Sclerostin is the protein product of the SOST (sclerosteosis) gene of which loss causes sclerosteosis, a sclerosing skeletal disorder characterized by progressive bone overgrowth leading to increased bone mass. Based on its amino acid sequence, sclerostin belongs to the DAN family of bone morphogenetic protein (BMP) antagonists. It has been shown in the literature that sclerostin can antagonize BMP-induced bone formation and compete with BMP binding to type I and II BMP receptors. There are, however, two features that distinguish sclerostin from other BMP antagonists. Firstly, not all BMP-induced biological responses are able to be antagonized by sclerostin. Furthermore, this is cell dependent. Sclerostin may, therefore, only act as a BMP antagonist in a certain cellular context or possibly another BMP-induced factor may be the actual ligand for sclerostin. Secondly, sclerostin/SOST expression is restricted to osteocytes in human and mouse bone biopsies, whereas other BMP antagonists are expressed in osteoblasts and osteocytes largely independent of differentiation stage.
Our goal at Percuros is to unravel the mechanism of action by identifying the (co-) factor needed for sclerostin to antagonize BMP activity and to identify a therapeutic strategy which can modulate this process in order to prevent osteoporosis.