Membrane Localization of Membrane Type 1 Matrix Metalloproteinase by CD44 Regulates the Activation of Pro-Matrix Metalloproteinase 9 in Osteoclasts

Abstract EN

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.