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

The Journal of Cell Biology
Sanjay SawRama Khokha

Abstract

Regulated growth plate activity is essential for postnatal bone development and body stature, yet the systems regulating epiphyseal fusion are poorly understood. Here, we show that the tissue inhibitors of metalloprotease (TIMP) gene family is essential for normal bone growth after birth. Whole-body quadruple-knockout mice lacking all four TIMPs have growth plate closure in long bones, precipitating limb shortening, epiphyseal distortion, and widespread chondrodysplasia. We identify TIMP/FGF-2/IHH as a novel nexus underlying bone lengthening where TIMPs negatively regulate the release of FGF-2 from chondrocytes to allow IHH expression. Using a knock-in approach that combines MMP-resistant or ADAMTS-resistant aggrecans with TIMP deficiency, we uncouple growth plate activity in axial and appendicular bones. Thus, natural metalloprotease inhibitors are crucial regulators of chondrocyte maturation program, growth plate integrity, and skeletal proportionality. Furthermore, individual and combinatorial TIMP-deficient mice demonstrate the redundancy of metalloprotease inhibitor function in embryonic and postnatal development.

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Citations

Aug 11, 2020·Calcified Tissue International·Kazuhiro YamamotoGeorge Bou-Gharios
Oct 11, 2020·Nature Communications·Juliane WinklerZena Werb
Sep 10, 2021·Blood Advances·Ashley WeissRama Khokha

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Methods Mentioned

BETA
Profiler
PCR
transgenic
ELISA
gene knockouts
chips
acetylation

Software Mentioned

Enrichr
Limma
Microview
cystoscope
R
: Profiler
Bioconductor
ImageJ
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Zen blue

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