title: The mouse osteopetrotic grey-lethal mutation induces a defect in osteoclast maturation/function.
abstract: The osteopetrotic grey-lethal (gl) mouse mutant displays many similarities to the human malignant autosomal-recessive form of osteopetrosis. In this study, we show that the gl osteopetrotic bone phenotype is characterized by the presence of numerous differentiated multinucleated osteoclasts. A significant increase in the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts was detected in vivo, suggesting induction of differentiation in the osteoclast lineage as a compensatory mechanism. These gl osteoclast cells demonstrated a defective cytoskeletal reorganization and an underdeveloped ruffled border, a membrane structure essential for active bone 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-K, and in signaling factors, Src or TRAF-6, which were shown not to be significantly altered in gl osteoclasts. Thus, independently of a deficiency in V-ATPase, Src, cathepsin-K, and TRAF-6, the gl mutation results in increased number of osteoclasts, characterized by a disrupted cytoskeleton and an underdeveloped ruffled border.
authors.affiliation: Institut de recherches cliniques de Montréal, Faculté de Médecine de l'Université de Montréal, 110 avenue des Pins Quest, Montréal, Quebec H2W 1R7, Canada.
authors.forename: V
authors.initials: V
authors.lastname: Rajapurohitam
authors.forename: N
authors.initials: N
authors.lastname: Chalhoub
authors.forename: N
authors.initials: N
authors.lastname: Benachenhou
authors.forename: L
authors.initials: L
authors.lastname: Neff
authors.forename: R
authors.initials: R
authors.lastname: Baron
authors.forename: J
authors.initials: J
authors.lastname: Vacher
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001862:Bone Resorption / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured / Q000166:cytology / Q000378:metabolism; D018920:Coculture Techniques; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D005804:Genes, Lethal / Q000502:physiology; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains / Q000002:abnormalities* / Q000378:metabolism; D008854:Microscopy, Electron; D009154:Mutation / Q000502:physiology*; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010022:Osteopetrosis / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D010641:Phenotype; D011506:Proteins / Q000378:metabolism; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D006180:Proton-Translocating ATPases / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6; D000071681:Tartrate-Resistant Acid Phosphatase; D025262:Vacuolar Proton-Translocating ATPases
chemical_list: D003598:Cytoskeletal Proteins; D007527:Isoenzymes; D011506:Proteins; D048029:TNF Receptor-Associated Factor 6; D016392:Proto-Oncogene Proteins pp60(c-src); D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase; D025262:Vacuolar Proton-Translocating ATPases; D006180:Proton-Translocating ATPases