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.
Highlights
Metalloproteases are present across all kingdoms of living organisms and have expanded widely during eukaryotic evolution, comprising the largest class of protease genes in humans (Gomis-Rüth, 2003; Quesada et al, 2009)
A single Timp3 allele in QT3+/− mice was sufficient for a natural lifespan, whereas the complete absence of tissue inhibitors of metalloprotease (TIMP) was incompatible with normal life expectancy
We found that incorporation of the Chloe mutation rescued the shortening of both the tibia and femur of QT3+/− mice, demonstrating that TIMP regulation of matrix metalloproteinase (MMP) activity at this site is necessary for normal postnatal growth plate development
Summary
Metalloproteases are present across all kingdoms of living organisms and have expanded widely during eukaryotic evolution, comprising the largest class of protease genes in humans (Gomis-Rüth, 2003; Quesada et al, 2009). Tissue inhibitors of metalloproteases (TIMPs) are well known to control the turnover of matrix proteins in connective tissue (Sterchi et al, 2008). Flies have a single TIMP gene with conserved metalloprotease inhibitor function, loss of which causes blistered wings and death by digestive tract lysis (Godenschwege et al, 2000; Page-McCaw et al, 2003). The TIMP-metalloprotease axis controls major signaling pathways through ectodomain shedding, and deregulation of this axis has invariably been seen in human cancers and diseases (Murphy et al, 2008; Aiken and Khokha, 2010; Kessenbrock et al, 2010; Jackson et al, 2017). Concurrent deletion of the entire TIMP gene family is a prerequisite for understanding the function of this gene family in mammals
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