Discovery and Molecular Structure

• Sclerostin originates from the SOST gene, discovered during research on conditions affecting bone density like sclerosteosis and van Buchem disease.
• Part of the DAN/Cerberus family of bone morphogenetic protein (BMP) inhibitors.
• Composed of 213 amino acids with a unique cysteine knot structural pattern.
• Core held together by disulfide bonds, essential for its biological role.
• SOST gene mainly active in osteocytes, cells that sense mechanical forces within the bone.

Physiological Role in Bone Metabolism

• Acts as a strong inhibitor of bone formation.
• Inhibits the Wnt/β-catenin signalling pathway, involved in osteoblast differentiation and function.
• Binds to LRP5/6 co-receptors, hindering Wnt-Frizzled-LRP5/6 assembly, switching off canonical Wnt signalling.
• Leads to reduced bone formation and mineralization.
• Expression stimulated by mechanical loading, hormones, and cytokines, allowing dynamic regulation of bone turnover.

Clinical Significance and Disease Associations

• Important in bone homeostasis, exemplified by genetic conditions:
• Sclerosteosis and van Buchem disease: loss of SOST function, progressive bone overgrowth, increased bone mineral density.
• Elevated sclerostin levels associated with:
• Osteoporosis
• Chronic kidney disease-mineral bone disorder (CKD-MBD)
• Diabetes-related bone fragility

Therapeutic Applications and Anti-Sclerostin Antibodies

• Romosozumab: enhances bone formation, inhibits bone resorption, effective for severe osteoporosis.
• Considerations for anti-sclerostin therapy: potential cardiovascular risks and side effects.
• Other therapeutic interventions being explored: small molecule inhibitors, gene therapy.