Recent developments in the understanding of the pathophysiology of osteopetrosis
Authors: Felix Rolf , Hofstetter Willy , Cecchini Marco G 
Published: December 2008

Felix R, Hofstetter W, Cecchini MG. Recent developments in the understanding of the pathophysiology of osteopetrosis. Eur J Endocrinol 1996;134:143–56. ISSN 0804–4643
Osteopetrosis is a rare metabolic bone disease characterized by a generalized increase in skeletal mass. It is inherited in a number of mammalian species, including man, and results from a congenital defect in the development or function of the osteoclasts. The consequent impairment of bone resorption prevents formation of bone marrow cavities, causes delayed or absent tooth eruption and results often in abnormally shaped bone. The pathogenetic defect may be intrinsic either to the osteoclast lineage or to the mesenchymal cells that constitute the microenvironment supporting the development and activation of the osteoclasts. In the first example, the disease can be cured by transplantation of hemopoietic cells. In some cases, bone marrow transplantation has also 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 mutations have been identified. This new information has been essential for the understanding of osteoclast biology. Colony stimulating factor 1 (CSF-1), the growth factor for cells of the mononuclear phagocytic system, is also essential for the development of osteoclasts. In the osteopetrotic (op) mouse, no biologically active CSF-1 is synthesized due 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 (tl) 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-helixleucine zipper (bHLH-ZIP) protein family of transcription factors. The mi gene product seems to play a role in the fusion process of osteoclast precursor cells. Finally, osteopetrosis has been the result of experimental gene disruption in mice. Targeted disruption of the c-src proto-oncogene encoding a non-receptor tyrosine kinase leads to a form of osteopetrosis where osteoclasts are present but inactive. This indicates that pp60c−src, localized primarily on ruffled border membranes and vacuoles of the osteoclasts, is important for osteoclastic function. Disruption of the c-fos proto-oncogene, a major component of the AP-1 transcription factor complex, leads to an osteopetrotic phenotype characterized by a complete absence of osteoclasts. The defect is intrinsic to hemopoietic precursors that are unable to progress beyond an early stage of osteoclast differentiation. In humans, deficiency of carbonic anhydrase II has been identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. A lack of expression of the vacuolar proton pump has been observed in osteoclasts of a patient with craniometaphyseal dysplasia. In conclusion, the disease, although rare, is of great pathophysiological relevance for our understanding of the processes that govern the development and function of osteoclasts.
R Felix, Department of Pathophysiology, University of Berne, Murtenstrasse 35, CH-3010 Berne, Switzerland