Affinage

SOST

Sclerostin · UniProt Q9BQB4

Length
213 aa
Mass
24.0 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Sclerostin (SOST) is a secreted cystine-knot glycoprotein produced predominantly by osteocytes and osteoblast-lineage cells that acts as a paracrine negative regulator of bone formation (PMID:11181578, PMID:11179006, PMID:29750826). It functions by directly binding the extracellular domains of the Wnt co-receptors LRP5 and LRP6, disrupting Wnt-induced Frizzled-LRP complex formation and thereby suppressing canonical Wnt/β-catenin signaling (PMID:15908424); high-bone-mass LRP5 mutations that weaken this interaction render the receptor refractory to sclerostin inhibition (PMID:17052975), and Sost-deficiency-driven bone anabolism depends partially on LRP5 but fully on Wnt1-class LRP6 activity (PMID:23901037). Integrity of the cystine-knot motif and an intact signal peptide are required for sclerostin folding, secretion, and LRP5 binding (PMID:21221996, PMID:20583295). SOST transcription in osteocytes is controlled through a bone-specific enhancer ~35 kb downstream of the gene, where MEF2 transcription factors (MEF2A/C/D) drive expression (PMID:17696759); this enhancer region is the element deleted in van Buchem disease (PMID:11836356, PMID:12116252). SOST is positively regulated by BMP signaling acting through osteoblast/osteocyte BMPRIA and ACVR1 receptors (PMID:19874086, PMID:21945937, PMID:27402532) and is suppressed by mechanical loading and by PTH, the latter via a cAMP/PKA pathway that targets the MEF2-dependent enhancer rather than the promoter (PMID:15946907, PMID:17696759, PMID:18089564). Mechanically induced suppression of SOST is an obligatory step in load-induced osteogenesis: forced maintenance of SOST during loading abolishes the Wnt-driven bone formation response (PMID:22075208), and is transduced via the mechanosensitive channel Piezo1–Akt axis, COX-2/PGE2–EP4–ERK signaling, estrogen receptor β, periostin, and nitric oxide (PMID:31708103, PMID:21723865, PMID:23362266, PMID:19837663, PMID:24322886). Recessive loss-of-function SOST mutations cause sclerosteosis and van Buchem disease through unopposed Wnt signaling and bone overgrowth, while dominant-negative signal-peptide mutations that block secretion cause craniodiaphyseal dysplasia (PMID:11181578, PMID:11179006, PMID:11836356, PMID:12116252, PMID:21221996). Beyond bone, SOST has been implicated in limb digit patterning together with its paralog Sostdc1 (PMID:23994639) and in breast cancer bone metastasis via a STAT3 interaction (PMID:36581888).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2001 High

    Establishing that SOST encodes a secreted bone-formation inhibitor answered what gene underlies sclerosteosis and placed sclerostin in the cystine-knot factor family.

    Evidence Positional cloning and mutation analysis in sclerosteosis families with protein domain analysis

    PMID:11179006 PMID:11181578

    Open questions at the time
    • Molecular target of secreted sclerostin not yet identified
    • Cell of origin within bone not yet defined
  2. 2002 High

    Mapping van Buchem disease to a downstream non-coding deletion revealed that a distant cis-regulatory element, not the coding sequence, governs SOST expression in bone.

    Evidence Linkage analysis and deletion mapping in van Buchem families

    PMID:11836356 PMID:12116252

    Open questions at the time
    • Identity of the transcription factors acting on the enhancer not yet known
    • Tissue specificity of the element not yet dissected
  3. 2005 High

    Demonstrating direct binding of sclerostin to LRP5/LRP6 defined the molecular mechanism by which SOST inhibits bone formation—antagonism of canonical Wnt signaling.

    Evidence LRP extracellular-domain binding assays plus Xenopus and mammalian Wnt reporter assays

    PMID:15908424

    Open questions at the time
    • Relative contributions of LRP5 vs LRP6 in vivo not resolved
    • Structural basis of binding not determined
  4. 2006 High

    Showing that LRP5 high-bone-mass mutations reduce sclerostin binding mechanistically linked the SOST-LRP5 interaction directly to bone mass set-point.

    Evidence Binding and Wnt-inhibition assays comparing wild-type vs HBM mutant LRP5

    PMID:17052975

    Open questions at the time
    • Did not address LRP6 contribution
    • In vivo consequences of altered binding inferred not measured
  5. 2005 High

    Identifying that PTH suppresses SOST transcription via cAMP/PKA, independent of protein synthesis, established hormonal control of sclerostin as direct and transcriptional.

    Evidence In vivo PTH administration plus UMR-106 cell pharmacology with cycloheximide and PKA modulators

    PMID:15946907

    Open questions at the time
    • Transcription factor target downstream of PKA not identified in this study
    • Specific cis-element not localized here
  6. 2007 High

    Localizing MEF2 binding to the downstream bone enhancer connected the van Buchem regulatory region to its transcription factors and revealed PTH acts on the enhancer rather than the promoter.

    Evidence EMSA, reporter assays, siRNA knockdown of MEF2 isoforms, and bone co-localization

    PMID:17696759

    Open questions at the time
    • Upstream signals coupling PTH/PKA to MEF2 inactivation not fully defined
    • Chromatin context of enhancer not characterized
  7. 2007 High

    Showing that mechanical loading reduces and unloading increases osteocyte sclerostin established SOST as a strain-responsive regulator of bone formation.

    Evidence In vivo ulnar loading and hindlimb unloading with Sost mRNA and protein readouts

    PMID:18089564

    Open questions at the time
    • Mechanotransduction pathway upstream of Sost not yet identified
    • Whether suppression is required for osteogenesis not yet tested
  8. 2011 High

    Engineering persistent SOST during loading proved that sclerostin downregulation is an obligatory step for load-induced Wnt activation and bone formation.

    Evidence Ulnar loading of DMP1-driven SOST-transgenic mice with histomorphometry and Wnt target qPCR

    PMID:22075208

    Open questions at the time
    • Sensors and intermediate signaling not addressed in this model
    • Residual bone formation source not defined
  9. 2010 High

    Genetic and pharmacological dissection of BMP receptors established that BMP signaling through BMPRIA and ACVR1 positively regulates Sost expression, with osteocyte BMPR1A deletion nearly abolishing Sost.

    Evidence Conditional Bmpr1a and Acvr1 knockouts, BMP/Noggin treatment, Wnt reporters, and serum SOST ELISA

    PMID:19874086 PMID:21945937 PMID:27402532

    Open questions at the time
    • Direct BMP-responsive cis-elements in SOST not fully mapped in osteocytes
    • Differential downstream signaling for Sost vs Dkk1 partially characterized
  10. 2013 High

    Double-knockout and class-selective LRP6 antibody experiments resolved that Sost-deficiency anabolism depends only partially on LRP5 but fully on Wnt1-class LRP6 signaling.

    Evidence Sost-/-;Lrp5-/- mice with anti-LRP6 antibodies, microCT and histomorphometry

    PMID:23901037

    Open questions at the time
    • Ligand source for Wnt1-class signaling in bone not defined
    • Molecular reason for LRP6 dominance not established
  11. 2019 Medium

    Identifying Piezo1, PGE2/EP4-ERK, ERβ, periostin, and nitric oxide as mediators progressively mapped the mechanotransduction cascade that suppresses SOST in osteocytes.

    Evidence Pharmacological and genetic loss-of-function across osteocyte cell lines and loading/fluid-flow models

    PMID:19837663 PMID:21723865 PMID:23362266 PMID:24322886 PMID:31708103

    Open questions at the time
    • How these inputs converge on the MEF2 enhancer not integrated
    • Relative contribution of each pathway in vivo unclear
  12. 2016 Medium

    Defining the LRP6-dependent, N-cadherin-modulated PTH-PTH1R axis showed how PTH-induced SOST suppression is mechanistically wired in osteocytes.

    Evidence Osteoblast/osteocyte-specific Lrp6 and Cdh2 knockouts with iPTH challenge and LRP6-PTHR1 co-IP

    PMID:25847683 PMID:27723935

    Open questions at the time
    • Precise step where LRP6 couples to MEF2/HDAC regulation not resolved
    • Single-lab findings on N-cadherin modulation
  13. 2013 Medium

    Promoter-level studies extended SOST regulation to additional transcription factors and epigenetic inputs (RUNX2, Sirt1/H3K9 deacetylation, HIF-1α, DNA methylation, vitamin D).

    Evidence EMSA, ChIP, promoter-reporter, siRNA, and methylation analyses across osteosarcoma, osteocyte, and chondrocyte models

    PMID:14739291 PMID:21952235 PMID:23776575 PMID:26071314 PMID:26690786

    Open questions at the time
    • Many findings are single-lab and cell-line based
    • Integration with the dominant downstream enhancer not established
  14. 2011 Medium

    Functional analysis of secretion-defective mutants distinguished dominant-negative craniodiaphyseal dysplasia mutations from recessive loss-of-function alleles and established cystine-knot requirement for secretion and LRP5 binding.

    Evidence Transfection secretion assays, ER-retention, LRP5 binding and Wnt reporter assays for signal-peptide and Cys167Arg mutants

    PMID:20583295 PMID:21221996

    Open questions at the time
    • Dominant-negative mechanism on wild-type secretion not fully characterized
    • Single-study functional data
  15. 2018 High

    Cell-type-specific deletions established sclerostin's paracrine, non-endocrine mode of action and identified multiple osteoblast-lineage sources contributing to the bone microenvironment.

    Evidence Four Cre-driven conditional Sost knockouts with microCT, DXA, histomorphometry, and B-cell FACS

    PMID:29750826

    Open questions at the time
    • Molecular basis of paracrine vs endocrine restriction not defined
    • B-cell phenotype mechanism not resolved
  16. 2022 Medium

    Identifying non-skeletal roles—limb digit patterning with Sostdc1, joint MMP regulation, and a STAT3 interaction in cancer—broadened SOST function beyond bone Wnt antagonism.

    Evidence Compound knockouts with Shh/Gli epistasis, PTOA transgenic/KO models, and SOST-STAT3 Co-IP with metastasis assays

    PMID:23994639 PMID:29377313 PMID:36581888

    Open questions at the time
    • STAT3 interaction rests on a single-lab Co-IP in cancer context
    • Mechanistic depth of MMP and developmental roles limited

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse upstream regulators (mechanical, hormonal, BMP, epigenetic) converge on the MEF2-dependent downstream enhancer to set quantitative SOST output remains unresolved.
  • No integrated model linking signaling inputs to enhancer occupancy
  • Structural basis of sclerostin-LRP binding not in corpus
  • Non-bone functions need independent validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2
Partners
LRP5LRP6STAT3

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Loss-of-function mutations in the SOST gene (nonsense and splice site mutations) cause sclerosteosis, establishing that the SOST protein product (sclerostin) is a secreted negative regulator of bone formation. The protein contains a signal peptide and a cysteine-knot motif, placing it in the DAN family of cystine knot-containing factors. Positional cloning, mutation analysis in sclerosteosis patients, protein domain analysis Human molecular genetics / American journal of human genetics High 11179006 11181578
2002 Van Buchem disease is caused by a 52-kb deletion located ~35 kb downstream of the SOST gene (not within its coding region), establishing that this non-coding region contains a cis-regulatory element essential for SOST transcription in bone. Linkage analysis, deletion mapping, haplotype analysis in van Buchem families Journal of medical genetics / American journal of medical genetics High 11836356 12116252
2005 SOST/sclerostin antagonizes Wnt signaling by directly binding to the extracellular domain of the Wnt co-receptors LRP5 and LRP6, disrupting Wnt-induced Frizzled-LRP complex formation. Binding assays (LRP5/LRP6 extracellular domain binding), Xenopus embryo Wnt antagonism assay, mammalian cell Wnt reporter assays The Journal of biological chemistry High 15908424
2006 LRP5 high bone mass (HBM) mutations cluster in the extracellular domain and reduce LRP5 binding to SOST, rendering LRP5 more refractory to inhibition by sclerostin, mechanistically linking SOST-LRP5 antagonism to bone mass regulation. Binding assays comparing SOST interaction with wild-type vs. HBM mutant LRP5 proteins, functional Wnt inhibition assays The Journal of biological chemistry High 17052975
2005 PTH directly suppresses SOST transcription in vivo and in vitro via the cAMP/PKA pathway; the effect is not blocked by cycloheximide (indicating direct transcriptional regulation) and PTH does not alter SOST mRNA stability, pointing to transcriptional rather than post-transcriptional control. In vivo PTH administration (calvarial, systemic, intermittent) + qPCR; in vitro UMR-106 cell treatment with PTH, PKA/PKC pathway inhibitors/activators, cycloheximide, and PTH antagonist Bone High 15946907
2007 MEF2 transcription factors (MEF2A, MEF2C, MEF2D) bind a MEF2 response element in the SOST bone enhancer (within the 52-kb van Buchem deletion) to activate SOST transcription in osteocytes; PTH suppresses SOST by inhibiting this MEF2-dependent enhancer activity rather than the SOST promoter. Luciferase reporter assays, footprint/mutation analysis, gel retardation (EMSA), antibody supershift, siRNA knockdown of MEF2 isoforms, ISH/IHC co-localization in bone Journal of bone and mineral research High 17696759
2007 Mechanical loading (ulnar loading) dramatically reduces Sost mRNA and sclerostin protein in osteocytes in a strain-magnitude-dependent manner, while hindlimb unloading increases Sost expression, establishing osteocyte-expressed sclerostin as a mechanically regulated bone formation inhibitor. In vivo ulnar loading and hindlimb unloading models; ISH (Sost mRNA) and IHC (sclerostin protein) in mouse tibia/ulna The Journal of biological chemistry High 18089564
2011 Sost downregulation in osteocytes is an obligatory step in the mechanotransduction cascade: transgenic mice engineered to maintain high SOST expression during loading showed 70-85% reduction in load-induced bone formation and absence of Wnt target gene induction, demonstrating that sclerostin suppression is required to unleash local Wnt signaling for osteogenesis. In vivo ulnar loading in SOST-transgenic mice (DMP1-driven human SOST transgene) vs. wild-type; bone formation histomorphometry; Wnt target gene qPCR Bone High 22075208
2004 RUNX2/Cbfa1 binds the proximal SOST promoter and contributes to differential SOST expression in osteosarcoma cells, and an E-box binding motif in the 1.8-kb proximal SOST promoter is also functional in SAOS-2 cells. Gel shift (EMSA), transient transfection luciferase assays in osteosarcoma cell lines The Journal of biological chemistry Medium 14739291
2004 BMP-2, BMP-4, and BMP-6 induce SOST expression in human osteoblasts in a time- and dose-dependent manner; this effect is enhanced by retinoic acid and 1,25-dihydroxyvitamin D3, but blocked by dexamethasone. This regulation differs from other BMP antagonists (noggin, gremlin), indicating unique upstream control of SOST. RT-PCR/Northern analysis in human osteoblast cultures treated with BMPs, steroids, and growth factors Bone Medium 15268896
2010 BMP signaling through BMPRIA in osteoblasts positively regulates Sost and Dkk1 expression: conditional knockout of Bmpr1a in osteoblasts reduces Sost and Dkk1 levels and increases Wnt/β-catenin signaling; BMP2 upregulates and Noggin downregulates both inhibitors; BMP2-induced Dkk1 (but not Sost) is blocked by p38 MAPK inhibition, indicating differential downstream signaling. Conditional knockout mice (Bmpr1a cKO), Wnt reporter assays (TOPGAL, TOPFLASH), BMP2/Noggin/dorsomorphin treatment, SB202190 inhibitor; qPCR Journal of bone and mineral research High 19874086
2011 Loss of ACVR1 (BMP receptor for BMP7) specifically in osteoblasts increases bone mass and suppresses expression of both Sost and Dkk1, activating canonical Wnt signaling; BMP7 dose-dependently upregulates Sost and Dkk1 in vitro, defining a BMP7-ACVR1-SOST/DKK1 axis. Inducible osteoblast-specific Acvr1 conditional KO mice, qPCR, in vitro BMP7 treatment of osteoblasts Biochemical and biophysical research communications Medium 21945937
2011 Sirt1 directly represses Sost gene expression by deacetylating histone 3 at lysine 9 at the Sost promoter, as demonstrated by chromatin immunoprecipitation; Sirt1 haploinsufficiency increases sclerostin levels and reduces bone formation. ChIP analysis in Sirt1+/- mice; siRNA knockdown of Sost; sclerostin-neutralizing antibody rescue experiments; osteocalcin/bone sialoprotein gene expression and mineralization assays Endocrinology Medium 21952235
2011 Strain-induced Sost downregulation in human osteoblastic cells (Saos2) is mediated by COX-2-dependent prostaglandin E2 (PGE2) acting through the EP4 receptor and requires ERK signaling; strain-induced osteocalcin upregulation uses the EP2 receptor and PKC, demonstrating early pathway divergence. Dynamic strain of Saos2 cells; COX-2 inhibitors; EP receptor agonists/antagonists; MEK/ERK inhibitors; qRT-PCR FEBS letters Medium 21723865
2013 Estrogen receptor β (ERβ), not ERα, mediates the acute down-regulation of Sost expression by mechanical strain and estradiol in osteoblastic cells; ERβ agonists recapitulate Sost suppression, ERβ antagonist or ERβ deletion prevents it, and the effect requires MEK/ERK signaling. ERα/ERβ selective agonists/antagonists in mouse long bone osteoblasts and Saos-2 cells; in vivo ERα-null mouse; ERβ-null osteoblasts; MEK/ERK inhibitors; qPCR The Journal of biological chemistry Medium 23362266
2013 HIF-1α transcriptionally activates Sost expression in osteoblasts under hypoxia by directly binding a hypoxia response element in the Sost promoter (within the −260 bp minimal region); HIF-1α siRNA reduces Sost expression; DFO (HIF-1α activator) further increases Sost. qRT-PCR; siRNA knockdown of HIF-1α; deletion mutant Sost promoter-luciferase reporters; gel shift (EMSA); DFO treatment of osteoblasts PloS one Medium 23776575
2011 Signal peptide mutations (Val21Met, Val21Leu) in the SOST gene cause autosomal dominant craniodiaphyseal dysplasia by dramatically reducing SOST secretion, acting through a dominant negative mechanism distinct from the recessive loss-of-function mutations causing sclerosteosis/van Buchem disease. Transfection of mutant SOST constructs into 293E cells; secretion assay Human genetics Medium 21221996
2010 The missense mutation p.Cys167Arg in the SOST cystine-knot motif causes retention of mutant sclerostin in the ER (impaired folding/secretion) and significantly reduces LRP5 binding and Wnt signaling inhibition, establishing that the cystine-knot integrity is required for sclerostin's secretion and function. Functional assays: LRP5 binding assay, Wnt signaling reporter assay, ER retention/secretion assay in transfected cells Human mutation Medium 20583295
2014 Sost deficiency-induced bone anabolism partially requires LRP5, but fully depends on Wnt1 class-induced LRP6 activity: selective blockade of Wnt1-class LRP6 signaling completely reversed bone overgrowth in Sost-/- and Sost-/-;Lrp5-/- mice to wild-type levels. Sost-/-;Lrp5-/- double knockout mice; treatment with class-selective anti-LRP6 antibodies; microCT and histomorphometry Journal of bone and mineral research High 23901037
2013 DNA methylation of the SOST promoter CpG region regulates SOST expression in osteoarthritic chondrocytes; BMP-2 increases SOST expression via Smad1/5/8 binding to the hypomethylated CpG region of the SOST promoter, as shown by ChIP; 5-AzadC (demethylation) increases SOST expression. Methylation-specific PCR, bisulfite sequencing, 5-AzadC treatment, ChIP for Smad1/5/8 binding, qRT-PCR and Western blot in OA chondrocytes Arthritis research & therapy Medium 26071314
2015 LRP6 is required for PTH-induced suppression of Sost in osteocytes: osteoblast-specific Lrp6 KO mice show elevated Sost/sclerostin levels and blunted PTH-induced Sost suppression; PTH-induced downregulation of MEF2C/D and HDAC changes in osteocytes were abrogated in LRP6-KO mice. Osteoblast-specific Lrp6-KO mice; intermittent PTH treatment; qPCR for Sost; IHC for sclerostin+ osteocytes; MEF2 and HDAC protein analysis Annals of the New York Academy of Sciences Medium 25847683
2016 N-cadherin restrains PTH-mediated suppression of sclerostin/SOST by reducing LRP6-PTH1R interaction and endocytosis; overexpression of N-cadherin blunts PTH-induced downregulation of MEF2A/C/D and SOST; osteocyte-specific N-cadherin deletion (Cdh2ΔDmp1) accentuates iPTH-induced SOST suppression and enhances PTH bone anabolic effects. N-cadherin overexpression in vitro; osteocyte-specific Cdh2 KO (Dmp1-Cre) mice; iPTH treatment; LRP6-PTHR1 co-IP/endocytosis; qPCR; immunoblot Annals of the New York Academy of Sciences Medium 27723935
2019 Mechanical stretch-induced suppression of Sost expression in osteocytes (IDG-SW3 cells) is mediated by the mechanosensitive ion channel Piezo1 and requires downstream Akt activation; Piezo1 agonist (Yoda1) decreases Sost expression, and this is abrogated by Piezo1 inhibitor GsMTx4, Piezo1 deficiency, or Akt inhibition. IDG-SW3 osteocyte cell line; Yoda1 treatment; mechanical stretch; GsMTx4 (Piezo1 inhibitor); Piezo1 siRNA/knockout; Akt inhibitor; qPCR for Sost; intracellular calcium imaging Biochemical and biophysical research communications Medium 31708103
2009 The matricellular protein periostin (Postn) is required for mechanical stimulation-induced inhibition of Sost in bone; Postn-/- mice have elevated baseline Sost expression that is unresponsive to exercise/loading, and sclerostin-blocking antibody rescues the impaired bone biomechanical response in these mice. Postn-/- mice; exercise and axial tibial compression models; anti-sclerostin antibody rescue; bone microarchitecture and biomechanics; gene expression (Sost, periostin) The Journal of biological chemistry Medium 19837663
2013 Nitric oxide (NO) is involved in pulsating fluid flow (PFF)-induced downregulation of SOST expression in human bone cells; NOS inhibitor 1400W prevents the PFF effect on SOST; NO donor SNAP decreases SOST mRNA; conditioned medium from PFF-stimulated cells decreases SOST promoter transcriptional activity, indicating secreted factors also contribute. Pulsating fluid flow on AzadC-treated human bone cells; NOS inhibitor (1400W); NO donor (SNAP); SOST promoter-reporter assay; conditioned medium transfer Calcified tissue international Medium 24322886
2015 PIGMENT EPITHELIUM DERIVED FACTOR (PEDF) suppresses Sost/sclerostin expression by 70% in mineralizing osteoblast cultures and by 50% in primary osteocytes, leading to increased total β-catenin (Wnt signaling activation) and enhanced mineralization. Exogenous PEDF treatment of mineralizing human osteoblast cultures and primary osteocytes; qRT-PCR; Western blot; immunoprecipitation; β-catenin assay Journal of cellular physiology Low 25363869
2018 Sclerostin (SOST) inhibits MMP2/3 expression and activity after joint injury; SOST transgenic mice develop less severe PTOA and osteophytes, with ~2-fold less MMP activation; intra-articular recombinant Sost protein post-injury decreases MMP activity; Sost induction in response to joint injury is TNFα and NF-κB dependent. SOST transgenic and Sost-/- mice; noninvasive tibial compression overload PTOA model; MMP activity quantification; MMP2/3 protein measurement; recombinant Sost intra-articular injection; TNFα and NF-κB pathway analysis Journal of bone and mineral research Medium 29377313
2007 SOST is expressed in the medial vessel wall smooth muscle cells of the great arteries (ascending aorta, aortic arch, brachiocephalic, common carotids, pulmonary trunk) from embryonic day 15.5 to neonatal period, but its expression does not correspond with inhibition of Smad-dependent BMP or β-catenin-dependent Wnt activity in these vessels. In situ hybridization and IHC for SOST/sclerostin; BMP signaling (pSmad) and Wnt (β-catenin) reporter/IHC in mouse embryo cardiovascular tissue sections Developmental dynamics Low 17195180
2015 The human SOST gene is directly and positively regulated by 1α,25-dihydroxyvitamin D3 (1,25D) in osteocyte-like SaOS2 cells, mediated at least in part by a DR3-type vitamin D response element; SOST mRNA and sclerostin protein increase within 3 hours of 1,25D treatment and decrease within 3 hours of PTH treatment. 1,25D and PTH treatment of differentiated SaOS2 osteocyte-like cells; qRT-PCR and protein measurement at early time points; CYP24A1 induction assay The Journal of steroid biochemistry and molecular biology Low 26690786
2015 Compressive force upregulates SOST (and POSTN) expression in human PDL fibroblasts via TGF-β1: cycloheximide, TGF-β inhibitor (SB431542), or TGF-β1 neutralizing antibody attenuate force-induced SOST and POSTN expression; TGF-β1 accumulates intracellularly/in matrix (not in medium) in response to force. Computer-controlled compressive force loading apparatus on hPDL cells; qRT-PCR; Western blot; cycloheximide; TGF-β receptor inhibitor; neutralizing antibody; ELISA for TGF-β1 Journal of dental research Medium 25870205
2017 Notch signaling participates in TGF-β-induced SOST expression in human PDL cells under compressive stress: compressive force induces NOTCH2, NOTCH3, HES1, HEY1; γ-secretase inhibitor (DAPT) reduces stress-induced SOST; TGF-β receptor inhibitor reduces Notch activation; recombinant TGF-β1 enhances SOST and Notch gene expression, and DAPT attenuates TGF-β1-induced SOST. Intermittent compressive stress apparatus on hPDL cells; TGF-β receptor inhibitor (SB431542); γ-secretase inhibitor (DAPT); recombinant TGF-β1; qPCR; Western blot Journal of cellular physiology Medium 27966788
2018 Osteocyte-derived sclerostin impairs osteogenesis and angiogenesis via inhibiting the Wnt pathway; co-culture of osteocytes with MC3T3-E1 or endothelial cells in the presence of dexamethasone worsened inhibition, and SOST-silencing of osteocytes rescued these effects; in vivo SOST KO ameliorated glucocorticoid-associated osteonecrosis of femoral head. Co-culture of Ocy454 osteocytes (± SOST silencing) with MC3T3-E1 and endothelial cells + dexamethasone; SOST KO rat GA-ONFH model; histology, IHC, bone metabolic markers Molecular medicine Medium 39342093
2018 Osteocyte Dmp1-Cre-specific deletion of Bmpr1a reduces Sost mRNA in bone by >95% and serum SOST protein by ~85%, activates Wnt/β-catenin signaling, and also dramatically decreases RANKL while increasing OPG, leading to osteosclerosis—establishing that BMP signaling through BMPR1A in osteocytes positively regulates Sost expression. Dmp1-Cre conditional Bmpr1a KO mice; microCT; histomorphometry; qPCR; ELISA for serum SOST and RANKL; β-catenin/Tcf target gene expression; mechanical testing Bone High 27402532
2022 SOST interacts with STAT3 to enhance TGF-β/KRAS signaling in breast cancer cells, increasing tumor growth and bone metastasis; SOST silencing reduces bone metastatic capacity of SCP2 cells; small molecule S6 inhibiting SOST-STAT3 interaction suppresses breast cancer growth and bone metastasis in vivo. Co-IP (SOST-STAT3 interaction); SOST silencing/overexpression in SCP2 cells; in vitro and in vivo bone metastasis assays; small molecule screen; breast cancer organoid treatment Molecular cancer Medium 36581888
2013 Sost and its paralog Sostdc1 coordinately regulate digit number: in the developing limb, Sost is restricted to distal ectoderm and Sostdc1 to proximal ectoderm/mesenchyme; Sost-/-;Sostdc1-/- double KO mice show elevated Wnt signaling leading to misregulation of SHH signaling, ectopic Sox9 activation, and preaxial polydactyly in a Gli1/Gli3-dependent manner; syndactyly in Sost-/- is driven by misregulation of Fgf8 in the AER. Sost-/-, Sostdc1-/-, and double KO mice; limb phenotype analysis; Shh/Gli signaling analysis; ISH; epistasis with Gli1/Gli3 mutants Developmental biology Medium 23994639
2018 Multiple osteoblast lineage cell types contribute paracrine sclerostin to the bone microenvironment: conditional deletion of Sost in Prx1 (osteoprogenitor), Col1 (midstage osteoblast), Dmp1 (mature osteocyte), and ColX (hypertrophic chondrocyte) lineages all increased trabecular bone mass; only Prx1-Cre deletion fully recapitulated the full HBM phenotype and the B-cell defect of global Sost KO. Sclerostin from axial skeleton does not influence appendicular bone in a circulating endocrine manner. Cell type-specific conditional Sost KO mice (4 Cre lines); microCT; DXA; cortical bone histomorphometry; B-cell FACS analysis Journal of bone and mineral research High 29750826

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2007 Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. The Journal of biological chemistry 1008 18089564
2001 Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Human molecular genetics 878 11181578
2001 Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. American journal of human genetics 769 11179006
2005 SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor. The Journal of biological chemistry 603 15908424
2002 Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. Journal of medical genetics 535 11836356
2005 SOST is a target gene for PTH in bone. Bone 444 15946907
2011 Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone 366 22075208
2005 SOST/sclerostin, an osteocyte-derived negative regulator of bone formation. Cytokine & growth factor reviews 266 15869900
2002 A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12-q21 is associated with van Buchem disease in the Dutch population. American journal of medical genetics 241 12116252
2010 Parathyroid hormone (PTH)-induced bone gain is blunted in SOST overexpressing and deficient mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 200 19594304
2007 Control of the SOST bone enhancer by PTH using MEF2 transcription factors. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 188 17696759
2010 Wnt inhibitors Dkk1 and Sost are downstream targets of BMP signaling through the type IA receptor (BMPRIA) in osteoblasts. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 180 19874086
2006 LRP5 mutations linked to high bone mass diseases cause reduced LRP5 binding and inhibition by SOST. The Journal of biological chemistry 177 17052975
2009 The matricellular protein periostin is required for sost inhibition and the anabolic response to mechanical loading and physical activity. The Journal of biological chemistry 173 19837663
2011 Sirt1 is a regulator of bone mass and a repressor of Sost encoding for sclerostin, a bone formation inhibitor. Endocrinology 156 21952235
2013 Exendin-4 increases bone mineral density in type 2 diabetic OLETF rats potentially through the down-regulation of SOST/sclerostin in osteocytes. Life sciences 116 23357248
2016 Protection From Glucocorticoid-Induced Osteoporosis by Anti-Catabolic Signaling in the Absence of Sost/Sclerostin. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 104 27163932
2017 Genetic deletion of Sost or pharmacological inhibition of sclerostin prevent multiple myeloma-induced bone disease without affecting tumor growth. Leukemia 102 28529307
2013 Estrogen receptor α mediates proliferation of osteoblastic cells stimulated by estrogen and mechanical strain, but their acute down-regulation of the Wnt antagonist Sost is mediated by estrogen receptor β. The Journal of biological chemistry 99 23362266
2011 Insulin-dependent diabetes mellitus decreases osteoblastogenesis associated with the inhibition of Wnt signaling through increased expression of Sost and Dkk1 and inhibition of Akt activation. International journal of molecular medicine 98 21567076
2010 Does osteocytic SOST suppression mediate PTH bone anabolism? Trends in endocrinology and metabolism: TEM 90 20074973
2004 Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites. American journal of human genetics 87 15514891
2012 Osteocyte network; a negative regulatory system for bone mass augmented by the induction of Rankl in osteoblasts and Sost in osteocytes at unloading. PloS one 85 22768243
2007 Effects of intermittent parathyroid hormone (PTH) administration on SOST mRNA and protein in rat bone. Journal of molecular histology 85 17549589
2019 Mechanotransduction via the Piezo1-Akt pathway underlies Sost suppression in osteocytes. Biochemical and biophysical research communications 77 31708103
2015 Methylation of bone SOST, its mRNA, and serum sclerostin levels correlate strongly with fracture risk in postmenopausal women. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 76 25155887
2011 Sost down-regulation by mechanical strain in human osteoblastic cells involves PGE2 signaling via EP4. FEBS letters 75 21723865
2004 Unique regulation of SOST, the sclerosteosis gene, by BMPs and steroid hormones in human osteoblasts. Bone 68 15268896
2016 Transcriptional control of Sost in bone. Bone 67 27771382
2004 Cbfa1/RUNX2 directs specific expression of the sclerosteosis gene (SOST). The Journal of biological chemistry 67 14739291
2014 Reversing LRP5-dependent osteoporosis and SOST deficiency-induced sclerosing bone disorders by altering WNT signaling activity. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 64 23901037
2018 Role of Osteocyte-PDL Crosstalk in Tooth Movement via SOST/Sclerostin. Journal of dental research 62 29863952
2015 Removal of SOST or blocking its product sclerostin rescues defects in the periodontitis mouse model. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 62 25757567
2011 Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia. Human genetics 62 21221996
2017 Genetics of Sost/SOST in sclerosteosis and van Buchem disease animal models. Metabolism: clinical and experimental 59 29080811
2013 HIF-1α inhibits Wnt signaling pathway by activating Sost expression in osteoblasts. PloS one 55 23776575
2009 Localization of SOST/sclerostin in cementocytes in vivo and in mineralizing periodontal ligament cells in vitro. Journal of periodontal research 54 19778325
2005 A generalized skeletal hyperostosis in two siblings caused by a novel mutation in the SOST gene. Bone 53 15869924
2012 The role of BMPs in bone anabolism and their potential targets SOST and DKK1. Current molecular pharmacology 51 21787290
2019 microRNA-96 promotes osteoblast differentiation and bone formation in ankylosing spondylitis mice through activating the Wnt signaling pathway by binding to SOST. Journal of cellular biochemistry 50 31111563
2011 Anabolic and catabolic regimens of human parathyroid hormone 1-34 elicit bone- and envelope-specific attenuation of skeletal effects in Sost-deficient mice. Endocrinology 50 21652726
2011 Loss-of-function of ACVR1 in osteoblasts increases bone mass and activates canonical Wnt signaling through suppression of Wnt inhibitors SOST and DKK1. Biochemical and biophysical research communications 50 21945937
2010 First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function. Human mutation 49 20583295
2018 SOST/Sclerostin Improves Posttraumatic Osteoarthritis and Inhibits MMP2/3 Expression After Injury. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 48 29377313
2015 Mechanical Force-induced TGFB1 Increases Expression of SOST/POSTN by hPDL Cells. Journal of dental research 48 25870205
2013 Sost and its paralog Sostdc1 coordinate digit number in a Gli3-dependent manner. Developmental biology 47 23994639
2018 Conditional Deletion of Sost in MSC-Derived Lineages Identifies Specific Cell-Type Contributions to Bone Mass and B-Cell Development. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 43 29750826
2016 Lipid Nanoparticle Delivery of siRNA to Osteocytes Leads to Effective Silencing of SOST and Inhibition of Sclerostin In Vivo. Molecular therapy. Nucleic acids 43 27623445
2013 High-concentration of BMP2 reduces cell proliferation and increases apoptosis via DKK1 and SOST in human primary periosteal cells. Bone 41 23360788
2020 Reduction of SOST gene promotes bone formation through the Wnt/β-catenin signalling pathway and compensates particle-induced osteolysis. Journal of cellular and molecular medicine 39 32134561
2016 Targeted disruption of BMP signaling through type IA receptor (BMPR1A) in osteocyte suppresses SOST and RANKL, leading to dramatic increase in bone mass, bone mineral density and mechanical strength. Bone 39 27402532
2009 The -9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPalpha and FOXA1 binding is associated with osteoporosis. Bone 39 19371798
2015 DNA methylation regulates sclerostin (SOST) expression in osteoarthritic chondrocytes by bone morphogenetic protein 2 (BMP-2) induced changes in Smads binding affinity to the CpG region of SOST promoter. Arthritis research & therapy 38 26071314
2015 Pigment epithelium derived factor suppresses expression of Sost/Sclerostin by osteocytes: implication for its role in bone matrix mineralization. Journal of cellular physiology 37 25363869
2007 SOST expression is restricted to the great arteries during embryonic and neonatal cardiovascular development. Developmental dynamics : an official publication of the American Association of Anatomists 37 17195180
2010 SOST and DKK: Antagonists of LRP Family Signaling as Targets for Treating Bone Disease. Journal of osteoporosis 33 20948575
2015 Cancer-Osteoblast Interaction Reduces Sost Expression in Osteoblasts and Up-Regulates lncRNA MALAT1 in Prostate Cancer. Microarrays (Basel, Switzerland) 31 27600237
2022 Targeting SOST using a small-molecule compound retards breast cancer bone metastasis. Molecular cancer 30 36581888
2015 Lipoprotein receptor-related protein 6 is required for parathyroid hormone-induced Sost suppression. Annals of the New York Academy of Sciences 30 25847683
2002 Lack of association between the SOST gene and bone mineral density in perimenopausal women: analysis of five polymorphisms. Bone 30 12398949
2014 Associations of serum sclerostin and polymorphisms in the SOST gene with bone mineral density and markers of bone metabolism in postmenopausal Chinese women. The Journal of clinical endocrinology and metabolism 29 24423318
2015 SOST Inhibits Prostate Cancer Invasion. PloS one 27 26545120
2023 SOST gene suppression stimulates osteocyte Wnt/β-catenin signaling to prevent bone resorption and attenuates particle-induced osteolysis. Journal of molecular medicine (Berlin, Germany) 25 37121919
2019 Characterization of a novel murine Sost ERT2 Cre model targeting osteocytes. Bone research 25 30820362
2024 The miR-665/SOST Axis Regulates the Phenotypes of Bone Marrow Mesenchymal Stem Cells and Osteoporotic Symptoms in Female Mice. The American journal of pathology 24 39461772
2014 Low-dose PTH increases osteoblast activity via decreased Mef2c/Sost in senescent osteopenic mice. The Journal of endocrinology 24 25056116
2008 A known SOST gene mutation causes sclerosteosis in a familial and an isolated case from Brazilian origin. Genetic testing 24 19072561
2017 Thirty days of spaceflight does not alter murine calvariae structure despite increased Sost expression. Bone reports 23 28875158
2009 Analysis of association of LRP5, LRP6, SOST, DKK1, and CTNNB1 genes with bone mineral density in a Slovenian population. Calcified tissue international 23 19898734
2019 SOST Deficiency Aggravates Osteoarthritis in Mice by Promoting Sclerosis of Subchondral Bone. BioMed research international 21 31828128
2017 Notch Signaling Participates in TGF-β-Induced SOST Expression Under Intermittent Compressive Stress. Journal of cellular physiology 21 27966788
2017 SOST silencing promotes proliferation and invasion and reduces apoptosis of retinoblastoma cells by activating Wnt/β-catenin signaling pathway. Gene therapy 21 28485721
2012 Novel SOST gene mutation in a sclerosteosis patient and her parents. Bone 21 23079137
2018 Methylation of bone SOST impairs SP7, RUNX2, and ERα transactivation in patients with postmenopausal osteoporosis. Biochemistry and cell biology = Biochimie et biologie cellulaire 19 30257098
2016 Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation. Bone 19 27601226
2018 Computational and functional characterization of four SNPs in the SOST locus associated with osteoporosis. Bone 18 29307778
2017 Effects of SOST Gene Silencing on Proliferation, Apoptosis, Invasion, and Migration of Human Osteosarcoma Cells Through the Wnt/β-Catenin Signaling Pathway. Calcified tissue international 18 28246931
2015 Inhibition of GSK3β Stimulates BMP Signaling and Decreases SOST Expression Which Results in Enhanced Osteoblast Differentiation. Journal of cellular biochemistry 18 26095393
2013 Nitric oxide is involved in the down-regulation of SOST expression induced by mechanical loading. Calcified tissue international 18 24322886
2018 SOST Gene Inhibits Osteogenesis from Adipose-Derived Mesenchymal Stem Cells by Inducing Th17 Cell Differentiation. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 16 30041240
2016 Variations of SOST mRNA expression in human bone are associated with DNA polymorphism and DNA methylation in the SOST gene. Bone 16 27519970
2012 Combinatorial use of bone morphogenetic protein 6, noggin and SOST significantly predicts cancer progression. Cancer science 16 22364398
2011 Association study of polymorphisms in the SOST gene region and parameters of bone strength and body composition in both young and elderly men: data from the Odense Androgen Study. Calcified tissue international 16 22076526
2016 Distorted Patterns of Dentinogenesis and Eruption in Msx2 Null Mutants: Involvement of Sost/Sclerostin. The American journal of pathology 15 27524798
2016 Expression of SOST/sclerostin in compressed periodontal ligament cells. Journal of dental sciences 15 30894984
2017 SOST, an LNGFR target, inhibits the osteogenic differentiation of rat ectomesenchymal stem cells. Cell proliferation 14 29226516
2015 Early response of the human SOST gene to stimulation by 1α,25-dihydroxyvitamin D3. The Journal of steroid biochemistry and molecular biology 14 26690786
2024 SOST/Sclerostin impairs the osteogenesis and angiogesis in glucocorticoid-associated osteonecrosis of femoral head. Molecular medicine (Cambridge, Mass.) 13 39342093
2023 Inhibiting WNT secretion reduces high bone mass caused by Sost loss-of-function or gain-of-function mutations in Lrp5. Bone research 13 37612291
2022 Suppression of Sost/Sclerostin and Dickkopf-1 Augment Intervertebral Disc Structure in Mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 13 35278242
2020 lncRNA MEG3 Suppresses the Progression of Ankylosis Spondylitis by Regulating the Let-7i/SOST Axis. Frontiers in molecular biosciences 13 32793634
2019 Expression of Sclerostin in Osteoporotic Fracture Patients Is Associated with DNA Methylation in the CpG Island of the SOST Gene. International journal of genomics 13 30729116
2018 Common and rare variants of WNT16, DKK1 and SOST and their relationship with bone mineral density. Scientific reports 13 30026596
2014 Analysis of association of MEF2C, SOST and JAG1 genes with bone mineral density in Mexican-Mestizo postmenopausal women. BMC musculoskeletal disorders 13 25430630
2019 Polymorphisms of FDPS, LRP5, SOST and VKORC1 genes and their relation with osteoporosis in postmenopausal Romanian women. PloS one 12 31774873
2016 N-cadherin restrains PTH repressive effects on sclerostin/SOST by regulating LRP6-PTH1R interaction. Annals of the New York Academy of Sciences 12 27723935
2015 SOST polymorphisms and response to alendronate treatment in postmenopausal Chinese women with osteoporosis. Pharmacogenomics 12 26250343
2020 Cortical bone adaptation to a moderate level of mechanical loading in male Sost deficient mice. Scientific reports 11 33339872
2017 Endothelin signaling regulates mineralization and posttranscriptionally regulates SOST in TMOb cells via miR 126-3p. Physiological reports 11 28235973
2017 Sost Deficiency does not Alter Bone's Lacunar or Vascular Porosity in Mice. Frontiers in materials 11 29349060

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