RECENT DEVELOPMENTS IN THE UNDERSTANDING OF THE PATHOPHYSIOLOGY OF OSTEOPETROSIS

Osteopetrosis is a rare metabolic bone disease characterized by a gene ralized increase in skeletal mass, It is inherited in a number of mamm alian species, including man, and results from a congenital defect in the development or function of the osteoclasts. The consequent impairm ent of bone resorption prevents formation of bone marrow cavities, cau ses delayed or absent tooth eruption and results often in abnormally s haped bone. The pathogenetic defect may be intrinsic either to the ost eoclast lineage or to the mesenchymal cells that constitute the microe nvironment supporting the development and activation of the osteoclast s. In the first example, the disease can be cured by transplantation o f hemopoietic cells. In some cases, bone marrow transplantation has al so been successful in curing human osteopetrosis. This, together with the variability in the age of onset and severity of clinical aspects, suggests that a multiplicity of genetic mutations may cause the human disease. In recent years the genetic effects of some osteopetrotic mut ations have been identified. This new information has been essential f or the understanding of osteoclast biology, Colony stimulating factor 1 (CSF-1), the growth factor for cells of the mononuclear phagocytic s ystem, is also essential for the development of osteoclasts. In the os teopetrotic joy) mouse, no biologically active CSF-1 is synthesized du e to a point mutation in the coding region of its gene, This leads to an almost complete lack of osteoclast development and to impaired bone resorption. Altered CSF-1 production seems also to be involved in the toothless (tI) rat osteopetrosis. Recently, the mutation responsible for the microphthalmic (mi) mouse osteopetrosis has been identified in the gene encoding a member of the basic-helix-loop-helix-leucine zipp er (bHLH-ZIP) protein family of transcription factors. The mi gene pro duct seems to play a role in the fusion process of osteoclast precurso r cells. Finally, osteopetrosis has been the result of experimental ge ne disruption in mice. Targeted disruption of the c-src proto-oncogene encoding a nonreceptor tyrosine kinase leads to a form of osteopetros is where osteoclasts are present but inactive. This indicates that pp6 0(c-src), localized primarily on ruffled border membranes and vacuoles of the osteoclasts, is important for osteoclastic function. Disruptio n of the c-fos proto-oncogene, a major component of the AP-1 transcrip tion factor complex, leads to an osteopetrotic phenotype characterized by a complete absence of osteoclasts. The defect is intrinsic to hemo poietic precursors that are unable to progress beyond an early stage o f osteoclast differentiation. In humans, deficiency of carbonic anhydr ase II has been identified as the primary defect in the autosomal rece ssive syndrome of osteopetrosis with renal tubular acidosis and cerebr al calcification. A lack of expression of the vacuolar proton pump has been observed in osteoclasts of a patient with craniometaphyseal dysp lasia, In conclusion, the disease, although rare, is of great pathophy siological relevance for our understanding of the processes that gover n the development and function of osteoclasts.