Actin polymerization modulates CD44 surface expression, MMP-9 activation, and osteoclast function.
CD44 and MMP-9 are implicated in cell migration. In the current study, we tested the hypothesis that actin polymerization is critical for CD44 surface expression and MMP-9 activity on the cell surface. To understand the underlying molecular mechanisms involved in CD44 surface expression and MMP-9 activity on the cell surface, osteoclasts were treated with bisphosphonate (BP) alendronate, cytochalasin D (Cyt D), and a broad-spectrum MMP inhibitor (GM6001). BP has been reported to block the mevalonate pathway, thereby preventing prenylation of small GTPase signaling required for actin cytoskeleton modulation. We show in this study that osteoclasts secrete CD44 and MMP-9 into the resorption bay during migration and bone resorption. Results indicate that actin polymerization is critical for CD44 surface expression and osteoclast function. In particular, the surface expression of CD44 and the membrane activity of MMP-9 are reduced in osteoclasts treated with alendronate and Cyt D despite the membrane levels of MMP-9 being unaffected. Although GM6001 blocked MMP-9 activity, osteoclast migration, and bone resorption, the surface levels of CD44 were unaffected. We suggest that the surface expression of CD44 requires actin polymerization. Disruption of podosome and actin ring structures by Cyt D and alendronate not only resulted in reduced localization of MMP-9 in these structures but also in osteoclast migration and bone resorption. These results suggest that inhibition of actin polymerization by alendronate and Cyt D is effective in blocking CD44/MMP-9 complex formation on the cell surface, secretion of active form of MMP-9, and osteoclast migration. CD44/MMP-9 complex formation may signify a unique motility-enhancing signal in osteoclast function.
Samanna
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Department of Biomedical Sciences, Dental School, University of Maryland, Baltimore, Maryland 21201, USA.
Ma
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Mak
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Rogers
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Chellaiah
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MA
D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019386:Alendronate / Q000494:pharmacology; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000378:metabolism; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003470:Culture Media / Q000737:chemistry / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000032:analysis; D015638:Cytochalasin D / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D018960:Hyaluronan Receptors / Q000378:metabolism*; D007150:Immunohistochemistry; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D011108:Polymers / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D053245:RANK Ligand / Q000494:pharmacology; D013997:Time Factors
D000199:Actins; D050071:Bone Density Conservation Agents; D003470:Culture Media; D017077:Culture Media, Conditioned; D004151:Dipeptides; D018960:Hyaluronan Receptors; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011108:Polymers; D011480:Protease Inhibitors; D053245:RANK Ligand; D015638:Cytochalasin D; D016173:Macrophage Colony-Stimulating Factor; D020780:Matrix Metalloproteinase 9; D019386:Alendronate