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

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...

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Published inThe Journal of cell biology Vol. 218; no. 9; pp. 3134 - 3152
Main Authors Saw, Sanjay, Aiken, Alison, Fang, Hui, McKee, Trevor D, Bregant, Sarah, Sanchez, Otto, Chen, Yan, Weiss, Ashley, Dickson, Brendan C, Czarny, Bertrand, Sinha, Ankit, Fosang, Amanda, Dive, Vincent, Waterhouse, Paul D, Kislinger, Thomas, Khokha, Rama
Format Journal Article
LanguageEnglish
Published United States Rockefeller University Press 02.09.2019
Subjects
Animals
Bioavailability
Bone and Bones - metabolism
Bone Development
Bone growth
Bones
Chondrocytes
Chondrocytes - metabolism
Chondrodystrophy
Combinatorial analysis
Embryogenesis
Fibroblast growth factor 2
Fibroblast Growth Factor 2 - genetics
Fibroblast Growth Factor 2 - metabolism
Growth plate
Growth Plate - metabolism
Inhibitors
Metalloproteinase
Mice
Mice, Knockout
Redundancy
Regulators
Rodents
Tissue inhibitor of metalloproteinases
Tissue Inhibitor of Metalloproteinases - genetics
Tissue Inhibitor of Metalloproteinases - metabolism
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Summary: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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S. Saw and A. Aiken contributed equally to this paper.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.201906059