esclerostina

Esclerostina, or sclerostin, is a secreted glycoprotein produced primarily by osteocytes in the bone. It functions as a negative regulator of bone formation by inhibiting the Wnt/β-catenin signaling pathway in osteoblasts and their precursors, thereby reducing osteoblast activity and bone formation. In Spanish-language literature, the protein is commonly referred to as esclerostina.

Biology and mechanism: Sclerostin acts extracellularly by binding to the LRP5/6 co-receptors, and possibly LRP4, which prevents Wnt ligands from activating signaling that promotes osteoblast proliferation and activity. This results in decreased β-catenin signaling and diminished bone formation. Expression of sclerostin is responsive to mechanical load: mechanical stimulation lowers SOST expression and sclerostin secretion, while unloading or disuse increases it.

Genetics and disease: Loss-of-function mutations in the SOST gene cause conditions with high bone mass, such as sclerosteosis and Van Buchem disease, due to unchecked bone formation. Conversely, increased sclerostin activity is associated with reduced bone formation observed in osteoporosis and age-related bone loss.

Therapeutic and clinical relevance: Targeting sclerostin with monoclonal antibodies (for example, romosozumab) stimulates bone formation and increases bone mineral density, offering fracture risk reduction in osteoporosis. These therapies are approved in various regions and are often used in specific treatment sequences with antiresorptives. Safety considerations include monitoring for potential cardiovascular risks reported in some studies.