Genetics and bone disease

Abstract

Bone diseases are a common cause of morbidity and mortality in developed countries, and genetic factors play an important role in the pathogenesis of these diseases. The most common form of bone disease is osteoporosis, which is characterized by reduced bone mineral density (BMD) and an increased risk of fracture. Environmental factors such as diet and exercise influence BMD but genetic factors play a predominant role, accounting for up to 85% of the variation in peak BMD. Several candidate genes have been identified that regulate BMD and susceptibility to fracture, including bone morphogenic protein 2, collagen type I alpha 1, the vitamin D receptor, the estrogen receptor and lipoprotein receptor related protein 5 (LRP5). Paget's disease of the bone (PDB) is characterised by focal abnormalities of increased bone turnover. Mutations in several genes have been identified as causes of PDB and related syndromes including receptor activator of NF-κB (RANK), osteoprotegerin, sequestosome 1 and valosin containing protein. All of these genes play a role in the RANK signalling pathway, which is essential for osteoclast activation. Rare bone diseases such as osteopetrosis and hereditary osteoscleroses are also caused by mutations in genes that affect bone cell function. Osteopetrosis is characterised by increased BMD, and failure of osteoclastic bone resorption due to mutations in genes that encode proteins that are essential for osteoclast activity like the chloride pump and proton pump, or mutations in genes like cathepsin K, which breakdown bone matrix. Although the bones are dense, fractures are common in osteopetrosis because of reduced bone quality. Osteosclerosis occurs because of mutations in genes that increase osteoblast activity, including SOST, transforming growth factor beta and LRP5. Osteosclerotic patients also have increased BMD but fractures are rare, because bone quality is normal. From a clinical standpoint, advances in knowledge about the genetic basis of bone disease offers the prospect of developing new markers for assessing fracture risk and the identification of new molecular targets that will form the basis for the design of new treatments.