Bone morphogenetic proteins and their antagonists: the sclerostin paradigm.

Sclerosteosis and Van Buchem disease are two closely related sclerosing disorders, characterized by progressive bone thickening due to increased bone formation. Sclerosteosis is due to premature termination mutations in the SOST gene, whereas Van Buchem disease has been associated with a 52 kb deletion downstream of the SOST gene that most likely inhibits SOST gene transcription. The gene product, sclerostin, is an osteocyte-expressed negative regulator of bone formation with amino acid sequence similarity with the DAN family of secreted glycoproteins, that share the capacity to antagonize bone morphogenetic protein (BMP) activity. The exact mechanism, however, by which sclerostin inhibits osteoblastic bone formation is still uncertain. While it binds BMPs and antagonizes their bone forming capacity, it cannot antagonize all BMP responses. Sclerostin's mechanism of action is, therefore, distinct from that described for classical BMP antagonists. The restricted expression of sclerostin and the exclusive bone phenotype of good quality of patients with sclerosteosis or Van Buchem disease provide the basis for the development of therapeutics that stimulate bone formation, such as, for example, an antibody against sclerostin.