Details for: SOST

Gene ID: 50964

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: SOST

Ensembl ID: ENSG00000167941

Description: sclerostin

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • podocyte CL0000653
    CSI 2.82
    rCSI 12.53%
    PRS 99.43

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [SOST](/details-gene/50964) is the gene encoding sclerostin, a secreted glycoprotein that functions as a key negative regulator of bone formation. It is a well-established antagonist of the canonical Wnt signaling pathway, which is critical for osteoblast proliferation and differentiation. By binding to the LRP5/LRP6 co-receptors, sclerostin prevents Wnt ligands from initiating the signaling cascade that promotes bone growth ([Link](https://pubmed.ncbi.nlm.nih.gov/15908424/)). Loss-of-function mutations in [SOST](/details-gene/50964) are associated with high bone mass phenotypes, including sclerosteosis ([122860](https://omim.org/entry/122860)) and van Buchem disease ([269500](https://omim.org/entry/269500)), highlighting its crucial role in skeletal homeostasis ([Link](https://pubmed.ncbi.nlm.nih.gov/11181578/), [Link](https://pubmed.ncbi.nlm.nih.gov/11179006/)). While primarily studied in the context of bone, expression analysis suggests a significant and specific role in [podocytes](/details-cell/CL0000653), specialized epithelial cells of the kidney glomerulus. ## Cellular Roles and Expression Landscape The **Overall** expression profile for [SOST](/details-gene/50964) indicates a highly specific expression pattern. The analysis identifies [podocytes](/details-cell/CL0000653) (CSI: 2.82) as the cell type where this gene has the most significant expression signature. This is a notable finding, as [SOST](/details-gene/50964) is classically characterized by its expression in osteocytes embedded within the bone matrix. The high significance in [podocytes](/details-cell/CL0000653) suggests a potentially important, though less characterized, function for [SOST](/details-gene/50964) in the kidney, possibly related to the regulation of glomerular filtration barrier integrity or response to mechanical forces, a known stimulus for its expression ([GO:0009612](https://www.ebi.ac.uk/QuickGO/term/GO:0009612)). This specialized expression pattern points toward a role beyond skeletal biology. ## Pathways and Molecular Function Functionally, [SOST](/details-gene/50964) is deeply integrated into signaling pathways that control tissue development and homeostasis. As a secreted protein found in the [extracellular space](/details-cell/CL0000653) ([GO:0005615](https://www.ebi.ac.uk/QuickGO/term/GO:0005615)), its primary role is the negative regulation of key signaling cascades. * **Wnt Signaling:** [SOST](/details-gene/50964) is a potent inhibitor of the [canonical Wnt signaling pathway](/details-cell/CL0000653) ([GO:0060070](https://www.ebi.ac.uk/QuickGO/term/GO:0060070)). It directly antagonizes Wnt signaling by binding to LRP5/LRP6 co-receptors, which is reflected in its annotation to [Negative regulation of TCF-dependent signaling by Wnt ligand antagonists](/details-cell/CL0000653) ([R-HSA-3772470](https://reactome.org/content/detail/R-HSA-3772470)). This inhibitory action is central to its function in preventing excessive bone formation ([Negative regulation of ossification](/details-cell/CL0000653) ([GO:0030279](https://www.ebi.ac.uk/QuickGO/term/GO:0030279))). * **BMP Signaling:** In addition to Wnt, [SOST](/details-gene/50964) also modulates the [BMP signaling pathway](/details-cell/CL0000653) ([GO:0030509](https://www.ebi.ac.uk/QuickGO/term/GO:0030509)). Functional annotations indicate it is involved in the [negative regulation of BMP signaling](/details-cell/CL0000653) ([GO:0030514](https://www.ebi.ac.uk/QuickGO/term/GO:0030514)) and can directly bind BMPs ([BMP binding](/details-cell/CL0000653) ([GO:0036122](https://www.ebi.ac.uk/QuickGO/term/GO:0036122))), suggesting a multi-faceted role in controlling osteogenesis. Its molecular function as a [molecular function inhibitor](/details-cell/CL0000653) ([GO:0140678](https://www.ebi.ac.uk/QuickGO/term/GO:0140678)) is consistent with its antagonistic roles in these critical developmental and homeostatic pathways. ## Research Directions The established role of [SOST](/details-gene/50964) in bone metabolism is well-documented, but its significant expression in [podocytes](/details-cell/CL0000653) opens new avenues for investigation. **Proposed Testable Hypotheses:** 1. **Hypothesis 1:** [SOST](/details-gene/50964) expression by [podocytes](/details-cell/CL0000653) serves as a local, paracrine mechanism to inhibit Wnt signaling within the glomerulus, thereby maintaining the structural integrity of the podocyte foot processes and the glomerular basement membrane. Dysregulation of this local [SOST](/details-gene/50964) signaling could contribute to the pathology of proteinuric kidney diseases. 2. **Hypothesis 2:** In chronic kidney disease, altered expression of [SOST](/details-gene/50964) by [podocytes](/details-cell/CL0000653) contributes to the systemic pool of sclerostin, thereby influencing the renal osteodystrophy phenotype by directly impacting bone remodeling independently of its production by osteocytes. **Suggested Experimental Approach:** To test Hypothesis 1, a podocyte-specific knockout of [SOST](/details-gene/50964) could be generated in mice using a Cre-Lox system (e.g., *Nphs2-Cre;Sost-flox/flox*). These mice could then be subjected to a model of diabetic nephropathy or hypertensive kidney disease. The primary readouts would include quantification of albuminuria, assessment of podocyte effacement and glomerular basement membrane thickening via transmission electron microscopy, and molecular analysis (qPCR, Western blot) of Wnt pathway activation (e.g., beta-catenin, Axin2) in isolated glomeruli compared to control animals. **Therapeutic Potential:** [SOST](/details-gene/50964) is already a major therapeutic target. Given that its function is to inhibit bone formation, **inhibition** of its product, sclerostin, is a validated strategy to treat conditions of low bone mass like osteoporosis. Monoclonal antibodies that neutralize sclerostin (e.g., Romosozumab) are clinically approved and function by releasing the brake on Wnt signaling in osteoblasts, leading to a potent anabolic effect on bone. As a secreted protein with a highly specific inhibitory function, it represents an excellent drug target, allowing for specific intervention with minimal off-target effects. The potential role of [SOST](/details-gene/50964) in kidney physiology may suggest additional therapeutic applications or considerations for sclerostin-inhibiting therapies in patients with comorbid bone and kidney disease.

Genular Protein ID: 848747059

Symbol: SOST_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q9BQB4 Q495N9

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEMBL 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DisProt 1 DrugBank 1 DrugCentral 1 ELM 1 EMBL 10 Ensembl 1 EvolutionaryTrace 1 GO 20 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 2 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 IDEAL 1 InParanoid 1 IntAct 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 7 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 3 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 2 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 neXtProt 1

Citations:

PubMed ID: 11181578

Title: Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST).

PubMed ID: 11181578

DOI: 10.1093/hmg/10.5.537

PubMed ID: 11179006

Title: Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein.

PubMed ID: 11179006

DOI: 10.1086/318811

PubMed ID: 12975309

Title: The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment.

PubMed ID: 12975309

DOI: 10.1101/gr.1293003

PubMed ID: 16625196

Title: DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.

PubMed ID: 16625196

DOI: 10.1038/nature04689

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 15340161

Title: Signal peptide prediction based on analysis of experimentally verified cleavage sites.

PubMed ID: 15340161

DOI: 10.1110/ps.04682504

PubMed ID: 11836356

Title: Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease.

PubMed ID: 11836356

DOI: 10.1136/jmg.39.2.91

PubMed ID: 15908424

Title: SOST is a ligand for LRP5/LRP6 and a Wnt signaling inhibitor.

PubMed ID: 15908424

DOI: 10.1074/jbc.m504308200

PubMed ID: 20551380

Title: Proteomics characterization of extracellular space components in the human aorta.

PubMed ID: 20551380

DOI: 10.1074/mcp.m110.001693

PubMed ID: 21221996

Title: Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia.

PubMed ID: 21221996

DOI: 10.1007/s00439-011-0947-3

PubMed ID: 21471202

Title: Bone overgrowth-associated mutations in the LRP4 gene impair sclerostin facilitator function.

PubMed ID: 21471202

DOI: 10.1074/jbc.m110.190330

PubMed ID: 19208630

Title: Characterization of the structural features and interactions of sclerostin: molecular insight into a key regulator of Wnt-mediated bone formation.

PubMed ID: 19208630

DOI: 10.1074/jbc.m807994200

PubMed ID: 20583295

Title: First missense mutation in the SOST gene causing sclerosteosis by loss of sclerostin function.

PubMed ID: 20583295

DOI: 10.1002/humu.21274

Sequence Information:

  • Length: 213
  • Mass: 24031
  • Checksum: 30DBD55CE73D5BB2
  • Sequence:
    • MQLPLALCLV CLLVHTAFRV VEGQGWQAFK NDATEIIPEL GEYPEPPPEL ENNKTMNRAE 
NGGRPPHHPF ETKDVSEYSC RELHFTRYVT DGPCRSAKPV TELVCSGQCG PARLLPNAIG 
RGKWWRPSGP DFRCIPDRYR AQRVQLLCPG GEAPRARKVR LVASCKCKRL TRFHNQSELK 
DFGTEAARPQ KGRKPRPRAR SAKANQAELE NAY