Molecular mechanism of Sclerostin-mediated Wnt-inhibition

• Applicant: Professor Dr. Thomas Müller
• Subject Area: Biochemistry
• Term: from 2012 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 222166749

The bones of our skeleton do not constitute dead tissue, but cycle through a life-long reorganization process. Three cell types organize this remodeling: bone-forming osteoblasts, osteoclasts dismantling bone tissue and osteocytes as the master regulators keeping the balance between osteocatabolic and osteoanabolic action. Two protein families, the bone morphogenetic proteins (BMPs) and the Wnt family, harbor key components of this regulatory network. Deregulation of bone buildup and removal lead to severe diseases such as osteopetrosis (bone overgrowth) or osteoporosis (bone loss). The latter is affecting a large group of patients as more than 30% of women after menopause suffer from osteoporosis. Sclerostin was identified in 2003 as a factor which, if neutralized, leads to an increase in bone mass making it to a prime target for bone growth related diseases. Similar to Dickkopf (Dkk) proteins Sclerostin binds to Wnt coreceptors of the LRP family thereby blocking Wnt activity. The molecular mechanism by which Sclerostin blocks Wnt activity is still largely unknown. Recent own studies have yielded first insights into the structure/function relationship of Sclerostin suggesting that it impairs Wnt activity by a mechanism different from that of the Dkk proteins. In this proposal we want to unravel the mechanism of Sclerostin-mediated Wnt inhibition by biochemical and biophysical means. As Sclerostin is a highly promising target for a new osteoporosis therapy we want to determine the structures of Sclerostin-neutralizing antibodies alone and in complex bound to Sclerostin. To understand the inhibition mechanism we will also determine the structure of the Sclerostin-LRP6 complex. Together with a functional analysis of the binding epitope of Sclerostin on LRP6 these data will facilitate the development of new drugs for the treatment of bone growth related diseases such as osteoporosis and Sclerosteosis/Van Buchem disease.

• DFG Programme: Research Grants