Wnt signalling pathway: a new target for the treatment of osteoporosis

Abstract

The prevention and treatment of osteoporosis traditionally involves the use of antiresorptive agents that target osteoclast function. Antiresorptive therapy is not associated with a significant increase in bone mass and, thus, only partially reduces the risk of fractures. For that reason, the search for anabolic agents, which target osteoblast function, represents an urgent medical need. The first approved bone anabolic drug for the treatment of osteoporosis was teriparatide (human parathyroid hormone 1-34). Recently, both human genetics and animal studies have pointed out the role of the Wnt/LRP5 pathway as a major regulator of bone mass accrual. Wnts are secreted glycoproteins that bind to receptor complexes including low-density lipoprotein receptor-related protein (LRP)-5/6 and Frizzled proteins. A subsequent intracellular cascade of events stabilises β-catenin, leading to its translocation into the nucleus where, associated with Tcf/Lef transcription factors, it triggers gene expression. The existence of many potential pharmacological targets in this pathway makes it attractive for bone anabolic drug discovery.

Keywords::

• low-density lipoprotein receptor-related protein-5 (LRP5)
• osteoblast
• osteoclast
• osteoporosis
• Wnt