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  • Collagen X is a homotrimeric molecule of three X chains

    2021-01-18

    Collagen X is a homotrimeric molecule of three α1(X) chains (Mr 59 kDa) comprising a 45 kDa triple-helical domain flanked by an N-terminal (NC2) and a larger C-terminal (NC1) non-collagenous domains (Shen, 2005). In the hypertrophic ECM, collagen X most likely forms an extended hexagonal network, as shown by in vitro studies (Kwan et al., 1991) and by electron microscopy on the murine growth plate (Jacenko et al., 2001), and is particularly abundant in the pericellular matrix of hypertrophic chondrocytes (LuValle et al., 1992, Tselepis et al., 1996). Mutations of the human Col10A1 gene are known to cause Schmid metaphyseal chondrodysplasia, an autosomal dominant disorder characterised by short stature, widened growth plates, bowing of the long bones and coxa vara (Warman et al., 1993, Wallis et al., 1994, Mäkitie et al., 2005) with the majority of mutations being found in the NC1 domain (Chan and Jacenko, 1998). Skeletal defects characteristic of spondylometaepiphyseal chondrodysplasia were reported in mice expressing a truncated collagen X transgene containing a large in-frame p-selectin (Jacenko et al., 1993). These studies indicate that either a reduction collagen X deposition due to haploinsufficiency or disruption of the normal collagen X network due to dominant interference can lead to aberrant EO. Furthermore, the complete lack of collagen X deposition in the matrix of Col10A1 −/− mice resulted in growth plate compression, displacement of proteoglycans, altered mineral deposition, and hematopoietic changes (Kwan et al., 1997, Gress and Jacenko, 2000, Jacenko et al., 2002). Based on the disease phenotypes observed in these transgenic mouse models, the pericellular collagen X network appears to be an important link between the hypertrophic chondrocytes and the interterritorial matrix especially in stabilising the proteoglycan network. We therefore propose that the interactions between hypertrophic chondrocytes and the collagen X network are important in maintaining the integrity of the hypertrophic matrix and regulate chondrocyte metabolism through cell adhesion molecules. This hypothesis is partially supported by our recent findings that hypertrophic chondrocytes can adhere and spread on a collagen X substrate (Luckman et al., 2003). Hypertrophic chondrocyte adhesion to collagen X is primarily mediated through the α2β1 integrin. In this study, we report the interactions between collagen X and a non-integrin collagen receptor, the discoidin domain receptor DDR2. The discoidin domain receptors, DDR1 and DDR2, are receptor tyrosine kinases that are activated by different types of collagen (Shrivastava et al., 1997, Vogel et al., 1997). Both receptors interact with a number of fibrillar collagens, and DDR1, but not DDR2, is also activated by the network-forming collagen IV. Interaction of the DDRs with collagen leads to receptor autophosphorylation, the fist step in transmembrane signalling. The DDRs are unusual in that collagen-induced autophosphorylation is very slow and sustained (∼hours), compared to the much more rapid response of typical receptor tyrosine kinases to their ligands (∼seconds to minutes). The DDRs are widely expressed in human and mouse tissue, with DDR1 mainly found in epithelial cells (Alves et al., 1995), but also on leukocytes (Yoshimura et al., 2005), and DDR2 mainly expressed in mesenchymal cells (Alves et al., 1995). Both DDRs are expressed early in embryonic development and are found in many adult tissues, with high levels of DDR1 found in lung, kidney, breast, and brain tissue, while the mesenchymal DDR2 shows highest levels in skeletal muscle, skin, kidney and lung tissue (reviewed in Vogel et al., 2006). The generation of DDR1 −/− mice resulted in viable, but smaller animals, the smaller size being a result of defective mammary gland development of female mice resulting in a failure to lactate (Vogel et al., 2001). DDR2 −/− mice, on the other hand, exhibited a real growth defect with shortened long bones (Labrador et al., 2001). Evidence from in vitro studies and the DDR1 −/− and DDR2 −/− mice shows that the DDRs regulate cell proliferation, adhesion and motility, and control remodelling of the extracellular matrix by influencing the expression and activity of matrix metalloproteinases (Hou et al., 2001, Labrador et al., 2001, Olaso et al., 2001, Olaso et al., 2002, Vogel et al., 2001, Ferri et al., 2004). The DDRs are associated with a growing number of human diseases, including fibrotic diseases of the lung, kidney and liver, atherosclerosis, osteoarthritis, as well as several types of cancer (reviewed in Vogel et al., 2006).