LRP5 and bone mass regulation: Where are we now?

The discovery of causal mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene underlying conditions of altered bone mass ushered in a new era in bone research. Since those original publications, the role of Lrp5 and the Wnt/β-catenin signaling pathway controlled by Lrp5 and its homologs, Lrp6 and Lrp4, in bone mass regulation has been an intense area of investigation. Studies to date have implicated this pathway in skeletal development, osteoblast differentiation and proliferation, osteoblast/osteocyte apoptosis, regulation of the balance between osteogenesis-chondrogenesis-adipogenesis, regulation of osteoclastogenesis and the response of bone to mechanical loading. Interestingly, the data from knockout and transgenic mice involving Lrp4/5/6 and/or their regulators, as well as β-catenin signaling pathway components, and in vitro studies have sometimes yielded conflicting results. Adding to the complexity of the system are the studies that suggested Lrp5 regulated bone mass through a gut-bone endocrine signaling system involving Lrp5 mediated control of gut serotonin synthesis. However, recent studies have called this into question and so this provocative concept remains an open question. Clearly, the manipulation of Lrp5/Wnt/β-catenin pathway presents as a major target for drug development to treat diseases of low bone mass such as osteoporosis and these new therapies are in full progress. At present, although it is clear that Lrp5 has a role in bone mass regulation, much of the details remain to be elucidated and this is a major and exciting challenge for future studies.