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Metalloprotease inhibitor TIMP proteins control FGF-2 bioavailability and regulate skeletal growth

Sanjay Saw1, Alison Aiken1, Hui Fang1

  • 1Princess Margaret Cancer Centre/Ontario Cancer Institute, University Health Network, Toronto, Canada.

The Journal of Cell Biology
|August 3, 2019
PubMed

Insights

Tissue inhibitors of metalloprotease (TIMPs) are vital for postnatal bone growth. TIMP deficiency causes growth plate closure, limb shortening, and skeletal deformities in mice.

Area of Science:

  • Biochemistry
  • Genetics
  • Developmental Biology

Background:

  • Regulated growth plate activity is crucial for bone development and stature.
  • The molecular mechanisms governing epiphyseal fusion remain incompletely understood.

Purpose of the Study:

  • To investigate the role of the tissue inhibitors of metalloprotease (TIMP) gene family in postnatal bone growth.
  • To elucidate the regulatory pathways involving TIMPs in chondrocyte maturation and skeletal development.

Main Methods:

  • Generation and analysis of whole-body quadruple-knockout mice lacking all four TIMPs.
  • Utilizing knock-in mouse models with MMP-resistant or ADAMTS-resistant aggrecans to assess TIMP function.
  • Examining growth plate activity, epiphyseal fusion, and skeletal morphology.

Main Results:

  • TIMP deficiency leads to premature growth plate closure, limb shortening, epiphyseal distortion, and chondrodysplasia.
  • A novel nexus involving TIMPs, FGF-2, and IHH was identified, where TIMPs regulate FGF-2 release and IHH expression.
  • TIMPs are essential negative regulators of chondrocyte maturation and growth plate integrity.
  • Redundancy in metalloprotease inhibitor function during development was observed.

Conclusions:

  • Tissue inhibitors of metalloprotease (TIMPs) are critical regulators of chondrocyte maturation, growth plate integrity, and skeletal proportionality.
  • The TIMP/FGF-2/IHH pathway is a key determinant of bone lengthening.
  • Metalloprotease inhibitors play essential roles in both embryonic and postnatal skeletal development.

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