Sclerostin

Sclerostin is a secreted glycoprotein produced primarily by osteocytes in bone. It is encoded by the SOST gene. Sclerostin functions as an inhibitor of the Wnt signaling pathway in bone, thereby suppressing bone formation.

Mechanism: Sclerostin binds to LRP5/6 co-receptors on osteoblasts, antagonizing canonical Wnt signaling and reducing osteoblast proliferation and activity. By restraining osteoblast function, it helps regulate bone formation and remodeling. Mechanical loading lowers sclerostin expression, while unloading or disuse increases it.

Clinical relevance: Mutations that reduce sclerostin activity cause sclerosteosis and van Buchem disease, rare conditions with progressive high bone mass. Conversely, pharmacologic inhibition of sclerostin with monoclonal antibodies (for example romosozumab) stimulates bone formation, increases bone mineral density, and reduces fracture risk in osteoporosis, though safety considerations remain.

Expression and measurement: Sclerostin is detected in circulation and can serve as a biomarker of bone metabolism in some settings. Its levels reflect bone mass, aging, and response to therapy. The biology of sclerostin continues to be explored in relation to vascular biology and mechanotransduction.