Sclerostin (SOST) is a negative regulator of bone growth, acting by inhibiting Wnt signaling and bone formation. SOST regulates bone metabolism and is also expressed in cardiovascular, renal, and hepatic tissues, influencing the development of diseases in these organs and tissues. Extra-skeletal organ diseases such as atherosclerosis, aneurysms, chronic kidney disease (CKD), and cirrhosis may be associated with SOST expression.
(Data source: Chen M, et al. Biomolecules. 2025)
SOST expression distribution
SOST is mainly synthesized and secreted by mature osteocytes and expressed in nephron cells, congenital lymphocytes, and endothelial cells.
(Data source: unprot)
The structure and receptor of SOST
SOST is a glycoprotein with a molecular weight of 24 kDa, composed of 213 amino acids. Its secretory signal peptide consists of the first 23 amino acids. At the core of the SOST protein is a cystine knot-like domain, a key region for binding to ligands and receptors in the Wnt signaling pathway. The "cystine knot" structure is a finger-like structure formed by two pairs of twisted, antiparallel β-chains, with the cystine knot at the bottom. Within the cystine knot motif, four highly conserved cysteine residues form two intrachain disulfide bonds, creating a ring structure typically composed of 8-14 residues. The conserved cysteine residues form a third disulfide bond on the ring, resulting in an exceptionally stable structural motif.
Its N-terminus contains a flexible loop region, which is crucial for the biological activity of SOST and is the main binding site for its receptors LRP5/6. SOST is a glycosylated protein, and its glycosylation modifications may affect its stability, secretion, and affinity for receptors.
SOST 's Loop 2 binds to the E1 extracellular domain of LRP6, while a portion of the C-terminal arm interacts with the E2 extracellular domain.
(Data source) Omran A, et al. Int J Mol Sci. 2022)
The functions of SOST
The core function of SOST is as an extracellular antagonist of the classic Wnt/β-catenin signaling pathway. Its mechanism of action is direct and efficient. In the absence of SOST, Wnt ligands bind to Frizzled receptors and LRP5/6 co-receptors on the cell membrane, forming a trimer complex. This inhibits the downstream " disruption complex , " stabilizes β-catenin in the cytoplasm, allows it to enter the nucleus, and initiates the transcription of osteogenic-related genes, thereby promoting bone formation.
Inhibitory effect of SOST: As an antagonist, SOST directly binds to the LRP5/6 co-receptor of the Wnt signaling pathway. The binding of SOST to LRP5/6 competitively blocks the binding of Wnt ligands to LRP5/6, thereby preventing the formation of the signaling complex.
Even in the presence of Wnt ligands, SOST binding may induce conformational changes in LRP5/6, preventing them from effectively cooperating with the Frizzled receptor. The Wnt signaling pathway is disrupted, and the " destruction complex " remains active, continuously degrading β-catenin. The inability of β-catenin to enter the nucleus inhibits osteoblast differentiation, activity, and survival, thereby weakening bone formation.
(Data source: Omran A, et al. Int J Mol Sci. 2022)
SOST targeted therapy
Sclerosstatin is an inhibitor of the WNT/β-ligand signaling pathway, stimulating osteoblast differentiation and bone formation. Sclerosstatin monoclonal antibodies, by inhibiting sclerosstatin activity, can promote bone formation, reduce bone resorption, and increase bone density and strength, thereby reversing the symptoms of osteoporosis .
Blosozumab is a monoclonal antibody targeting SOST , initially developed by Eli Lilly, and later licensed to Transcenta Holding in Greater China. It is a humanized monoclonal antibody with sclerosing activity. Eli Lilly has completed Phase II trials of Blosozumab in postmenopausal women in the United States and Japan. Data showed that Blosozumab, compared to placebo, induced a significant dose-dependent increase in bone mineral density (BMD) in the spine, femoral neck, and total hip joint. Results from the Blosozumab SAD study were presented at the 2024 WCO-IOF-ES CEO Conference in April. Following a single dose of up to 1200 mg of Blosozumab, all dose groups showed an average increase in lumbar spine BMD of 3.52% to 6.20% and an average increase in total hip BMD of 1.30% to 2.24% on day 85. The increase in lumbar spine BMD exceeded the minimum significance level (2.77%), representing a substantial clinical outcome.
(Data source: Chuangsheng Group official website)
Romosozumab is a monoclonal antibody that targets SOST and is used to treat fractures, postmenopausal osteoporosis, and osteoporosis.
Setrusumab ( UX-143 ) is a monoclonal antibody targeting SOST, used to treat osteogenesis imperfecta type III, osteogenesis imperfecta type IV, and other osteogenesis disorders. Mereo biopharma is investigating it as a potential treatment for osteogenesis imperfecta (OI). It is designed to inhibit sclerostin, a mechanism believed to improve bone formation and strength, potentially reducing fractures and improving the quality of life for OI patients. In October 2024, setrusumab received Breakthrough Therapy Designation from the FDA. The FDA's decision was based on preliminary clinical evidence, including positive 14-month results from the Phase 2 Orbit study, which showed a rapid and clinically significant decrease in fracture rates in patients (5 to <26 years old) treated with setrusumab compared to pre-treatment fracture rates; and completed data from the Phase 2b ASTEROID study in adult patients. Breakthrough Therapy designation aims to accelerate the development and approval of drugs for the treatment of serious or life-threatening diseases based on preliminary clinical evidence that the drug may provide significant improvement over existing therapies on one or more clinically meaningful endpoints.
