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α 9 β 1 : A Novel Osteoclast Integrin That Regulates Osteoclast Formation and Function
Author(s) -
Rao Hongwei,
Lu Ganwei,
Kajiya Hiroshi,
GarciaPalacios Veronica,
Kurihara Noriyoshi,
Anderson Judy,
Patrene Ken,
Sheppard Dean,
Blair Harry C,
Windle Jolene J,
Choi Sun Jin,
Roodman G David
Publication year - 2006
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.060718
Subject(s) - osteoclast , disintegrin , integrin , bone resorption , alpha v beta 3 , chemistry , rankl , collagen receptor , microbiology and biotechnology , alpha (finance) , chinese hamster ovary cell , medicine , endocrinology , metalloproteinase , biology , receptor , biochemistry , matrix metalloproteinase , vitronectin , activator (genetics) , construct validity , nursing , patient satisfaction
We identified a previously unknown integrin, α 9 β 1 , on OCLs and their precursors. Antibody to α 9 inhibited OCL formation in human marrow cultures, and OCLs from α 9 knockout mice had a defect in actin ring reorganization and an impaired bone resorption capacity. Introduction: Integrins play important roles in osteoclast (OCL) formation and function. Mature OCLs mainly express α v β 3 integrin, a heterodimer adhesion receptor that has been implicated in osteoclastic bone resorption. We identified ADAM8, a disintegrin and metalloproteinase, as a novel stimulator of OCL differentiation and showed that the disintegrin domain of ADAM8 mediated its effects on OCL formation. Because the disintegrin domain of ADAM8 does not bind Arg‐Gly‐Asp (RGD) sequences, we determined which integrin bound ADAM8 and characterized its role in OCL formation and activity. Materials and Methods: Chinese hamster ovary cells (CHO) expressing different integrin subunits were tested for their capacity to bind the disintegrin domain of ADAM8. Mouse or human bone marrow cells and purified OCL precursors were tested for α 9 β 1 integrin expression by Western blot, immunocytochemistry, and real‐time RT‐PCR. A monoclonal antibody to human α 9 was used to block α 9 β 1 on OCL precursors stimulated by 1α,25‐dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] or RANKL. Vertebrae of 7‐day‐old α 9 −/− mice and wildtype (WT) littermates were compared using bone histomorphometry and 3D μCT analysis. Results: α 9 integrin was expressed by mouse and human bone marrow–derived OCLs and their precursors. Importantly, the anti‐α 9 antibody inhibited human OCL formation stimulated by 1α,25(OH) 2 D 3 or RANKL dose‐dependently. Furthermore, analysis of OCLs formed in marrow cultures from α 9 −/− mice showed that the OCLs formed were more contracted and formed significantly less bone resorption pits on dentin slices. Histologic analysis of α 9 −/− vertebrae showed thickened trabecular regions and retained cartilage within vertebral bodies of α 9 −/− mice. 3D μCT analysis of α 9 −/− vertebrae also showed a significant increase in trabecular bone volume/total tissue volume and a tendency for decreased trabecular separation compared with WT mice. Conclusions: These results support a previously unknown role for α 9 β 1 integrin in OCL formation and function.