Type I collagen-containing fibrils are major structural components of the extracellular matrix of vertebrate tissues, especially tendon, but how they are formed is not fully understood. MMP14 is a potent pericellular collagenase that can cleave type I collagen in vitro. Here we show that tendon development is arrested in Scleraxis-Cre::Mmp14 lox/lox mice that are unable to release collagen fibrils from plasma membrane fibripositors. In contrast to its role in collagen turnover in adult tissue, MMP14 promotes embryonic tissue formation by releasing collagen fibrils from the cell surface. Notably, tendons grow to normal size and collagen fibril release from fibripositors occurs in Col-r/r mice that have a mutated collagen-I that is uncleavable by MMPs. Furthermore, fibronectin (not collagen-I) accumulates in tendons of Mmp14-null mice. We propose a model for cell-regulated collagen fibril assembly during tendon development in which MMP14 cleaves a molecular bridge tethering collagen fibrils to the plasma membrane of fibripositors.
Animal experimentation: The care and use of all mice in this study was carried out in accordance with UK Home Office regulations, UK Animals (Scientific Procedures) Act of 1986 under the UK Home Office licence (PPL 40/3485). All animals were sacrificed by a Schedule 1 procedure by trained personnel. MMP14 KO mice were as described previously (Zhou et al., 2000). To generate mice in which MMP14 is ablated in tendon-lineage cells, we crossed mice expressing Cre recombinase under the control of Scleraxis (ScxCre; C57BL/6) (Blitz et al., 2013) with mice carrying the floxed exons (exons 2 to 4) of the MMP14 gene (MMP14-floxed; C57BL/6) (Zigrino et al., 2012). MMP13 KO embryos were a generous gift from Zena Werb (Stickens et al., 2004). MMP2 heterozygous mice were imported from RIKEN BioResource Center (GelAKO/RBRC00398; C57) (Itoh et al., 1997) and bred to homozygosity. Col-r/r mice were imported from Jackson Laboratory (B6;129S4-Col1a1tm1Jae/J) (Liu et al., 1995). X-ray analyses were performed as described previously (Yeung et al., 2014).
- Robb Krumlauf, Stowers Institute for Medical Research, United States
© 2015, Taylor et al.
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