title: Membrane localization of membrane type 1 matrix metalloproteinase by CD44 regulates the activation of pro-matrix metalloproteinase 9 in osteoclasts.
abstract: CD44, MT1-MMP, and MMP9 are implicated in the migration of osteoclast and bone resorption. This study was designed to determine the functional relationship between CD44 and MT1-MMP in the activation of pro-MMP9. We used osteoclasts isolated from wild-type and CD44-null mice. Results showed that MT1-MMP is present in multiple forms with a molecular mass ~63, 55, and 45 kDa in the membrane of wild-type osteoclasts. CD44-null osteoclasts demonstrated a 55 kDa active MT1-MMP form in the membrane and conditioned medium. It failed to activate pro-MMP9 because TIMP2 binds and inhibits this MT1-MMP (~55 kDa) in CD44-null osteoclasts. The role of MT1-MMP in the activation of pro-MMP9, CD44 expression, and migration was confirmed by knockdown of MT1-MMP in wild-type osteoclasts. Although knockdown of MMP9 suppressed osteoclast migration, it had no effects on MT1-MMP activity or CD44 expression. These results suggest that CD44 and MT1-MMP are directly or indirectly involved in the regulation of pro-MMP9 activation. Surface expression of CD44, membrane localization of MT1-MMP, and activation of pro-MMP9 are the necessary sequence of events in osteoclast migration.
authors.affiliation: Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, MD 21201, USA. mchellaiah@umaryland.edu
authors.forename: Meenakshi A
authors.initials: MA
authors.lastname: Chellaiah
authors.forename: Tao
authors.initials: T
authors.lastname: Ma
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000201:enzymology / Q000473:pathology; D002462:Cell Membrane / Q000201:enzymology*; D054443:Cell Migration Assays; D002465:Cell Movement; D016764:Cell Polarity; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000201:enzymology*; D055785:Gene Knockdown Techniques; D018960:Hyaluronan Receptors / Q000378:metabolism*; D015151:Immunoblotting; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D010010:Osteoclasts / Q000166:cytology* / Q000201:enzymology*; D011485:Protein Binding; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; C507096:Mmp14 protein, mouse; D034741:RNA, Small Interfering; D019716:Tissue Inhibitor of Metalloproteinase-2; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D053511:Matrix Metalloproteinase 14