Analysis of the roles of the Wnt-ligands Wnt9a and Wnt4 in adult bone and joint homeostasis

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Osteoporosis (OP) and osteoarthritis (OA) are degenerative musculoskeletal diseases with a very high prevalence. They occur primarily in elderly people. The hallmarks of osteoporosis are: decreased bone mineral density, loss of bone and increased bone fragility. OA is also associated with bone alterations. Here, it is primarily the subchondral bone that changes during the course of the disease. In early OA, bone turnover is increased in the subchondral bone, while subchondral bone thickening is a characteristic feature of late OA. As such, drugs, such as the anti catalytically acting bisphosphonates and the anabolically active Teriparatide, which are normally used to treat OP, have been tested in OA animal models for potential beneficial effects. These studies showed that these drugs can alter disease progression. Wnt-ligands, amongst them Wnt9a and Wnt4, and members of Wnt signaling pathways have been implicated to play roles in OP and OA. In the project proposed here, we will examine the roles of Wnt9a and Wnt4 in adult bone and joint-homeostasis of the mouse using different conditional knockout approaches. The loss of Wnt9a in the limb mesenchyme results in the development of spontaneous OA-like changes in the joints of aged mice. The onset of these changes is accelerated upon additional loss of Wnt4 in the limb mesenchyme. In addition to the joint alterations, we observed alterations in the bone, which are not restricted to the subchondral region. In the proposed project we want to complete the phenotypic characterization of the musculoskeletal alterations upon loss of Wnt9a and the combined loss of Wnt9a and Wnt4 in the limb mesenchyme. Both Wnt-ligands are produced by cells in the joint as well as by osteoblasts. Hence, in order to phenotypically distinguish between the contribution of the different cells / tissues to the observed skeletal alterations we want to examine the phenotypic changes after postnatal deletion of Wnt9a or Wnt4 in superficial chondrocytes using the Prg4-Cre line and in osteoblast precursors using the Osx-Cre line. Using in vivo and in vitro approaches, we expect to answer the questions which signaling pathways are used by the two Wnt-ligands in osteoblasts, articular chondrocytes, and synoviocytes and whether these differ between the Wnt-ligands or the different cell types. In addition, we want to generate transgenic mice expressing increased levels in superficial articular chondrocytes to see whether this has a beneficial effect on OA-progression in a surgically induced model of OA.