Human osteopetroses and the osteoclast V-H+-ATPase enzyme system

Osteopetroses are a heterogeneous group of human genetic diseases characterized by generalized increase in bone density due either to a decreased osteoclast population, defect in osteoclast function, or both. Current knowledge of the pathogenesis suggests defects that may be either intrinsic to osteoclast-monocyte lineage or extrinsic to the mesenchymal cells that support osteoblast ontogeny and activation. Four clinically distinct forms of human osteopetroses currently recognized are the infantile malignant autosomal recessive form, the intermediate autosomal recessive form, the adult benign autosomal dominant osteopetrosis type I, and the autosomal dominant osteopetrosis type II. Propensity to fracture is high in all types of osteopetrosis, and other characteristic clinical problems include hematologic and metabolic abnormalities, infections of affected bone, and neurologic sequela. Among the infantile malignant clinical forms 50-60% of patients present with defects in the OC116-KDa (also refers to ATP6i, TCIRGI, a3) subunit of the osteoclast vacuolar H+-ATPase (V-H+-ATPase) proton pump. Approaches that have been applied to the treatment of osteopetrosis include those aimed at stimulating host osteoclasts. These approaches however have met with little success, and it would appear that the future for the successful treatment of osteopetrosis lies with bone marrow transplantation. Various animal models mimicking some of the clinical subtypes of osteopetrosis have been generated in efforts to elicit further understanding of the pathogenesis. This review is an update on the various phenotypic presentations of human osteopetroses alongside their known animal models. Further studies on these animal models will not only expand our basic understanding of the molecular mechanisms of osteopetroses, but will also aid our ability to develop therapeutic means of intervention in diseases involving osteopetroses.