Bone Abstracts (2015) 4 IS17 | DOI: 10.1530/boneabs.4.IS17

Molecular and cellular bases of high bone mass

Anna Villa1,2


1Milan Unit, Institute of Genetic and Biomedical Research (IRGB), National Research Council (CNR), Milan, Italy; 2Humanitas Clinical and Research Center, Rozzano, Italy.


Bone remodelling is maintained by a balanced activity of osteoclasts and osteoblasts. Alterations in this cross-talk result in bone pathological conditions. High bone mass defines a complex and heterogenous genetic condition characterized by increased bone density. In particular, osteopetrosis is a genetic condition of high bone mass caused by impairment in osteoclast generation or function. Molecular analysis of human osteopetrosis has allowed the identification of novel genes playing key roles in osteoclast function and generation. In my presentation, I will focus on the genes involved in the pathogenesis of the dominant and recessive forms of osteopetrosis. This disease is highly heterogeneous in presentation and is often misdiagnosed in the mild forms. To date, seven genes have been identified as being responsible for autosomal recessive osteopetrosis (ARO). In humans, mutations in TCIRG1, CLCN7, OSTM1, SNX10, and PLEKHM1 molecules have been described to cause osteoclast-rich ARO in which osteoclasts are present but severely impaired in their ability to resorb bone. Conversely, mutations in TNFSF11 and TNFRSF11A genes lead to osteoclast-poor ARO, characterized by the absence of multinucleated osteoclast. Mutations in the carbonic anhydrase II gene result in osteopetrosis associated with renal tubular acidosis, while mutations impairing the NFκB essential modulator (NEMO) gene have been reported in a rare X-linked syndrome characterized by increased bone density associated with anhidrotic ectodermal dysplasia, immunodeficiency, and lymphoedema. The molecular basis underlying the disease is crucial for the identification of the best therapeutic approach to offer to affected individuals.

Disclosure: The author declared no competing interests.

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