SOST

Detailed Information

The SOST gene is located on human chromosome 17q21.31 and consists of two exons, encoding a secreted glycoprotein known as Sclerostin. This protein is composed of 190 amino acids, with a molecular weight of approximately 22 kDa. Its structural features include a signal peptide region, a core domain, and a C-terminal cysteine knot-like (CTCK) domain. Sclerostin belongs to the DAN (differential screening-selected gene aberrative in neuroblastoma) family, a group of proteins known for their ability to antagonize Bone Morphogenetic Protein (BMP) signaling. Sclerostin is primarily expressed in mature osteocytes, which are embedded within the bone matrix and interconnected through slender cell protrusions that allow them to sense mechanical stress. As a soluble inhibitor of the Wnt/β-catenin signaling pathway, Sclerostin blocks the interaction between Wnt proteins and the Wnt co-receptors LRP5/6, thereby negatively regulating bone formation. Its expression is regulated by various factors, including mechanical stress, hormonal signals (such as parathyroid hormone and estrogen), and transcription factors (such as Runx2 and Osterix). Notably, the expression of the SOST gene is also regulated by a distal enhancer region, whose deletion is associated with the development of Van Buchem disease.

Biological Functions and Molecular Mechanisms

Sclerostin plays a crucial role in maintaining the balance of bone metabolism by acting as a physiological brake on bone formation, ensuring the orderly progression of bone remodeling. At the molecular level, Sclerostin inhibits bone formation through two main mechanisms: firstly, as an antagonist of the Wnt signaling pathway, it binds to the Wnt co-receptors LRP5/6, preventing the formation of the Wnt-Frizzled-LRP complex, thereby inhibiting the stabilization and nuclear translocation of β-catenin, a key transcription factor that promotes osteoblast differentiation and function. Secondly, Sclerostin acts as a weak antagonist of the BMP signaling pathway, binding to type I or II BMP receptors and interfering with the interaction between BMP and its receptors, thus inhibiting BMP-induced osteoblast differentiation. The expression of Sclerostin is dynamically regulated by mechanical stress: when the skeleton is subjected to mechanical loading, the expression of Sclerostin in osteocytes is downregulated, relieving the inhibition on the Wnt pathway and promoting bone formation. In contrast, when mechanical stimulation is lacking (such as in prolonged bed rest or weightlessness), Sclerostin expression is upregulated, inhibiting bone formation. Additionally, the expression of Sclerostin is regulated by hormones, such as parathyroid hormone (PTH) and estrogen, which suppress SOST gene transcription, while calcitonin promotes its expression.

Figure 1. Exercise (or mechanical stimulation) modulation of SOST. (Chen M, et al., 2025)

Multi-Level Expression Regulation Network

The expression of the SOST gene is tightly regulated through multiple levels, including transcription factors, epigenetic modifications, and microRNAs. At the transcriptional level, several key transcription factors are involved: Runx2 and Osterix (Osx), as primary regulators of osteoblast differentiation, directly bind to the SOST gene promoter region to promote its transcription. Mef2c regulates the specific expression of SOST in osteocytes through enhancer elements, while Sirt1 negatively regulates SOST expression, with its reduced activity being closely associated with age-related bone loss. At the epigenetic level, the DNA methylation status of the SOST gene promoter region significantly affects its expression, with hypermethylation correlating with suppression of expression. Furthermore, several microRNAs, such as miR-218 and miR-125b, post-transcriptionally regulate SOST by targeting its mRNA. Notably, a key enhancer region exists 35 kb downstream of the SOST gene; deletions or mutations in this region lead to significantly reduced SOST expression, causing excessive bone mass accumulation, a feature observed in Van Buchem disease and Sclerosteosis.

Hereditary Bone Metabolic Diseases

Loss-of-function mutations in the SOST gene are associated with two rare hereditary diseases characterized by elevated bone density: Sclerosteosis and Van Buchem disease. Sclerosteosis is an autosomal recessive disorder caused by homozygous mutations in the SOST gene, characterized by progressive bone overgrowth, cranial nerve compression, and distinctive facial deformities. Studies have identified various mutations in the SOST gene in these patients, including missense, nonsense, and frameshift mutations, leading to complete or partial loss of Sclerostin function. Van Buchem disease is also an autosomal recessive disorder but with milder clinical manifestations than Sclerosteosis, caused by a 52 kb deletion downstream of the SOST gene, which includes a critical enhancer region that reduces the specific expression of SOST in bone tissue. The common pathological feature of both diseases is the continuous activation of the Wnt signaling pathway due to the absence of Sclerostin, leading to enhanced osteoblast activity and excessive bone formation. Research on these rare genetic diseases has provided valuable insights into the molecular regulatory mechanisms of bone metabolism and has pointed the way for targeted therapies for osteoporosis.

Osteoporosis and Metabolic Diseases

In common bone metabolic diseases such as Osteoporosis (OP), Sclerostin has gained attention as a key pathological factor. Serum Sclerostin levels are significantly elevated in postmenopausal women with osteoporosis and negatively correlate with bone mineral density (BMD). Studies have shown that polymorphisms in the SOST gene are associated with changes in bone density and fracture risk. For example, the rs10534024 polymorphism is significantly associated with spinal and hip BMD loss in elderly women. Postmenopausal women carrying certain genotypes (TCC.DEL/TCC.TCC) have significantly lower femoral neck BMD compared to wild-type individuals (0.69±0.13 vs. 0.76±0.10, p<0.05). In type 2 diabetes (T2DM) patients, bone metabolic abnormalities present as a paradox of "high bone density, high fracture risk." Studies have found an interaction between SOST gene polymorphisms and bone metabolism indicators in postmenopausal T2DM women. The carriers of the rs10534024 mutation have significantly reduced femoral neck BMD, and there is a significant interaction between SOST and LRP5 gene polymorphisms affecting BMD (p<0.01). Furthermore, SOST rs10534024 polymorphisms are positively correlated with lumbar spine BMD. Additionally, in chronic kidney disease-mineral and bone disorder (CKD-MBD), elevated serum Sclerostin levels are associated with vascular calcification and increased cardiovascular event risks, suggesting its important mediating role in the bone-vascular axis.

Systemic Metabolic Regulation

Recent studies have shown that Sclerostin's biological functions extend beyond bone metabolism to involve systemic energy metabolism regulation. In glucose metabolism, serum Sclerostin levels are positively correlated with insulin resistance index (HOMA-IR), suggesting its involvement in glucose metabolism regulation. Animal models of Sost knockout mice show not only increased bone mass but also reduced white adipose tissue and enhanced insulin sensitivity. In lipid metabolism, clinical studies have found that carriers of the SOST rs851054 AG/AA genotype have significantly lower triglyceride (TG) levels compared to GG genotype carriers. These findings suggest that Sclerostin may be a key molecule linking bone metabolism and energy metabolism, with potential mechanisms related to regulating adipocyte differentiation and insulin signaling pathways. Additionally, Sclerostin is involved in the pathological process of vascular calcification by regulating BMP and Wnt signaling, influencing the osteoblastic differentiation of vascular smooth muscle cells, a feature particularly prominent in chronic kidney disease patients.