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MT1-MMP inactivates ADAM9 to regulate FGFR2 signaling and calvarial osteogenesis

Kui Ming Chan1, Hoi Leong Xavier Wong, Guoxiang Jin

  • 1Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China.

Developmental Cell
|May 29, 2012
PubMed

Insights

Matrix metalloproteinase-14 (MT1-MMP) protects FGFR2 signaling in osteoblasts by inactivating ADAM9. This maintains calvarial bone growth, and its absence causes craniofacial abnormalities.

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Biochemistry

Background:

  • Matrix metalloproteinase-14 (MT1-MMP) is crucial for extracellular matrix remodeling and cell surface receptor modulation.
  • Loss of MT1-MMP function leads to craniofacial abnormalities, indicating its importance in skeletal development.

Purpose of the Study:

  • To elucidate the mechanism by which MT1-MMP regulates FGFR2 signaling in osteoblasts.
  • To investigate the role of MT1-MMP in calvarial bone development and its interaction with ADAM9 and FGFR2.

Main Methods:

  • Investigated protein interactions between MT1-MMP, ADAM9, and FGFR2 in osteoblasts.
  • Analyzed FGF-induced proliferation and signaling pathways in Mmp14-/- osteoblasts.
  • Assessed calvarial bone growth in Mmp14-/- embryos and the effect of Adam9 depletion.

Main Results:

  • MT1-MMP forms a complex with FGFR2 and ADAM9, proteolytically inactivating ADAM9 and preventing FGFR2 shedding.
  • Mmp14-/- osteoblasts exhibit compromised FGF-induced proliferation and signaling due to ADAM9 upregulation and FGFR2 shedding.
  • MT1-MMP deficiency causes retarded parietal bone growth starting at 15.5 dpc, linked to impaired FGFR2 signaling.
  • Adam9 depletion rescues FGFR2 signaling and restores calvarial bone growth in Mmp14-/- embryos.

Conclusions:

  • MT1-MMP acts as a critical negative regulator of ADAM9 activity, preserving FGFR2 signaling essential for calvarial osteogenesis.
  • This study reveals a novel regulatory mechanism for FGFR2 signaling involving MT1-MMP and ADAM9 in bone development.

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