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Investigating Ror2-dependent non-canonical Wnt signaling in bone remodeling

Periodic Reporting for period 1 - ROR2BONE (Investigating Ror2-dependent non-canonical Wnt signaling in bone remodeling)

Reporting period: 2015-05-01 to 2017-04-30

Osteoporosis is a very common disease in aging societies, leading to a decrease in bone mass and strength and ultimately fragility fractures. Fragility fractures cause pain and an immobilization and lead to an increased morbidity and mortality. Thus, osteoporosis has a great socio-economic impact that is very likely to increase as populations age. Bones are constantly dismantled and rebuild by bone-resorbing osteoclasts and bone-forming osteoblasts. Thus, current specific osteoporosis therapies are focusing on decreasing bone resorption or on increasing bone formation. However, the drugs that are available thus far have side effects, might not be applicable due to concomitant diseases or can only be administered for a limited period of time. It is therefore important to better understand the molecular and cellular processes by which the bone tissue is formed and resorbed, to identify novel targets that could facilitate the development of future therapies. This project is focusing on exploring novel regulatory circuits of the Wnt pathway, which is known to be a strong inducer of bone formation.
In this project we focused on investigating the function of the Ror2 on bone turnover. We uncovered that this receptor regulates osteoblast differentiation and function and controls bone mass. This effect was mediated in a cell-autonomous manner and the findings were confirmed in vitro and in vivo. Next, we performed an unbiased screen to obtain information regarding the underlying molecular mechanisms. This screen revealed strong candidate genes and our ongoing experiments are aimed at further elucidating the molecular mechanisms by which the receptor affects bone remodeling. In a next step, we intend to investigate this mechanism in the context of a novel anti-osteopororsis therapy.
This project provides novel insights on the regulation of bone metabolism. This knowledge might help to identify new candidate targets that could be used to develop future therapies to treat conditions of bone fragility. This could improve the cure of osteoporosis as a debilitating disease and therefore have a great societal impact.
Scheme of the domains of Ror2