cre) Fgf18 knockout mice, in vivo FGF18 protein delivery, hair cycle analysis\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific conditional KO with defined phenotypic readout plus rescue by protein delivery, replicated by two complementary approaches\",\n      \"pmids\": [\"22297635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Foxp1 maintains hair follicle stem cell quiescence by directly regulating FGF18 expression. Loss of Foxp1 in skin epithelial cells leads to shortened telogen and precocious stem cell activation; exogenous FGF18 rescues premature stem cell activation in Foxp1-null mice, placing FGF18 as a key downstream target of Foxp1.\",\n      \"method\": \"Conditional Foxp1 knockout, Foxp1 overexpression, exogenous FGF18 rescue experiment in Foxp1-null mice, hair cycle analysis\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with rescue experiment (FGF18 rescues Foxp1 KO phenotype), multiple orthogonal approaches, identifies pathway order\",\n      \"pmids\": [\"23946441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FGF18 and FGF8 signal through divergent intracellular pathways in bovine granulosa cells: FGF8 increases ERK1/2 phosphorylation and induces SPRY1/2/4, NR4A1/3, and FOS expression, whereas FGF18 does not activate ERK1/2 or induce these genes. FGF18 activates EGR1, FOSL1, BAMBI, PLK2 but not FOS or XIRP1.\",\n      \"method\": \"Primary bovine granulosa cell culture, ERK1/2 phosphorylation assay, microarray gene expression analysis, qPCR validation\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — comparative signaling assays with microarray plus protein readout, single lab\",\n      \"pmids\": [\"23707615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PHLPP1 phosphatase deficiency leads to increased FGF18 expression via a FoxO1-dependent mechanism, and elevated FGF18 drives increased MEK/ERK activity and chondrocyte metabolic activity. Chemical inhibition of FGFR signaling abrogated the elevated ERK1/2 phosphorylation in Phlpp1-null cultures, placing FGF18/FGFR downstream of PHLPP1/FoxO1.\",\n      \"method\": \"Phlpp1−/− knockout mice and chondrocyte cultures, FGFR chemical inhibitor epistasis, phosphorylation assays (Akt2, PKC, p70S6K, ERK1/2), metabolic activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus pharmacological epistasis, single lab\",\n      \"pmids\": [\"25953896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A Shh-Foxf-Fgf18-Shh circuit operates in palate development: Foxf1 and Foxf2 repress Fgf18 expression in palatal mesenchyme downstream of Shh signaling; elevated FGF18 (in Foxf mutants) inhibits Shh expression in the palatal epithelium. Exogenous FGF18 protein added to cultured palatal explants directly inhibited Shh expression.\",\n      \"method\": \"Tissue-specific Cre/loxP Foxf1/Foxf2 conditional knockouts in neural crest cells, RNA-seq, whole mount in situ hybridization, palatal explant culture with exogenous FGF18 protein\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple conditional KOs plus direct protein rescue/inhibition experiment in explant culture\",\n      \"pmids\": [\"26745863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FGF9 and FGF18 redundantly regulate all stages of skeletogenesis; compound loss of Fgf9 and Fgf18 alleles reveals variable potency along the proximodistal limb axis and affects expression of IHH, PTHrP, and RUNX2, placing FGF9/18 signaling upstream of these skeletal regulators.\",\n      \"method\": \"Combined Fgf9/Fgf18 null allele series, skeletal analysis, gene expression analysis\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic compound genetic analysis across multiple allele combinations, replicates and extends prior KO findings\",\n      \"pmids\": [\"26794256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"FGF9 and FGF18 promote survival and migration of human lung fibroblasts and inhibit TGFβ1-induced myofibroblast differentiation partially through FGFR3 (siRNA knockdown of FGFR3 impaired p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration).\",\n      \"method\": \"Primary human lung fibroblast cultures, siRNA knockdown of FGFR isoforms, ERK phosphorylation assay, apoptosis assay, migration assay, differentiation markers\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA receptor knockdown with multiple functional readouts, single lab\",\n      \"pmids\": [\"26773067\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FGF18 activates the AKT/GSK3β/β-catenin signaling pathway in breast cancer cells, promoting EMT and cell migration. FGF18 increased Akt-Ser473 and Thr308 phosphorylation and GSK3β-Ser9 phosphorylation; β-catenin bound to target gene promoters was confirmed by ChIP.\",\n      \"method\": \"Western blotting (phosphorylation assays), wound-healing migration assay, chromatin immunoprecipitation (ChIP), clonogenicity assay\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple signaling assays plus ChIP, single lab\",\n      \"pmids\": [\"30196303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FGF18 promotes angiogenesis in hepatocellular carcinoma by enhancing Wnt/β-catenin-mediated FGF18 expression via RPS15A; FGF18 binds FGFR3 on endothelial cells to activate AKT and ERK pathways.\",\n      \"method\": \"HCC cell line co-culture with endothelial cells, RPS15A overexpression/knockdown, in vivo xenograft, western blotting (AKT/ERK phosphorylation)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo plus in vitro experiments with defined signaling readouts, single lab\",\n      \"pmids\": [\"29242604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FGF18 is required for acetylcholine receptor (AChR) clustering and neuromuscular junction (NMJ) formation. FGF18 is expressed in spinal motor neurons and localized at NMJs. Fgf18−/− embryos show reduced NMJ size, simplified motor endplates, reduced Chrne and Colq expression, and low-amplitude miniature endplate potentials. In C2C12 myotubes, FGF18 enhanced AChR clustering via FGFR and MEK1 signaling.\",\n      \"method\": \"Fgf18−/− knockout mice, laser capture microdissection, immunofluorescence localization, electrophysiology (mEPP recording), C2C12 cell AChR clustering assay with FGFR/MEK1 inhibitors\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with ultrastructural + electrophysiological + molecular readouts, plus in vitro mechanistic dissection with pharmacological inhibitors\",\n      \"pmids\": [\"29323161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FGF18-FGFR2 signaling activates the c-Jun–YAP1 axis in gastric cancer: stimulation of FGFR2 with recombinant FGF18 induces F-actin formation, nuclear accumulation of YAP1, and overexpression of YAP1 targets, effects attenuated by FGFR2 depletion or AZD4547. FGF18-FGFR2 upregulates YAP1 through c-Jun, an effector of MAPK signaling.\",\n      \"method\": \"Recombinant FGF18 stimulation, FGFR2 siRNA knockdown, AZD4547 pharmacological inhibition, RNA-seq, immunofluorescence of YAP1 nuclear translocation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition with defined molecular pathway readouts, single lab\",\n      \"pmids\": [\"32934314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sprifermin (rhFGF18) is transiently internalized in chondrocytes through clathrin- and dynamin-independent endocytosis, is intracellularly degraded together with FGFR3, causing receptor desensitization. Receptor activation is not required for sprifermin endocytosis. Removal of sprifermin allows re-sensitization of cells.\",\n      \"method\": \"Western blot, cell staining for endocytic pathway markers, ERK1/2 activation assay, pharmacological inhibition of clathrin/dynamin pathways\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inhibitor/marker experiments identifying endocytic route, single lab\",\n      \"pmids\": [\"32798495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TGF-β signaling in neural crest-derived perimysial fibroblasts, cooperating with transcription factor Creb5, activates Fgf18 expression to support pharyngeal muscle development. Exogenous FGF18 partially rescues myogenic cell numbers in Osr2 mutants lacking TGF-β signaling.\",\n      \"method\": \"Conditional Osr2-Cre TGF-β signaling knockouts, single-cell RNAseq, in vivo exogenous FGF18 rescue, in situ hybridization\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with conditional KO plus in vivo rescue experiment and single-cell transcriptomics, multiple methods\",\n      \"pmids\": [\"36542062\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC7 promotes FGF18 expression via reducing β-catenin acetylation at Lys49 and phosphorylation at Ser45, facilitating nuclear translocation of β-catenin which then activates FGF18 transcription through TCF4 binding. USP10 deubiquitinase interacts with and stabilizes HDAC7.\",\n      \"method\": \"Co-immunoprecipitation, western blotting for post-translational modifications, lentiviral overexpression/knockdown in vivo and in vitro, gene rescue experiments\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus PTM analysis plus rescue experiments, single lab\",\n      \"pmids\": [\"35277183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FGF18 secreted by hepatic stellate cells alleviates hepatic ischemia-reperfusion injury through the USP16/KEAP1/Nrf2 pathway: FGF18 reduces USP16 levels, leading to increased ubiquitination of KEAP1 and activation of Nrf2. USP16 interacts with and deubiquitinates KEAP1, and Nrf2 directly binds the USP16 promoter, forming a negative feedback loop.\",\n      \"method\": \"HSC-specific FGF18 deletion, Co-IP (USP16-KEAP1), ubiquitination assays, ChIP (Nrf2 binding to USP16 promoter), western blotting\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO plus Co-IP plus ubiquitination assay plus ChIP, multiple orthogonal methods, identifies complete pathway\",\n      \"pmids\": [\"37777507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FGF18 promotes human lung branching morphogenesis by regulating mesenchymal progenitor cells: FGF18 treatment of human fetal lung explants promotes branching, increases epithelial proliferation, maintains SOX2/SOX9 double-positive distal bud progenitors, and increases expression of SOX9, FN1, and COL2A1 in mesenchyme.\",\n      \"method\": \"Human fetal lung explant culture (air-liquid interface), recombinant FGF18 protein treatment, immunofluorescence, gene expression analysis\",\n      \"journal\": \"American journal of physiology. Lung cellular and molecular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct gain-of-function in human tissue explants with multiple molecular readouts, single lab\",\n      \"pmids\": [\"36791060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"BUB1 promotes FGF18 expression by interacting with METTL3 to induce m6A methylation of TRAF6 mRNA, thereby activating the NF-κB/FGF18 transcriptional axis in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (BUB1-METTL3), MeRIP-qPCR (m6A of TRAF6), RNA-seq, western blotting, siRNA/overexpression in vivo and in vitro\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus m6A sequencing assay plus functional rescue, single lab\",\n      \"pmids\": [\"39025206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"FGF18 facilitates intercellular communication between hepatic stellate cells and myofibroblasts in liver fibrosis by efficiently inducing osteopontin (Spp1/OPN) expression in culture-activated αSMA+ HSCs (but not in quiescent HSCs); OPN in turn upregulates profibrotic genes in quiescent HSCs. FGF18 and TGFβ synergistically increase OPN expression. Myofibroblast-derived Spp1 signals back to HSCs, forming a feedforward fibrotic loop.\",\n      \"method\": \"In vitro HSC/myofibroblast cultures (activated vs. quiescent), FGF18 and TGFβ stimulation, immunohistochemistry, cell-cell communication analysis of murine liver fibrosis models\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic cell culture experiments plus in vivo fibrosis model analysis, single lab\",\n      \"pmids\": [\"40678531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FGF18 expressed in the distal limb mesenchyme induces premature expression of myogenic determination genes Myf5 and MyoD in chick limb myoblasts via ERK MAP kinase signaling (not PI3K). Retinoic acid inhibits the myogenic activity of FGF18, and blocking RA signaling allows premature FGF18-induced MyoD expression.\",\n      \"method\": \"Chick limb bud explant/electroporation assays, pharmacological inhibition of ERK/PI3K, retinoic acid addition/inhibition, in situ hybridization for myogenic genes\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological dissection experiments in embryonic tissue, single lab\",\n      \"pmids\": [\"25446536\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FGF18 is a secreted glycoprotein that signals primarily through FGFR3 (and also FGFR2c) to regulate skeletal development, hair follicle cycling, lung alveologenesis, NMJ formation, and diverse cancer-related processes by activating ERK, p38 MAPK, AKT/GSK3β/β-catenin, and FGFR-dependent pathways; its transcription is directly controlled by β-catenin/TCF-Runx2 complexes, calcineurin/NFAT4, Foxp1, Glis3, Creb5/TGF-β, and HDAC7/β-catenin, while its extracellular activity is modulated by perlecan domain III binding and by the co-receptor Cfr (which is antagonized by Dlk), and following receptor activation sprifermin/FGF18 undergoes clathrin- and dynamin-independent endocytosis leading to FGFR3 co-degradation and transient cellular desensitization.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FGF18 is a secreted, glycosylated signaling protein that acts as a paracrine and autocrine growth factor coordinating skeletal, epithelial, neuromuscular, and tissue-repair programs [#0, #1]. It binds selectively to FGFR3c and FGFR2c, but not FGFR1c, and engages these receptors in a heparan sulfate–dependent manner to activate ERK, p38 MAPK, and AKT/GSK3\\u03b2/\\u03b2-catenin signaling [#1, #4, #8]. In the skeleton FGF18 is a positive regulator of osteogenesis and a context-dependent regulator of chondrogenesis: knockout mice show delayed suture closure and altered chondrocyte proliferation, and FGF18 drives osteoblast/chondrocyte proliferation through ERK (and p38 in chondrocytes), promotes osteoclast formation via RANKL/COX-2, suppresses noggin to enhance BMP-dependent chondrogenesis, and is required for VEGF-driven growth plate vascularization [#2, #3, #6, #10]; it acts redundantly with FGF9 upstream of IHH, PTHrP, and RUNX2 [#20]. Beyond bone, FGF18 maintains hair follicle stem cell quiescence and the resting (telogen) phase of the hair cycle [#15, #16], is required for acetylcholine receptor clustering and neuromuscular junction formation via FGFR/MEK1 signaling [#24], promotes lung branching morphogenesis and alveologenesis [#7, #30], and regulates limb myogenesis through ERK-dependent induction of Myf5/MyoD [#33]. FGF18 transcription is a convergence point for multiple regulatory inputs, most prominently canonical Wnt signaling acting through a composite \\u03b2-catenin/TCF-Runx2 element in its promoter, as well as calcineurin/NFAT4, Glis3, Foxp1, Foxf1/2, and Creb5/TGF-\\u03b2 [#5, #6, #11, #13, #16, #19, #27]. Extracellular FGF18 activity is tuned by direct binding to perlecan domain III, which antagonizes its mitogenic effect, and by the co-receptor Cfr/Glg1, whose interaction with FGF18 is blocked by Dlk [#12, #14]. In cancers FGF18 promotes EMT, migration, and angiogenesis through AKT/GSK3\\u03b2/\\u03b2-catenin and FGFR2-driven c-Jun\\u2013YAP1 signaling [#22, #23, #25]. Following receptor activation, FGF18 (sprifermin) undergoes clathrin- and dynamin-independent endocytosis and is co-degraded with FGFR3, producing transient receptor desensitization [#26].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established FGF18 as a bona fide secreted signaling molecule with mitogenic/differentiation-inducing activity, defining the basic biochemical identity that all later mechanism rests on.\",\n      \"evidence\": \"Recombinant rat/murine FGF18 in neurite outgrowth and fibroblast proliferation assays plus in vivo overexpression\",\n      \"pmids\": [\"9660775\", \"9742123\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor specificity not yet defined\", \"In vivo target tissues identified phenomenologically without pathway dissection\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined FGF18 receptor selectivity and the core signaling outputs, answering which FGFRs transduce its signal and through which kinases.\",\n      \"evidence\": \"BIAcore binding to FGFR3c/FGFR2c vs FGFR1c, and ERK/p38 phosphorylation dissection in osteoblasts and chondrocytes with kinase inhibitors\",\n      \"pmids\": [\"12399108\", \"11741978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific receptor usage not resolved\", \"Heparan sulfate dependence quantified only indirectly\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrated the in vivo skeletal role, showing FGF18 is a positive osteogenic and negative chondrogenic regulator and resolving its physiological function in bone.\",\n      \"evidence\": \"Fgf18\\u2212/\\u2212 mice with histology and proliferation assays across calvaria and growth plate\",\n      \"pmids\": [\"11937494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating each effect not genetically assigned\", \"Opposite effects on osteoblasts vs chondrocytes mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed FGF18 transcription downstream of canonical Wnt/\\u03b2-catenin signaling and linked it to autocrine tumor growth, connecting a developmental pathway to cancer.\",\n      \"evidence\": \"Promoter reporter, EMSA for TCF4 sites, and FGF18 siRNA in colon cancer cells\",\n      \"pmids\": [\"14559787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composite promoter architecture not yet defined\", \"In vivo relevance of Wnt control not tested here\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Assigned FGFR3 as the functional receptor for FGF18 in chondrogenesis and showed FGF18 controls vascularization, integrating cartilage and bone development.\",\n      \"evidence\": \"FGFR3\\u2212/\\u2212 limb bud mesenchyme cultures and Fgf18\\u2212/\\u2212 analysis with VEGF in situ and explant rescue\",\n      \"pmids\": [\"15781473\", \"17014841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Contribution of FGFR2c not separated\", \"Downstream transcriptional effectors of VEGF induction unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Resolved the composite transcriptional mechanism by showing Runx2 forms a complex with Lef1/TCF4 on the FGF18 promoter, and that calcineurin/NFAT4 and Glis3 also drive its expression.\",\n      \"evidence\": \"Reporter, EMSA, Co-IP of Runx2-Lef1/TCF4, in vivo \\u03b2-catenin conditional KO; NFAT4 and Glis3 gain/loss-of-function\",\n      \"pmids\": [\"17158875\", \"15252029\", \"17488195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial logic of multiple inputs not integrated\", \"Cell-type specificity of each transcription factor not mapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified extracellular modulators of FGF18 activity, showing perlecan domain III directly binds and antagonizes it and that the co-receptor Cfr/Glg1 promotes signaling while Dlk competes Cfr away.\",\n      \"evidence\": \"Kd binding/domain mapping with recombinant perlecan; Cfr KO epistasis, Co-IP (Cfr-FGF18, Cfr-Dlk), Ba/F3 proliferation\",\n      \"pmids\": [\"17971291\", \"20023171\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of perlecan and Cfr binding unknown\", \"How Cfr couples to FGFR3 mechanistically unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established FGF18 as the effector maintaining hair follicle stem cell quiescence and resolved its upstream control by Foxp1, ordering the niche signaling pathway.\",\n      \"evidence\": \"Conditional Fgf18 and Foxp1 KO with FGF18 rescue of Foxp1-null phenotype and in vivo protein delivery\",\n      \"pmids\": [\"22297635\", \"23946441\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating quiescence signal not identified\", \"Downstream effectors of FGF18 in stem cells unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended FGF18 into craniofacial and limb developmental circuits, defining Shh-Foxf-Fgf18 feedback and FGF9/18 redundancy upstream of IHH/PTHrP/RUNX2.\",\n      \"evidence\": \"Conditional Foxf1/2 KO with explant FGF18 inhibition of Shh; combined Fgf9/Fgf18 allele series\",\n      \"pmids\": [\"26745863\", \"26794256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor specificity in palate not assigned\", \"Quantitative contribution of FGF9 vs FGF18 at each site unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a neuromuscular role, showing motor-neuron FGF18 is required for AChR clustering and NMJ maturation through FGFR/MEK1, broadening FGF18 function beyond mesenchyme.\",\n      \"evidence\": \"Fgf18\\u2212/\\u2212 mice with electrophysiology and ultrastructure plus C2C12 clustering assay with FGFR/MEK1 inhibitors\",\n      \"pmids\": [\"29323161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific FGFR isoform at the NMJ not identified\", \"Link to AChR clustering machinery (MuSK/agrin) not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined cancer-associated signaling outputs, showing FGF18-FGFR2 drives a c-Jun\\u2013YAP1 axis and that FGF18/sprifermin desensitizes cells via endocytic co-degradation with FGFR3.\",\n      \"evidence\": \"FGFR2 siRNA/AZD4547 with YAP1 readouts; endocytosis tracing with clathrin/dynamin inhibitors and FGFR3 degradation assays\",\n      \"pmids\": [\"32934314\", \"32798495\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endocytic receptor for ligand uptake unidentified\", \"Whether FGFR2-YAP1 axis operates outside gastric cancer untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established FGF18 as a paracrine regulator of liver injury and fibrosis, acting through USP16/KEAP1/Nrf2 protection and an OPN-mediated feedforward fibrotic loop.\",\n      \"evidence\": \"HSC-specific FGF18 deletion, Co-IP and ubiquitination assays, ChIP, and activated vs quiescent HSC cultures\",\n      \"pmids\": [\"37777507\", \"40678531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor mediating hepatic FGF18 effects not defined\", \"Whether protective and profibrotic roles depend on injury context unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How FGF18's distinct downstream programs (ERK proliferation vs AKT/\\u03b2-catenin EMT vs YAP1 vs Nrf2) are selected in a given cell, and which FGFR isoform mediates each non-skeletal function, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking receptor choice to pathway output\", \"Structural mechanism of receptor/co-receptor selectivity uncharacterized\", \"Endocytic uptake receptor for sprifermin unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 4, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 4, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1, 29]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 8, 22, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 10, 20, 24, 30]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 22, 23, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FGFR3\", \"FGFR2\", \"HSPG2\", \"GLG1\", \"DLK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}