Characterizing the bone anabolic function of Wnt1

• Applicants: Professor Dr. Michael Amling; Dr. Jean-Pierre David, Ph.D. (†)
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: from 2017 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 337863858

Bone remodeling is a physiologically relevant process occurring throughout life required to ensure bone regeneration and long-term stability. It is the result of the coupling between two physiological activities i.e. the coupling between bone resorption by a specialized bone macrophage (the osteoclast) and bone formation by a mesenchymal cell type (the osteoblast). With age, this coupling will be progressively shifted in favor of an excess bone resorption and decreased bone formation leading to osteoporosis, a pathology characterized by an increased fracture risk. So far, osteoporosis is mainly treated with anti-resorptive drugs either inhibiting osteoclast activity (bisphosphonates) or differentiation (Denosumab). A consequence of these treatments is to interrupt the normal coupling between bone resorption and formation leading to a secondary inhibition of bone formation that affects the bone quality and lead to new pathologies (necrosis of the jaw and atypical bone fractures). In contrary, it is generally believed that increasing bone formation would not be disturbing the normal bone coupling and therefore would certainly offer a better alternative. However, whether unwanted side effects would be a consequence of bone anabolic therapies remains to be established and is the central point of this application. Indeed, we observed that osteosclerotic mice over-expressing Fra1 (Fra1Tg) display high levels of circulating Wnt1, a newly identified bone-anabolic molecule in humans. Importantly, we previously characterized numerous pathologies in Fra1Tg mice including severe lipodystrophy, general fibrosis and impaired plasma cell differentiation. We now propose, with the help of a mouse model conditionally over-expressing Wnt1 in the bone, to determine whether Wnt1 could indeed be used as a bone-anabolic therapy without inducing the unwanted side effects observed in Fra1Tg mice.

• DFG Programme: Research Grants