The mouse osteopetrotic grey-lethal mutation induces a defect in osteoclast maturation/function

The osteopetrotic grey-lethal (gl) mouse mutant displays many similarities to the human malignant autosomal-recessive form of osteopetrosis, In this s tudy, we show that the gl osteopetrotic bone phenotype is characterized by the presence of numerous differentiated multinucleated osteoclasts, A signi ficant increase in the number of tartrate-resistant acid phosphatase (TRAP) -positive osteoclasts was detected in vivo, suggesting induction of differe ntiation in the osteoclast lineage as a compensatory mechanism. These gl os teoclast cells demonstrated a defective cytoskeletal reorganization and an underdeveloped ruffled border, a membrane structure essential for active bo ne resorption, Accordingly, resorption activity of these cells is markedly impaired by four-to tenfold as evaluated with the pit formation assay, This low bone resorption in gl osteoclasts is highly reminiscent of the loss in key enzymes, V-ATPase or cathepsin-g, and in signaling factors, Src or TRA F-6, which were shown not to be significantly altered in gl osteoclasts. Th us, independently of a deficiency in V-ATPase, Src, cathepsin-g, and TRAF-6 , the gl mutation results in increased number of osteoclasts, characterized by a disrupted cytoskeleton acid an underdeveloped ruffled border. (C) 200 1 by Elsevier Science Inc. All rights reserved.