Osteopetrosis is a genetically and clinically heterogeneous bone disorder characterized by a reduction in bone resorption and a generalized net accumulation of skeletal mass. The causative genes identified so far all play a role in acidification of the resorption lacuna, and loss-of-function mutations in these genes severely affect mature osteoclast function. The CA2 (carbonic anhydrase 2) gene produces the protons necessary for acidification of the resorption lacuna, the extracellular compartment between the bone tissue and the osteoclast where bone resorption occurs. The α3 subunit of the H+ ATPase is involved in the transportation of these protons through the ruffled border into the resorption lacuna, while chloride channel 7 (ClC-7) translocates chloride ions to maintain electroneutrality.

In animals, osteopetrotic mutations affecting both formation and function of osteoclasts have been described. One of the spontaneous mutations is the incisors absent (ia) rat which exhibits a generalized skeletal sclerosis and delay of tooth eruption. These mutants have 2 to 3 times more osteoclasts than do normal littermates, and ia osteoclasts lack ruffled borders but contain numerous small cytoplasmic vesicles containing tartrate-resistant acid phosphatase, suggesting a dysfunction of the secretory pathways.

In this study [1], the gene responsible for ia mutation has been identified as pleckstrin homology domain¿containing family M (with RUN domain) member 1 (PLEKHM1). Loss-of-function mutations of this protein underlie the osteopetrotic phenotype of the ia rat as well as an intermediate type of human osteopetrosis. Monocytes from a patient homozygous for the mutation differentiated into osteoclasts normally, but cultured osteoclasts failed to form ruffled borders and showed little evidence of bone resorption.

In conclusion, PLEKHM1 appears to be a novel gene implicated in the development of osteopetrosis, with a putative critical function in vesicular transport in the osteoclast.

1. Van Wesenbeeck L et al. J Clin Invest. 2007;117:919-930.