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FLASH GENE
Symbol SOST contributors: mct/pgu - updated : 01-10-2015
HGNC name sclerostin
HGNC id 13771
Corresponding disease
CDD craniodiaphyseal dysplasia
HVB hyperostosis corticalis generalisata
SOST sclerosing bone dysplasia, progressive, sclerosteosis
Location 17q21.31      Physical location : 41.831.098 - 41.836.156
Synonym symbol(s) VBCH, CDD1
DNA
TYPE functioning gene
STRUCTURE 5.06 kb     2 Exon(s)
10 Kb 5' upstream gene genomic sequence study
regulatory sequence Promoter
cytosine-phosphate-guanine/HTF
Binding site
text structure
  • CREBBP, RUNX2 and E-box binding motif in the 1.8-kb proximal SOST promoter
  • promoter region between SOST-260 bp and SOST-106 bp contains critical binding site for SP7 (directly binds to GC-rich sequence within SOSTpromoter)
  • ECR5 represents a distal enhancer that has osteoblast- and osteocyte-specific activity and is located &
  • 8764;62 kb away from the SOST transcriptional start site
    MAPPING cloned Y linked N status provisional
    Physical map
    ARHN 17q21 ras homolog gene family, member N BRCA1 17q21 breast cancer 1, early onset RPL21P4 17q21 ribosomal protein L21 pseudogene 4 NBR2 17q21 neighbor of BRCA1 gene 2 LOC387620 17 membrane component, chromosome 17, surface marker 2 MGC20235 17q21.31 hypothetical protein MGC20235 LOC388388 17 LOC388388 RNU2P2 17q21.31 RNA, U2 small nuclear pseudogene 2 ARF4L 17q12-q21 ADP-ribosylation factor 4-like LOC284064 17q21.31 similar to 60S ribosomal protein L29 (Cell surface heparin binding protein HIP) DHX8 17q21.31 DEAH (Asp-Glu-Ala-His) box polypeptide 8 ETV4 17q21 ets variant gene 4 (E1A enhancer binding protein, E1AF) MEOX1 17q21 mesenchyme homeo box 1 LOC390797 17 similar to WHSC1L1 protein isoform long; Wolf-Hirschhorn syndrome candidate 1-like 1 protein SOST 17q12-q21 sclerosteosis DUSP3 17q21 dual specificity phosphatase 3 (vaccinia virus phosphatase VH1-related) LOC284067 17q21.31 hypothetical LOC284067 MPP3 17q12-q21 membrane protein, palmitoylated 3 (MAGUK p55 subfamily member 3) TREM4 17q21.31 triggering receptor expressed on myeloid cells 4 MPP2 17q12-q21 membrane protein, palmitoylated 2 (MAGUK p55 subfamily member 2) APR-2 17q21.31 apoptosis related protein LOC390798 17 similar to wingless-type MMTV integration site family, member 9B precursor; wingless-type MMTV integration site family, member 15 PPY 17q21.2 pancreatic polypeptide PYY 17q21.1 peptide YY NAGS 17q21.31 peptide YY MGC4251 17q21.31 hypothetical protein MGC4251 FLJ30656 17q21.31 hypothetical protein FLJ30656 G6PC3 17q21.31 glucose-6-phosphatase catalytic subunit 3 HDAC5 17q21 histone deacetylase 5 MGC3130 17q21.31 hypothetical protein MGC3130 ASB16 17q21.31 ankyrin repeat and SOCS box-containing 16 DKFZp762C2414 17q21.31 hypothetical protein DKFZp762C2414 MGC3123 17q21.31 hypothetical protein MGC3123 UBTF 17q21.3 upstream binding transcription factor, RNA polymerase I LOC390799 17 similar to SHC (Src homology 2 domain containing) transforming protein 1; SHC (Src homology 2 domain-containing) transforming protein 1 SLC4A1 17q21-q22 solute carrier family 4, anion exchanger, member 1 (erythrocyte membrane protein band 3, Diego blood group) RPIP8 17p13.2 solute carrier family 4, anion exchanger, member 1 (erythrocyte membrane protein band 3, Diego blood group) CGI-69 17q12 CGI-69 protein GRN 17q21.3 granulin MGC34829 17q21.31 Similar to hypothetical gene supported by AL050367; AK022946 LOC390800 17 similar to ribosomal protein L7-like 1 ITGA2B 17q21.32 integrin, alpha 2b (platelet glycoprotein IIb of IIb/IIIa complex, antigen CD41B) KIAA0553 17q21.31 KIAA0553 protein
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 2322 - 213 - 2001 11181578
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   highly
    Respiratorylung   highly
    Skeleton      Homo sapiens
    Urinarykidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Blood / hematopoieticbone marrow  highly
    Connectivebonesubchondral   Homo sapiens
    Connectivecartilage   
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Skeletonosteoblast Homo sapiens
    Skeletonosteoclast Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal, pregnancy
    Text placenta, skin, kidney, osteoblasts
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • putative secretion signal
  • 2-N-glycosylation sites
  • cysteine knot motif (AA 80-167) with high similarity to the dan family of secreted glycoprotein
  • a binding site for heparin, suggestive of a functional role in localizing sclerostin to the surface of target cells
  • N- and C-terminal arms highly flexible, and unaffected by heparin binding, may have a role in stabilizing interactions with target proteins
  • conjugated GlycoP
    HOMOLOGY
    interspecies homolog to murine Sost (88.2pc)
    homolog to rattus Sost (88.9pc)
    intraspecies homolog to NBL1,CER1,CKTSF1B1
    paralog to SOSTDC1
    Homologene
    FAMILY
  • sclerostin family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,cytoplasm,organelle,Golgi
    text secreted
    basic FUNCTION
  • involved in suppression of bone formation (key regulator of bone formation)
  • negatively regulating the formation of bone by repressing the differentiation and/or function of osteoblasts induced by BMPs
  • playing an important role in bone remodeling and linking bone resorption and bone apposition
  • osteocyte-derived bone formation inhibitor that in adult bone requires a distant enhancer controled by MEF2 transcription factors
  • bone morphogenetic protein (BMP) antagonist that decreases osteoblast activity and reduces the differentiation of osteoprogenitors
  • antagonist for WNT signaling and loss of SOST function likely leads to the hyperactivation of WNT signaling that underlies bone overgrowth seen in sclerosteosis patients
  • sclerostin production by osteocytes may regulate the linear extent of formation and the induction or maintenance of a lining cell phenotype on bone surfaces
  • may act as a key inhibitory signal governing skeletal microarchitecture
  • inhibiting (by binding) CYR61-mediated fibroblast attachment, and increasing vascular endothelial cell migration and osteoblast cell differentiation
  • functions in part, by modulating the activity of ERBB3
  • could function by modulating the activity of epidermal growth factor pathways in bone and cartilage
  • osteocyte-secreted bone formation inhibitor
  • important paracrine regulator of bone mass
  • role potential for sclerostin in the regulation of perilacunar mineral by osteocytes
  • relationship between circulating sclerostin and liver function indicates a possible role of the liver in sclerostin metabolism
  • osteocyte-derived inhibitor of the Wnt/CTNNB1 signaling pathway, which acts as a negative regulator of bone formation
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS locomotion
    PATHWAY
    metabolism
    signaling sensory transduction/hearing
    a component
  • the MEF2C-SOST transcriptional axis has important implications for the anabolic treatment of disorders in which bone loss is a significant component
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • binding to to BMP6 and BMP7
  • binding to RUNX2 by its proximal promoter (contributing to its differential expression in two osteosarcoma cell lines)
  • ligand for LRP5/LRP6 and a WNT signaling inhibitor
  • interacting with POSTN (mechanical loading increases POSTN expression, which is necessary to inhibit SOST expression and thereby to up-regulate osteoblast functions)
  • physical association of SP7 with SOST promoter
  • interaction between sclerostin and the C-terminal portion of the receptor tyrosine-protein kinase ERBB3, modulating the activity of this receptor in osteoblasts
  • LRP4 is a sclerostin (SOST) interaction partner (interaction of sclerostin with LRP4 is required to mediate the inhibitory function of sclerostin on bone formation, thus identifying a novel role for LRP4 in bone)
  • its expression is modulated by PTH through a MEF2 responsive element, present in the distal ECR5 SOST enhancer
  • interacting with ACVR1 (ACVR1 negatively regulates bone mass by suppressing Wnt signaling through SOST and DKK1)
  • MEF2C is the main transcription factor responsible for bone enhancer ECR5-dependent SOST transcriptional activation in the adult skeleton
  • complex role of POSTN on bone anabolism, through the regulation of SOST, Wnt-CTNNB1 signaling, and osteoblast differentiation
  • POSTN could be involved in the regulation of SOST expression and bone anabolism in response to PTH
  • BMP2 decreases periosteal cell proliferation and induces apoptosis via the activation of Wnt inhibitors DKK1 and SOST
  • regulates release of bone mineral by osteocytes by induction of carbonic anhydrase 2
  • SOST and its paralog SOSTDC1 coordinate digit number in a GLI3-dependent manner
  • SERPINF1 may regulate SOST expression by osteocytes leading to enhanced osteoblastic differentiation and increased matrix mineralization
  • cell & other
  • heparin-binding
  • REGULATION
    inhibited by PTH (SOST regulation may play a role in mediating PTH action in bone)
    Other regulated by RUNX2 suggesting a potential role in homeostatic regulation of osteoblast differentiation and function
    regulated by MEF2 transcription factors (control the enhancer and mediate inhibition of sclerostin expression by PTH)
    DNA methylation is involved in the regulation of SOST expression during osteoblast-osteocyte transition, presumably by preventing the binding of transcription factors to the proximal promoter
    ASSOCIATED DISORDERS
    corresponding disease(s) SOST , HVB , CDD
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    leads to the hyperactivation of Wnt signaling that underlies bone overgrowth seen in sclerosteosis patients
    constitutional     --over  
    women with T1DM exhibit higher sclerostin levels than men
    constitutional     --low  
    decreased sclerostin levels in osteogenesis imperfecta might reflect a down-regulation or negative feedback mechanism to prevent further bone loss
    Susceptibility
  • to decreased bone density (BMD)
  • Variant & Polymorphism other
  • SRP3 or SRP9 polymorphism associated with decreased bone density (BMD)
  • Candidate gene
  • expression in patients with spondylitis ankylosing is virtually absent, suggesting a specific alteration of osteocyte function in this disease
  • Marker
  • BMP6, NOG and SOST could be used in combination as a prognostic indicator in cancer progression
  • Therapy target
    SystemTypeDisorderPubmed
    osteoarticularboneostéoporosis
    potential target for therapeutics designed to treat conditions associated with low bone mass, such as osteoporosis
    osteoarticularboneostéoporosis
    sclerostin and DKK1 are emerging as the leading new targets for anabolic therapies to treat bone diseases such as osteoporosis and for bone repair
    ANIMAL & CELL MODELS
  • in Sost-KO mice endocortical bone exhibited altered bone composition, whereas subperiosteal bone was unchanged