BoneKEy Reports | BoneKEy Watch

Master protease plays an important role in skull development

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DOI:10.1038/bonekey.2012.152

Knockout mice that lack the gene Mmp14 are deficient in MT1-MMP, a membrane-bound metalloproteinase. In this study, Chan et al. showed that Mmp14−/− mice showed defective postnatal growth of the calvarial bones in the skullcap because of significantly reduced osteogenesis.

Mmp14 is co-expressed with several other genes that code for components of the FGF signaling pathway, and the decrease in osteoblast proliferation in the knockout mice is due specifically to an impairment in the FGF-Frs2α-MAPK-Erk1/2 pathway. The signaling defects result from accumulation of a truncated fragment of FGFR2, the receptor for FGF ligands. The amount of FGFR2 at the cell surface of calvarial osteoblasts is 40% less in Mmp14−/− mice compared to controls.

Further experiments revealed significant upregulation of Adam9 in the primary calvarial osteoblasts in Mmp14−/− mice. The authors postulate that MT1-MMP eliminates ADAM9 by proteolysis, and deficiency of MT1-MMP leads to ADAM9 upregulation. Depletion of Adam9 rescues FGF signaling and leads to normal calvarial bone development in Mmp14−/− mice.

Editor's comment: This study demonstrates a central role for MT1-MMP as a critical master protease that is required for normal FGFR2 signaling and normal osteogenesis in the calvaria. These new insights into the molecular basis of calvarial development offer future opportunities for targeted therapies for craniofacial abnormalities.

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