Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, MD 21201, USA.
Biomed Res Int. 2013;2013:302392. doi: 10.1155/2013/302392. Epub 2013 Jul 28.
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.
CD44、MT1-MMP 和 MMP9 参与破骨细胞的迁移和骨吸收。本研究旨在确定 CD44 和 MT1-MMP 在激活 pro-MMP9 中的功能关系。我们使用来自野生型和 CD44 缺失型小鼠的破骨细胞进行研究。结果表明，MT1-MMP 以多种形式存在于野生型破骨细胞膜中，分子量约为 63、55 和 45 kDa。CD44 缺失型破骨细胞的膜和条件培养基中存在 55 kDa 的活性 MT1-MMP 形式。由于 TIMP2 结合并抑制 CD44 缺失型破骨细胞中的这种 MT1-MMP（~55 kDa），因此无法激活 pro-MMP9。通过在野生型破骨细胞中敲低 MT1-MMP 证实了 MT1-MMP 在 pro-MMP9 激活、CD44 表达和迁移中的作用。尽管敲低 MMP9 抑制了破骨细胞迁移，但对 MT1-MMP 活性或 CD44 表达没有影响。这些结果表明，CD44 和 MT1-MMP 直接或间接地参与了 pro-MMP9 激活的调节。CD44 的表面表达、MT1-MMP 的膜定位和 pro-MMP9 的激活是破骨细胞迁移的必要事件序列。
