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  • Sweroside mg The significance of the difference in

    2020-06-22

    The significance of the difference in the DDR2 binding specificity towards fibrillar and non-fibrillar collagens is not understood, but may imply differences in biological responses when chondrocytes bind to different collagens in the growth plate. Investigations by Labrador et al. (2001) have shown that the regulation of cell proliferation in the growth plate could be mediated through activation of the DDR2 tyrosine kinase domain. In this context, the activation of DDR2 is likely to be the consequence of cells binding to collagen II in the proliferative zone of the growth plate. It is conceivable that the replacement of collagen II with the collagen X network in the transitional zone may interrupt/perturb the binding of DDR2 to type II collagen and hence cell proliferation. The binding of collagen X to DDR2, through different binding sites, may be the initiation signal for chondrocyte maturation and DDR2 may thus regulate important cellular processes leading to the final stages of EO. Our results show that DDR2 recognises both the collagenous domain of collagen X and the NC1 domain (Fig. 7). Binding to the collagenous domain is dependent on the native, triple-helical conformation. Thus, DDR2 recognises the triple helix of both fibrillar and non-fibrillar collagens in a conformation-specific manner. As the isolated NC1 domain has a tendency to form Sweroside mg (Frischholz et al., 1998, Zhang and Chen, 1999), there is a concern that this domain might show non-specific binding in in vitro binding assays. However, we believe that it is unlikely that we have measured non-specific DDR2 binding to the NC1 domain in our solid phase binding assays, as the DDR2 discoidin domain showed no reactivity to the isolated NC1 domain (data not shown). The collagenous domain, but not the NC1 domain interacts with DDR2 in a productive manner, leading to receptor autophosphorylation (Fig. 8). These findings are in agreement with the characterisation of all known DDR ligands; receptor activation requires binding of the DDRs to triple-helical collagen. Although our results show that the NC1 domain is dispensable for DDR2 autophosphorylation, it is conceivable that in tissues, cell adhesion to the NC1 domain can facilitate binding to the triple helix. Our previous study has demonstrated that the NC1 domain is involved in mediating the interaction of collagen X with cells and that cells adhere to the isolated NC1 domain (Luckman et al., 2003). In the growth plate ECM, collagen X molecules most likely form an extended hexagonal array with many NC1 domains forming large aggregates within the collagen network (Kwan et al., 1991, Jacenko et al., 2001). The binding of the NC1 domain to cell surface receptors may have a mechanical role to stabilise the cell–matrix interactions. The binding of collagen X to DDR2 differs from the binding of collagen X to α2β1 integrin in that the triple helical conformation is essential for DDR2 binding. We previously reported that heat denatured pepsinised collagen X supported cell adhesion via α2β1, indicating that the triple-helical conformation is not strictly required for α2β1 binding (Luckman et al., 2003). Although many previous studies have firmly established that collagen X is required for normal development of the growth plate (Warman et al., 1993, Wallis et al., 1994, Tselepis et al., 1996, Chan and Jacenko, 1998, Gress and Jacenko, 2000, Jacenko et al., 2002) the precise role of collagen X within the growth plate remains to be defined. Many of these studies favoured a structural role for the collagen X network in the hypertrophic zone. However, the interactions between the collagen X network and hypertrophic chondrocytes and the interactions between collagen X and other cartilage matrix components have not been studied to any significant extent. It has been proposed that the interaction of collagen X with other matrix components is important for regional extracellular matrix organisation permissive for mineralisation and vascularisation prior to new bone formation (Luckman et al., 2003). The present study further corroborates an earlier study that the collagen X network does support cell adhesion and also supports the notion that collagen X has regulatory roles besides its structural function in the matrix, possibly via activation of receptor tyrosine kinases. Since DDR2 is a signalling receptor with important functions in bone growth (Labrador et al., 2001), our present study provides the basis for future studies into the role of DDR2 signalling in bone formation.