Affinage

SOSTDC1

Sclerostin domain-containing protein 1 · UniProt Q6X4U4

Length
206 aa
Mass
23.3 kDa
Annotated
2026-06-10
55 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SOSTDC1 (USAG-1/Wise/ectodin) is a secreted DAN-family protein that acts as a dual extracellular antagonist of BMP and Wnt signaling to pattern epithelial appendages and protect tissues (PMID:15020244, PMID:20724449). It directly binds BMPs and blocks BMP-mediated receptor activation, exhibiting ligand selectivity for BMP-7 while sparing BMP-2 and Wnt3a (PMID:15020244, PMID:21113658), and it inhibits LRP5/6-dependent Wnt/β-catenin signaling, with reciprocal Lrp5/Lrp6 dosage reduction rescuing its loss-of-function phenotypes (PMID:20724449). Potent BMP antagonism is mechanistically tied to its formation of a stable non-covalent dimer, distinguishing it from the weak monomeric antagonist SOST (PMID:32779697). Through these two pathways SOSTDC1 limits tooth number by promoting apoptosis of odontogenic mesenchyme downstream of enhanced BMP and Wnt signaling (PMID:17555714, PMID:18329379, PMID:24816837), suppresses ectopic skin appendage and digit formation (PMID:22509524, PMID:23994639), and confers renoprotection by restraining BMP-7 signaling in distal tubules, such that its loss attenuates acute, chronic, and Alport-model kidney injury (PMID:16341262, PMID:20197625). SOSTDC1 also regulates immune cell fate cell-extrinsically, controlling NK cell maturation and driving follicular regulatory T cell differentiation by blocking the WNT-β-catenin axis (PMID:30814306, PMID:32820125). In cancer it generally restrains proliferation, acting through canonical and non-canonical (c-Jun/JNK) BMP outputs and an ALCAM/CD166-Src-PI3K/AKT interaction that maintains stem-cell traits (PMID:32801337, PMID:31815038), and it acquires distinct non-secreted roles: nuclear translocation to stabilize CHD1 and promote homologous-recombination repair (PMID:38864559), and promotion of ferroptosis by competitively disrupting the HSPA5-GPX4 chaperone axis (PMID:42177164).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2004 High

    Established the founding biochemical identity of SOSTDC1 as a direct BMP-binding antagonist, defining the molecular basis for all later signaling work.

    Evidence Recombinant protein binding and alkaline phosphatase assays in C2C12 cells plus Xenopus mRNA injection

    PMID:15020244

    Open questions at the time
    • Which specific BMP ligands are bound was not resolved
    • No structural basis for the binding interface
  2. 2005 High

    Placed SOSTDC1 genetically upstream of BMP-7 in vivo, showing it is the central BMP regulator conferring renoprotection.

    Evidence USAG-1-null mice with Smad phosphorylation readout and BMP-7 neutralizing antibody rescue in acute and chronic renal injury

    PMID:16341262

    Open questions at the time
    • Cell-type origin of the protective effect not dissected
    • Downstream effectors of renoprotection not identified here
  3. 2007 Medium

    Linked SOSTDC1 expression topography to its functional partner BMP-7 in both kidney and tooth, supporting a localized antagonism model.

    Evidence Immunohistochemistry and in situ hybridization across kidney development/injury and incisor primordia with apoptosis assays

    PMID:17555714 PMID:17943079

    Open questions at the time
    • Colocalization does not prove direct local antagonism
    • Apoptotic mechanism downstream of BMP not fully mapped
  4. 2010 High

    Resolved the dual-pathway logic by demonstrating SOSTDC1 inhibits LRP5/6-dependent Wnt signaling in tooth development, with reciprocal genetic epistasis.

    Evidence Wise-null mice rescued by Lrp5/Lrp6 dosage reduction, gain-of-function overexpression, and Fgf/Shh downstream readouts

    PMID:20724449

    Open questions at the time
    • Direct biochemical SOSTDC1-LRP5/6 interaction not shown here
    • Quantitative balance between BMP and Wnt inhibition unclear
  5. 2010 High

    Demonstrated ligand-selective BMP-7 antagonism and an effector (MMP-12) connecting SOSTDC1 loss to disease attenuation in the kidney.

    Evidence Recombinant SOSTDC1 selectivity assays in breast cancer cells and Col4a3/USAG-1 double-knockout Alport mice with mesangial MMP-12 assays

    PMID:20197625 PMID:21113658

    Open questions at the time
    • Structural determinant of BMP-7 selectivity not defined
    • Tubule-to-glomerulus crosstalk mechanism inferred
  6. 2014 High

    Confirmed BMP-7 as the functional ligand in tooth development through ligand-supplementation rescue.

    Evidence BMP-7 supplementation in USAG-1 mutant incisor explants and subrenal capsule transplants with Smad/Msx1/Dlx2 readouts

    PMID:24816837

    Open questions at the time
    • Relative Wnt contribution in this context not quantified
  7. 2014 Medium

    Identified upstream transcriptional and epigenetic control of SOSTDC1, explaining its silencing in cancer.

    Evidence E4BP4 promoter luciferase, bisulfite sequencing, shRNA and 5'-Aza-dC in breast cancer cells

    PMID:25338303

    Open questions at the time
    • Generality of E4BP4 regulation across tissues unknown
    • Whether methylation alone or with E4BP4 dominates silencing unclear
  8. 2012 Medium

    Extended SOSTDC1 function to skin appendage and metabolic patterning, showing tissue-specific dominance of Wnt versus BMP outputs.

    Evidence Sostdc1-null mice analyzed for hair follicle/mammary placodes (Wnt) and pancreatic islet insulin secretion (BMP target genes)

    PMID:22509524 PMID:22829579

    Open questions at the time
    • Mechanism of pathway choice per tissue not defined
    • Direct receptor interactions not tested
  9. 2013 High

    Revealed redundancy with Sost and a Wnt-SHH-Gli3 epistatic network governing digit patterning.

    Evidence Sost/Sostdc1 single and double knockouts with Sox9, Gli1, Gli3 expression analysis

    PMID:23994639

    Open questions at the time
    • Direct molecular link between SOSTDC1 and SHH/Gli not established
    • Non-cell-autonomous signal mediator unidentified
  10. 2016 Medium

    Established SOSTDC1 roles in bone via MSC quiescence and antagonistic interplay with RUNX2 in tooth, broadening the regulatory network.

    Evidence Sostdc1-/- fracture callus MSC quantification and Usag-1/Runx2 double-knockout tooth phenotyping

    PMID:27102547 PMID:27518316

    Open questions at the time
    • Direct RUNX2-SOSTDC1 regulatory mechanism not biochemically mapped
    • MSC-intrinsic versus niche effects not separated
  11. 2017 Medium

    Characterized SOSTDC1 tumor-suppressive outputs through cell-cycle and kinase-pathway control across multiple cancers.

    Evidence Overexpression in thyroid and NSCLC cells with cyclin/p21/p27/Rb/E2F and PI3K/Akt, MAPK/Erk readouts

    PMID:26378658 PMID:27087917 PMID:28551845

    Open questions at the time
    • Whether effects are secreted-antagonist or intracellular not resolved
    • Direct upstream receptor for these signals not identified
  12. 2019 High

    Uncovered cell-extrinsic immune regulation by SOSTDC1, controlling NK maturation and TFR differentiation via Wnt-β-catenin.

    Evidence Sostdc1-/- and conditional KO mice, reciprocal bone marrow transplants, fate tracking, and WNT pathway analysis

    PMID:30814306 PMID:32820125

    Open questions at the time
    • Receptor mediating immune-cell effects not defined
    • Whether BMP also contributes in immune contexts unclear
  13. 2019 High

    Expanded the mechanistic repertoire to non-canonical and receptor-coupled signaling, including a direct ALCAM/CD166 interaction driving stem-cell traits.

    Evidence Co-IP/MS/confocal/competition ELISA mapping SOSTDC1-ALCAM, domain mapping, and c-Jun/JNK rescue in gastric cancer; transgenic Sertoli BMP-Smad apoptosis; myeloma-osteoblast contact-dependent co-culture

    PMID:30776499 PMID:31391487 PMID:31815038 PMID:32801337

    Open questions at the time
    • How secreted-antagonist and ALCAM-receptor roles are integrated unknown
    • Structural basis of ALCAM binding not solved
  14. 2020 High

    Provided the biophysical basis for antagonist potency by showing SOSTDC1 functions as a stable dimer within the DAN family.

    Evidence SEC-MALS, analytical ultracentrifugation, non-denaturing PAGE, and cell-based BMP/GDF5 inhibition assays comparing dimeric SOSTDC1 to monomeric SOST

    PMID:32779697

    Open questions at the time
    • High-resolution structure of the SOSTDC1-BMP complex absent
    • Dimer interface residues not defined
  15. 2021 Medium

    Demonstrated therapeutic feasibility of SOSTDC1 silencing to rescue congenital tooth agenesis.

    Evidence In vivo Usag-1 siRNA delivery via cationized gelatin and renal capsule transplantation in Runx2-KO mice

    PMID:34211084

    Open questions at the time
    • Durability and off-target effects of silencing not assessed
    • Translation to human odontogenesis untested
  16. 2024 Medium

    Revealed an unexpected intracellular, nuclear function whereby SOSTDC1 stabilizes CHD1 to promote DNA repair and chemoresistance.

    Evidence Nuclear fractionation, importin-α-dependent translocation, SOSTDC1-CHD1 and SOSTDC1-β-TrCP Co-IP, and HR repair/BTIC assays after Olaparib

    PMID:38864559

    Open questions at the time
    • How a secreted protein accesses the nucleus mechanistically unclear
    • Single lab; reciprocal validation of CHD1 stabilization limited
  17. 2025 Medium

    Connected T-cell-derived SOSTDC1 to systemic metabolism through adipocyte LRP5/6-β-catenin signaling.

    Evidence T cell-specific Sostdc1 KO mice under obesity challenge with adipocyte Wnt pathway and TCR-stimulation secretion assays

    PMID:40173040

    Open questions at the time
    • Direct SOSTDC1-LRP5/6 binding in adipocytes not shown
    • Relative role versus BMP in adipose unclear
  18. 2026 High

    Identified a chaperone-disrupting, pro-ferroptotic activity, showing SOSTDC1 competitively binds HSPA5 to destabilize GPX4 in kidney injury.

    Evidence USAG-1 KO mice, USAG-1-HSPA5 and HSPA5-GPX4 Co-IP, truncation mutagenesis, ferroptosis/GPX4 stability assays, and human transplant biopsies

    PMID:42177164

    Open questions at the time
    • How extracellular antagonist activity relates to this intracellular axis unresolved
    • Structural HSPA5-binding determinant only mapped by truncation

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how SOSTDC1's distinct secreted-antagonist, receptor-coupled (ALCAM), nuclear (CHD1), and chaperone-disrupting (HSPA5) activities are spatially and functionally coordinated within a single cell.
  • No unifying model integrating extracellular and intracellular roles
  • No high-resolution structure of SOSTDC1 with any partner
  • Mechanism switching between secretion and nuclear translocation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140313 molecular sequestering activity 3
Localization
GO:0005576 extracellular region 3 GO:0005634 nucleus 1
Pathway
R-HSA-1266738 Developmental Biology 4 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 1
Partners
ALCAMBMP7BTRCCHD1GPX4HSPA5LRP5LRP6

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 USAG-1/SOSTDC1 recombinant protein directly binds BMPs and antagonizes BMP-mediated induction of alkaline phosphatase in C2C12 cells; injection of USAG-1 mRNA into Xenopus embryos induces secondary axis formation and hyperdorsalization, establishing it as a BMP antagonist. Recombinant protein binding assay, alkaline phosphatase in vitro cell assay, Xenopus mRNA injection Biochemical and biophysical research communications High 15020244
2005 USAG-1/SOSTDC1 is the central negative regulator of BMP function in the kidney; USAG-1-null mice show enhanced phosphorylation of Smad proteins (BMP signaling) and are resistant to acute and chronic renal injury; neutralizing antibody against BMP-7 abolishes renoprotection in USAG-1-null mice, placing USAG-1 upstream of BMP-7 in renal injury signaling. Knockout mouse model, Smad phosphorylation assay, neutralizing antibody treatment in vivo The Journal of clinical investigation High 16341262
2007 USAG-1/SOSTDC1 is localized in distal renal tubules overlapping with BMP-7 expression; its expression ratio to BMP-7 increases dramatically during later kidney development and after renal regeneration, consistent with its role as the BMP-7 regulatory counterpart in kidney. Immunohistochemistry, in situ hybridization, expression analysis during kidney development and injury models Kidney international Medium 17943079
2007 USAG-1/SOSTDC1 is expressed in the epithelium and mesenchyme of the rudimentary maxillary incisor and its abrogation rescues apoptotic elimination of odontogenic mesenchymal cells, leading to supernumerary tooth formation; USAG-1 controls tooth number by regulating apoptosis in this region. Knockout mouse model, localization by in situ hybridization/immunohistochemistry, apoptosis assays Biochemical and biophysical research communications Medium 17555714
2008 In USAG-1/SOSTDC1-null mice, BMP signaling (assessed by Msx1, Dlx2 expression and Smad phosphorylation) is significantly enhanced in the rudimentary maxillary incisor; Wnt signaling (nuclear β-catenin) is also upregulated; inhibition of BMP signaling in explant culture rescues supernumerary tooth formation, demonstrating that enhanced BMP signaling drives the supernumerary tooth phenotype downstream of USAG-1 loss. Knockout mouse model, Smad phosphorylation assay, β-catenin nuclear localization, BMP inhibitor rescue in explant culture Biochemical and biophysical research communications High 18329379
2009 SOSTDC1 expressed in dental mesenchyme limits supernumerary incisor induction; reducing mesenchymal tissue around tooth germs in vitro phenocopies the Sostdc1-null extra incisor; both Noggin and Dkk1 individually prevent extra incisor formation, demonstrating that inhibition of both BMP and Wnt signaling contribute to the inhibitory role of dental mesenchyme. Sostdc1-null mouse model, in vitro organ culture with tissue reduction, Noggin and Dkk1 treatment rescue experiments Development (Cambridge, England) High 19141669
2010 SOSTDC1/Wise inhibits Lrp5- and Lrp6-dependent Wnt signaling in tooth development; genetic reduction of Lrp5 and Lrp6 dosage rescues the Wise-null tooth phenotypes (supernumerary teeth); ectopic Wise reduces Wnt signaling and tooth number; Fgf and Shh pathways are major downstream targets; Shh acts as a negative-feedback regulator of Wnt signaling to determine vestigial bud fate. Knockout and genetic dosage reduction (Lrp5/Lrp6 hypomorphs), gain-of-function Wise overexpression, epistasis analysis Development (Cambridge, England) High 20724449
2010 Loss of USAG-1/SOSTDC1 in Col4a3-/- (Alport syndrome) mice substantially attenuates disease progression and normalizes glomerular basement membrane ultrastructure; USAG-1 and BMP-7 colocalize in the macula densa of distal tubules; in cultured mesangial cells, BMP-7 attenuates and USAG-1 enhances MMP-12 expression, suggesting USAG-1 promotes GBM degradation via crosstalk between tubules and glomerulus. Double-knockout mouse model, immunohistochemistry colocalization, cultured mesangial cell assay for MMP-12 expression The Journal of clinical investigation High 20197625
2010 Recombinant SOSTDC1 selectively blocks BMP-7-induced Smad phosphorylation in breast cancer cells without diminishing BMP-2 or Wnt3a-induced signaling, demonstrating ligand-selective BMP antagonism. Recombinant protein treatment of breast cancer cells, Western blot for Smad phosphorylation Breast cancer research and treatment Medium 21113658
2012 Loss of Sostdc1 in mammary gland, hair follicle, and vibrissa development increases placode number and size; Sostdc1 is essential for suppression of hair follicle fate in nipple epidermis; functions attributed largely to its ability to attenuate Wnt/β-catenin signaling. Sostdc1-null mouse model, developmental morphological and molecular analysis Developmental biology Medium 22509524
2012 Inactivation of Sostdc1 in adult pancreatic islets enhances insulin secretion and improves glucose homeostasis under high-fat diet conditions; this is associated with altered expression of BMP-responsive genes but not Wnt target genes in islets, indicating that Sostdc1 primarily regulates the BMP pathway in the murine pancreas. Global Sostdc1-knockout mouse model, high-fat diet metabolic challenge, BMP and Wnt target gene expression analysis in isolated islets American journal of physiology. Endocrinology and metabolism Medium 22829579
2013 Sost and Sostdc1 emerge through ancestral genome duplication with non-overlapping expression domains; in the limb, elevated Wnt signaling in Sost-/-; Sostdc1-/- double-null mice causes misregulation of SHH signaling, ectopic activation of Sox9 in the digit 1 field, and preaxial polydactyly in a Gli1- and Gli3-dependent manner, demonstrating genetic redundancy and epistasis between SOSTDC1, Wnt, SHH, and Gli3 pathways in digit patterning. Single and double knockout mouse models, gene expression analysis (Sox9, Gli1, Gli3), genetic epistasis Developmental biology High 23994639
2014 USAG-1/SOSTDC1 suppresses development of rudimentary incisors by antagonizing BMP-7; supplementation of BMP-7 to E15 USAG-1 mutant maxillary incisor primordia in explant culture and subrenal capsule transplantation rescues and promotes supernumerary tooth development, confirming USAG-1 as a functional BMP-7 antagonist in tooth development. Explant culture with BMP-7 supplementation, subrenal capsule transplantation, Smad phosphorylation and Msx1/Dlx2 expression assays PloS one High 24816837
2014 E4BP4 transcriptional repressor binds SOSTDC1 promoter and represses its expression in breast cancer cells; SOSTDC1 promoter is epigenetically silenced by CpG hypermethylation; shRNA knockdown of E4BP4 combined with demethylation (5'-Aza-dC) upregulates SOSTDC1 and inhibits cancer cell proliferation. Luciferase promoter assay, methylation-specific PCR, bisulfite sequencing, shRNA knockdown, 5'-Aza-dC demethylation Cellular oncology (Dordrecht, Netherlands) Medium 25338303
2015 Overexpression of SOSTDC1 in thyroid cancer cells inhibits proliferation and induces G1/S arrest by suppressing cyclin A2 and cyclin E2 expression. Ectopic overexpression in thyroid cancer cell lines, flow cytometry cell cycle analysis, Western blot for cyclin A2/E2, xenograft tumor growth assay Oncotarget Medium 26378658
2016 Sostdc1 marks periosteal mesenchymal stem cells (MSCs); Sostdc1-/- mice show >2-fold more MSCs in fracture callus at day 5 post-fracture, resulting in accelerated cartilage callus formation and faster bone remodeling, establishing Sostdc1 as a promoter of MSC quiescence in the periosteum. Sostdc1-/- mouse model, femoral fracture model, flow cytometry quantification of MSC populations, histology Bone Medium 27102547
2016 RUNX2 and USAG-1/SOSTDC1 act antagonistically during tooth development; double-null Usag-1-/-/Runx2-/- mice show reduced supernumerary teeth compared to Usag-1 null and further tooth development compared to Runx2 null; RUNX2 inhibits BMP and/or Wnt signaling regulated by USAG-1, while BMP signaling independently induces RUNX2 expression. Double-knockout mouse model, morphological phenotypic analysis, Sox2 immunostaining of odontogenic epithelial cells PloS one Medium 27518316
2016 SOSTDC1 overexpression in NSCLC cells increases p21Cip and p27Kip levels, decreases Rb phosphorylation, and reduces E2F transcription activity, inhibiting cancer cell proliferation. Ectopic overexpression in NSCLC cell lines, Western blot for p21/p27/Rb phosphorylation/E2F, in vitro proliferation and in vivo xenograft assays Cell & bioscience Medium 27087917
2017 SOSTDC1 overexpression in follicular thyroid cancer cells inhibits proliferation, migration, invasion, and EMT by inhibiting PI3K/Akt and MAPK/Erk signaling pathways. Ectopic overexpression in FTC cell lines, Western blot for PI3K/Akt and MAPK/Erk phosphorylation, in vitro invasion/migration assays, xenograft Molecular and cellular biochemistry Medium 28551845
2018 Shh positively regulates Sostdc1 expression in tooth development; reduction of Shh activity in vivo significantly reduces Sostdc1 expression; Sostdc1 loss and Shh suppression produce similar supernumerary cusp patterns; genetic interaction between Sostdc1 and Lrp (Wnt co-receptor) confirms that Shh inhibits cusp patterning through Wnt signaling via positive regulation of Sostdc1. In vivo Shh activity suppression, Sostdc1-/- and compound Sostdc1/Lrp mutant mice, molar cusp phenotypic analysis, expression analysis Journal of dental research Medium 30325689
2019 Sostdc1 regulates NK cell maturation in a cell-extrinsic manner from both non-hematopoietic and hematopoietic sources; Sostdc1-/- NK cells show higher Tcf7 and Lef1 levels (Wnt targets), decreased Id2 in immature and transitional NK cells, altered Ly49 receptor repertoire, and hyporesponsiveness against MHC class I-deficient targets; reciprocal bone marrow transplants demonstrate cell-extrinsic regulation. Sostdc1-/- mouse model, reciprocal bone marrow transplantation, flow cytometry, NK killing assays in vitro and in vivo, gene expression analysis Journal of immunology Medium 30814306
2019 Sostdc1 expressed in testicular Sertoli cells is a negative regulator of spermatogenesis; persistent transgenic expression of Sostdc1 in mature Sertoli cells causes reduced sperm counts; Sostdc1 selectively activates BMP target genes via phospho-Smad1/5/8 signaling in germ cells, leading to their apoptosis. Transgenic rat overexpression model, sperm count, Smad1/5/8 phosphorylation, apoptosis assays in germ cells Scientific reports Medium 31391487
2019 SOSTDC1 inhibits BMP4 to maintain cancer stem cell traits (SOX2, NANOG); SOSTDC1 associates with ALCAM/CD166 (confirmed by co-immunoprecipitation, mass spectrometry, confocal microscopy, and competition ELISA); interaction is mediated by the N-terminal region of SOSTDC1 containing a sequence similar to the ALCAM-binding motif of CD6; SOSTDC1-ALCAM interaction activates Src and PI3K/AKT signaling; ALCAM also interacts with α2β1 and α1β1 integrins, providing a link to Src activation. Co-immunoprecipitation, mass spectrometry, confocal microscopy, competition ELISA, domain-mapping with N-terminal SOSTDC1 region, siRNA knockdown, blocking antibodies, in vivo metastasis model Oncogene High 32801337
2019 The BMP antagonist SOSTDC1 restrains gastric cancer progression via inactivation of c-Jun (non-canonical BMP signaling) rather than canonical SMAD-dependent BMP pathway; JNK blockade attenuates cell proliferative and migratory advantages conferred by SOSTDC1 knockdown. SOSTDC1 knockdown/overexpression in gastric cancer cells, Western blot for c-Jun activation, JNK inhibitor rescue, lung metastasis in vivo model American journal of cancer research Medium 31815038
2019 Sostdc1, secreted when myeloma cells contact osteoblast lineage cells, inhibits both BMP2- and BMP7-mediated signaling and Wnt signaling in primary osteoblasts, suppressing their differentiation; Sostdc1 expression is induced in both cell types only when in direct contact. Co-culture of myeloma and osteoblast lineage cells, recombinant Sostdc1 treatment of primary osteoblasts, BMP and Wnt signaling assays, immunohistochemistry of in vivo 5TGM1 model bones Bone Medium 30776499
2020 SOSTDC1, secreted by a subset of follicular helper T (TFH) cells and T-B cell border fibroblastic reticular cells, blocks the WNT-β-catenin axis in follicular regulatory T (TFR) cells to facilitate their differentiation; Sostdc1 ablation in TFH cells substantially reduces TFR cell numbers and elevates germinal center responses. Reporter mice, fate tracking, transcriptome analysis, Sostdc1 conditional ablation in TFH cells, TFR cell quantification, WNT-β-catenin pathway analysis Science (New York, N.Y.) High 32820125
2020 SOSTDC1 forms a highly stable non-covalent dimer (unlike monomeric SOST); this dimeric state correlates with potent inhibition of multiple BMP signaling growth factors including GDF5 in a cell-based assay, while monomeric SOST is a very poor BMP antagonist, demonstrating that dimerization is mechanistically linked to BMP antagonism potency within the DAN family. Biophysical (SEC-MALS, analytical ultracentrifugation), biochemical (non-denaturing PAGE), structural techniques, cell-based BMP inhibition assay The Biochemical journal High 32779697
2021 Local application of Usag-1 siRNA loaded in cationized gelatin to mandibular tooth germs promotes tooth development in Runx2-knockout mice (which model congenital tooth agenesis); subrenal capsule transplantation experiments confirm that Usag-1 knockdown rescues arrested tooth formation caused by Runx2 deficiency. In vivo siRNA delivery with cationized gelatin, renal capsule transplantation, tooth morphology analysis in Runx2-KO mice Scientific reports Medium 34211084
2024 Following Olaparib treatment, SOSTDC1 translocates to the nucleus in an importin-α-dependent manner; nuclear SOSTDC1 interacts with the N-terminus of CHD1 (chromatin helicase DNA-binding factor) to promote homologous recombination (HR) repair and breast tumor-initiating cell (BTIC) maintenance; nuclear SOSTDC1 binds β-TrCP binding motifs on CHD1, blocking β-TrCP-mediated CHD1 ubiquitination and degradation. Nuclear fractionation, Co-immunoprecipitation (SOSTDC1-CHD1, SOSTDC1-β-TrCP), importin-α dependency assay, HR repair assays, BTIC functional assays, SOSTDC1 knockdown sensitization to Olaparib Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 38864559
2025 SOSTDC1 secreted by CD4+ T cells disrupts adipocyte lipid balance by promoting lipogenesis and inhibiting lipolysis through the LRP5/6-β-catenin pathway; T cell receptor (TCR) signaling amplifies SOSTDC1 secretion in CD4+ T cells; T cell-specific Sostdc1-deficient mice are protected against obesity-induced insulin resistance. T cell-specific KO mouse model, obesity/insulin resistance challenge, LRP5/6-β-catenin pathway analysis in adipocytes, TCR stimulation assays for SOSTDC1 secretion Cell reports Medium 40173040
2026 USAG-1/SOSTDC1 promotes ferroptosis in renal ischemia-reperfusion injury by competitively binding HSPA5 (a molecular chaperone), thereby disrupting the HSPA5-GPX4 interaction and destabilizing GPX4; USAG-1 truncation mutants that fail to bind HSPA5 do not promote GPX4 degradation or ferroptosis, confirming the USAG-1/HSPA5/GPX4 axis as the mechanistic basis. USAG-1 KO mouse model, Co-immunoprecipitation (USAG-1-HSPA5, HSPA5-GPX4), truncation mutagenesis of USAG-1, ferroptosis assays, GPX4 stability assays, human transplant kidney biopsies Cell death & disease High 42177164
2026 Rosuvastatin decreases USAG-1 expression by increasing HOXA13 expression (HOXA13 siRNA knockdown experiments implicate HOXA13 as the transcriptional regulator of USAG-1); decreased USAG-1 activates BMP-7-Smad1/5/9 signaling to attenuate renal tubulointerstitial fibrosis. In vivo UUO/ischemia-reperfusion model, HOXA13 siRNA knockdown in MDCK cells, Western blot for USAG-1/BMP-7/Smad1/5/9 phosphorylation Scientific reports Medium 42009708

Source papers

Stage 0 corpus · 55 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning. Development (Cambridge, England) 173 20724449
2005 Uterine sensitization-associated gene-1 (USAG-1), a novel BMP antagonist expressed in the kidney, accelerates tubular injury. The Journal of clinical investigation 122 16341262
2004 USAG-1: a bone morphogenetic protein antagonist abundantly expressed in the kidney. Biochemical and biophysical research communications 120 15020244
2009 Tinkering with the inductive mesenchyme: Sostdc1 uncovers the role of dental mesenchyme in limiting tooth induction. Development (Cambridge, England) 83 19141669
2010 Loss of the BMP antagonist USAG-1 ameliorates disease in a mouse model of the progressive hereditary kidney disease Alport syndrome. The Journal of clinical investigation 68 20197625
2007 Expression of BMP-7 and USAG-1 (a BMP antagonist) in kidney development and injury. Kidney international 66 17943079
2008 Enhanced BMP signaling results in supernumerary tooth formation in USAG-1 deficient mouse. Biochemical and biophysical research communications 57 18329379
2007 Rudiment incisors survive and erupt as supernumerary teeth as a result of USAG-1 abrogation. Biochemical and biophysical research communications 54 17555714
2012 Sostdc1 defines the size and number of skin appendage placodes. Developmental biology 50 22509524
2013 Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner. Developmental biology 47 23994639
2015 Down-regulation of SOSTDC1 promotes thyroid cancer cell proliferation via regulating cyclin A2 and cyclin E2. Oncotarget 40 26378658
2017 SOSTDC1 inhibits follicular thyroid cancer cell proliferation, migration, and EMT via suppressing PI3K/Akt and MAPK/Erk signaling pathways. Molecular and cellular biochemistry 39 28551845
2010 SOSTDC1 differentially modulates Smad and beta-catenin activation and is down-regulated in breast cancer. Breast cancer research and treatment 37 21113658
2012 Inactivation of the dual Bmp/Wnt inhibitor Sostdc1 enhances pancreatic islet function. American journal of physiology. Endocrinology and metabolism 35 22829579
2020 SOSTDC1-producing follicular helper T cells promote regulatory follicular T cell differentiation. Science (New York, N.Y.) 33 32820125
2016 Sostdc1 deficiency accelerates fracture healing by promoting the expansion of periosteal mesenchymal stem cells. Bone 33 27102547
2014 Interactions between BMP-7 and USAG-1 (uterine sensitization-associated gene-1) regulate supernumerary organ formations. PloS one 33 24816837
2009 Two candidate tumor suppressor genes, MEOX2 and SOSTDC1, identified in a 7p21 homozygous deletion region in a Wilms tumor. Genes, chromosomes & cancer 30 19760604
2014 E4BP4 is a repressor of epigenetically regulated SOSTDC1 expression in breast cancer cells. Cellular oncology (Dordrecht, Netherlands) 25 25338303
2020 SOSTDC1 promotes invasion and liver metastasis in colorectal cancer via interaction with ALCAM/CD166. Oncogene 24 32801337
2016 SOSTDC1 is down-regulated in non-small cell lung cancer and contributes to cancer cell proliferation. Cell & bioscience 24 27087917
2019 MiR-26a promotes fracture healing of nonunion rats possibly by targeting SOSTDC1 and further activating Wnt/β-catenin signaling pathway. Molecular and cellular biochemistry 20 31313025
2018 SOSTDC1 inhibits bone metastasis in non-small cell lung cancer and may serve as a clinical therapeutic target. International journal of molecular medicine 19 30320379
2016 Antagonistic Functions of USAG-1 and RUNX2 during Tooth Development. PloS one 19 27518316
2018 Shh Plays an Inhibitory Role in Cusp Patterning by Regulation of Sostdc1. Journal of dental research 18 30325689
2011 Contribution of the sclerostin domain-containing protein 1 (SOSTDC1) gene to normal variation of peak bone mineral density in Chinese women and men. Journal of bone and mineral metabolism 18 21221677
2021 Local application of Usag-1 siRNA can promote tooth regeneration in Runx2-deficient mice. Scientific reports 17 34211084
2010 Loss of heterozygosity and SOSTDC1 in adult and pediatric renal tumors. Journal of experimental & clinical cancer research : CR 17 21080955
2019 Febuxostat inhibits TGF‑β1‑induced epithelial‑mesenchymal transition via downregulation of USAG‑1 expression in Madin‑Darby canine kidney cells in vitro. Molecular medicine reports 14 30628645
2019 Sostdc1 Regulates NK Cell Maturation and Cytotoxicity. Journal of immunology (Baltimore, Md. : 1950) 14 30814306
2019 Differential expression of secreted factors SOSTDC1 and ADAMTS8 cause profibrotic changes in linear morphoea fibroblasts. The British journal of dermatology 13 30367460
2019 Sostdc1: A soluble BMP and Wnt antagonist that is induced by the interaction between myeloma cells and osteoblast lineage cells. Bone 13 30776499
2019 The BMP antagonist, SOSTDC1, restrains gastric cancer progression via inactivation of c-Jun signaling. American journal of cancer research 13 31815038
2015 Febuxostat Prevents Renal Interstitial Fibrosis by the Activation of BMP-7 Signaling and Inhibition of USAG-1 Expression in Rats. American journal of nephrology 13 26680283
2022 Role of Sostdc1 in skeletal biology and cancer. Frontiers in physiology 12 36338475
2022 Exosomal circ_0001190 Regulates the Progression of Gastric Cancer via miR-586/SOSTDC1 Axis. Biochemical genetics 10 35138469
2022 Sostdc1 Secreted from Cutaneous Lymphatic Vessels Acts as a Paracrine Factor for Hair Follicle Growth. Current issues in molecular biology 10 35678675
2021 lncRNA CDKN2A-AS1 facilitates tumorigenesis and progression of epithelial ovarian cancer via modulating the SOSTDC1-mediated BMP-SMAD signaling pathway. Cell cycle (Georgetown, Tex.) 9 34110955
2020 Characterization of the different oligomeric states of the DAN family antagonists SOSTDC1 and SOST. The Biochemical journal 9 32779697
2019 Downregulation of Sostdc1 in Testicular Sertoli Cells is Prerequisite for Onset of Robust Spermatogenesis at Puberty. Scientific reports 9 31391487
2025 SOSTDC1 downregulation in CD4+ T cells confers protection against obesity-induced insulin resistance. Cell reports 8 40173040
2023 MiR-22-3p facilitates bone marrow mesenchymal stem cell osteogenesis and fracture healing through the SOSTDC1-PI3K/AKT pathway. International journal of experimental pathology 8 38152045
2016 Effects of Usag-1 and Bmp7 deficiencies on murine tooth morphogenesis. BMC developmental biology 8 27178071
2025 MicroRNA-27a transfected dental pulp stem cells undergo odonto/osteogenic differentiation via targeting DKK3 and SOSTDC1 in Wnt/BMP signaling in vitro and enhance bone formation in vivo. Journal of translational medicine 6 39956898
2022 SOSTDC1 acts as a tumor inhibitor in acute myeloid leukemia by downregulating the Wnt/β-catenin pathway. Environmental toxicology 6 35442555
2024 SOSTDC1 Nuclear Translocation Facilitates BTIC Maintenance and CHD1-Mediated HR Repair to Promote Tumor Progression and Olaparib Resistance in TNBC. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 5 38864559
2018 Investigation of SOSTDC1 gene in non-syndromic patients with supernumerary teeth. Medicina oral, patologia oral y cirugia bucal 4 30148467
2007 Expression of uterine sensitization-associated gene-1 (USAG-1) in the mouse uterus during the peri-implantation period. The Journal of reproduction and development 4 17389776
2024 miR4352b a cross-species modulator of SOSTDC1, targets dual pathway to regulate bone health and fracture healing. Biochimica et biophysica acta. Molecular basis of disease 3 39326466
2019 Lack of association between PAX6/SOSTDC1/FAM20B gene polymorphisms and mesiodens. BMC oral health 3 31133012
2019 Sostdc1 is expressed in all major compartments of developing and adult mammalian eyes. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 2 31529323
2026 USAG-1 and Regenerative Dentistry, Therapeutic Implications and Future Directions: Review of the Literature. Clinical and experimental dental research 1 41632902
2026 Inhibition of USAG-1 improved delayed graft function in renal transplantation. Transplant immunology 0 41520687
2026 Rosuvastatin attenuates tubulointerstitial fibrosis by targeting the HOXA13 USAG1 BMP7 pathway. Scientific reports 0 42009708
2026 USAG-1 aggravates renal ischemia‒reperfusion injury via promoting GPX4 degradation-induced ferroptosis. Cell death & disease 0 42177164

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