Endocrine Abstracts

In the past 20 years or so careful observations in human and rodent diseases of bone metabolism have greatly helped to understand these diseases, but also uncover important pathways in bone metabolism. Such pathways have led to successful drug discovery programmes and some of the latest drugs to be licensed for use in common bone diseases have directly been the result of understanding such ‘experiments of nature’. An example is the targeting of cathepsin K as an anti-resorptive treatment, a target that was chosen after the gene CTSK was found to be involved in the rare disease pycnodysostosis in which osteoclasts cannot degrade bone collagen.

In this presentation I will first outline some of the key cellular pathways involved in bone formation and bone degradation and remodelling. I will then describe some of the rare diseases that have provided insights in these pathways. I will focus specifically on diseases caused by osteoclast dysfunction as we have most information in those conditions. I will discuss the various types of osteopetrosis, high bone mass disorders caused largely by defects in osteoclast function (TCIRG1, CLC7, OSTM1, CA2, PLEKHM1), but also, in some cases, by defects in osteoclast formation (RANK, RANKL).

I will then discuss some recent findings in the diseases classed as ‘Paget-like diseases of bone’, a group of conditions in which bone turnover is increased and in which mutations in Q5STM1, VCP and RANK have been identified. It has become clear that protein degradation pathways may be affected in these diseases.

Finally, I will briefly discuss the rare, but important high bone mass conditions caused by mutations in LRP5 and SOST. The discovery of these genes has led to a rapid translation of basic science to clinical applications and offers hope for treatment of common low bone mass disorders such as osteoporosis.