Osteoporosis is a skeletal disorder affecting hundreds of millions of people and is characterized by a reduced bone mineral density (BMD) and disruption of the bone micro-architecture, resulting in an increased risk of fragility fractures. Currently, one in three women and one in five men above the age of 50 experience an osteoporotic fracture, making osteoporosis a defining health problem of our ageing society. Hereto, the past decade, numerous candidate gene and genome-wide association studies were performed to identify new, putative therapeutic targets for osteoporosis. Here, WNT16, a modulator of WNT signaling, was discovered to be associated with BMD and fracture risk by several genetic studies. Subsequent in vitro and in vivo functional studies highlight WNT16 as an interesting target for osteoporosis and new treatment strategies targeting the regulation of WNT16 might be useful to reduce fracture risk.
Therefore, the general aim of this project is to explain the downstream effects of WNT16 on WNT signaling in osteoblasts. Our preliminary data indicate that WNT16 activates both canonical and non-canonical WNT signaling in osteoblasts, of which activation of canonical WNT signaling occurs in a non-standard manner. The current literature suggests that these preliminary data can be fully explained by the recruitment of specific Gα-subunits to the Frizzled receptor, after WNT16 binding to osteoblasts. This hypothesis will be investigated by performing knockdown of these Gα-subunits in osteoblasts, after which the activity of the different WNT signaling pathways by WNT16 will be monitored.
Performing these functional experiments could lead to a better understanding of the effects of WNT16 on osteoblasts. This knowledge can definitely be valuable in the research to new treatment strategies to reduce the risk for osteoporotic fractures in the future.