Human osteopetrosis and other sclerosing disorders: Recent genetic developments

Osteopetroses are rare human genetic disorders due to markedly decreased bo ne resorption. To date, the only gene whose inactivation was known to be re sponsible for human osteopetroses was that encoding carbonic anhydrase type II. Recessive malignant osteopetrosis is linked to decreased osteoclast fu nction, unlike several osteopetroses in rodents that are caused by the inac tivation of genes stimulating osteoclast differentiation. Recent advances i n genetics have shown that some patients affected with recessive malignant osteopetrosis have inactivating mutations in a subunit of the vacuolar prot on pump that is actively produced in the osteoclast brush border, but not i n the lysosomes of other cells. The same gene is mutated in osteopetrotic o c/oc mice. The genes responsible for autosomal dominant osteopetrosis (ADO) have not yet been identified. Also, different localizations have been obse rved for ADO II, the type with sandwich vertebrae, and ADO I, presenting wi th diffuse osteocondensation. Less data than in malignant osteopetrosis are avaible on the cellular mechanism of decreased bone resorption in ADO but there is also genetic heterogeneity in ADO II. Pycnodysostosis is also due to a decreased resorption, and is quite close to osteopetrosis. Pycnodysost osis is linked to an inactivating mutation in the CY gene encoding cathepsi n K, which is required for osteoclastic resorption. Decreased bone resorpti on is not the only defect inducing osteosclerosis, and Camurati-Engelmann d isease is due to increased bone formation. Recently it has been shown that it is associated with a mutation in the propeptide of TGF beta1. Thus, huma n osteosclerosing disorders have a wide range of phenotypes and genotypes a nd knowledge of them will contribute to a better understanding of the remod eling of normal bone.