Osteopetrosis--multiple pathways for the interception of osteoclast function

Osteopetrosis is a metabolic bone disease inherited in a number of species including human beings and characterized by a generalized increase in skeletal density detected radiographically. This condition results primarily from reduced osteoclast function which produces partial or complete absence of marrow spaces, a variable compensatory hepatosplenomegaly, interferences with tooth eruption and certain neurological complications. Experimental investigations of some mutations have shown that restoration of bone resorption and recovery from the disease follow bone marrow transplantation. These data indicate that in these mutations, including some children, the defect is intrinsic to osteoclasts or their stem cells. In other mutations in animals and children, bone marrow transplants do not restore bone resorption and the defect is believed to be one of local environmental products or signals whose importance in cell differentiation and regulation is becoming increasingly appreciated. These data, reviewed with respect to the emerging cell biology of the osteoclast, indicate that osteopetrotic mutations have much to teach us about the regulation of bone metabolism.