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  • The DDR mediated lysyl oxidase induction


    The DDR2-mediated lysyl oxidase induction in osteoblasts reported here is a novel function for this receptor. Various functions have been reported for DDR2. In an in-vitro study, Zhang and colleagues showed that DDR2 activation leads to Runx2 phosphorylation, which regulates osteoblast differentiation in pre-osteoblasts [34]. Mice in which DDR2 has been knocked out show abnormal post-natal bone growth and development [35]. Diminished chondrocyte proliferation was shown as a mechanism explaining this bone phenotype. Craniofacial deformities associated with DDR2 −/− mice [36] indicate other potential possibilities as well, since craniofacial skeletal growth and development is mostly based on intramembranous osteogenesis, which lacks the transient cartilage formation phase. Furthermore, DDR2 mutated mice (Slie/Slie), similar to DDR2 null mice, present with post-natal growth abnormalities in craniofacial and long bones. This spontaneous autosomal-recessive mutation was mapped to an approximately 150kbp 279 3 receptor that extended into the DDR2 gene [37]. The mutated mice also presented with gonadal dysfunction. The authors ruled out a central mechanism, namely hypopituitarism, for these complications and suggested local bone tissue-specific pathogenesis and only concentrated on determining a mechanism for the gonadal dysfunction. Our findings that DDR2 mediates collagen regulation of lysyl oxidase provide a new potential mechanism for skeletal complications, which occur in both DDR2 deficient and mutant mice. Our findings combined with the studies of DDR2 mutant mice, suggest that DDR2 regulates various cellular and extracellular events in bone growth and development, some of which may depend on lysyl oxidase. Mice null for the structurally related DDR1 receptor are small in stature [38], and develop osteoarthritis specifically in the temporomandibular joint and not in other joints [39]. Females have mammary gland defects, and exhibit decreased fertility. A role for DDR1 in atherosclerosis development and arterial calcification is known and may be related to its role in regulating the proliferation and differentiation of a variety of cell types including vascular smooth muscle cells and macrophages [40]. A possible role for type I collagen/DDR1 signaling in promoting megakaryocyte development has been reported [41], and contributions to fibrosis in lungs and kidney are known [42], [43]. To our knowledge, possible functions of DDR1 in extracellular matrix production by osteoblasts or in other mineralized extracellular matrix abnormalities have not been explored. We have shown that the glycation of collagen hinders collagen-DDR2 binding. McCarthy et al. previously showed reduced binding of rat osteosarcoma-derived cells (UMR106) to glycated collagen. The authors speculated that glycation of collagen attenuates collagen binding to collagen-specific integrins on these cells. They showed, however, that glycated collagen does not compete with RGD and DGEA peptides (specific sequence for α1β1 and α2β1 integrins), and proposed that glycation of collagen interferes with different collagen-integrin binding sites [44]. Based on our current study, we suggest that the loss of collagen interaction with DDR2 under diabetic conditions could potentially also contribute to the observed loss of cell adhesion. It is interesting that although carboxymethylation of lysine residues in our collagen preparations was about 5%, a strong inhibition of collagen stimulation of lysyl oxidase was found. DDR2 binding to collagens occurs at a consensus sequence of GVMGFO where O is hydroxyproline [45]. We speculate that regions of collagens in the vicinity of this sequence are likely to be highly susceptible to chemical modifications of lysine residues, suggesting that they may be more exposed to solvent conditions than other regions of collagen, or that other regions of collagen may also bind and activate DDRs [46]. If true, this notion could have important physiological implications with respect to mechanisms of AGE-dependent extracellular matrix complications, including effects on lysyl oxidase regulation and collagen homeostasis in diabetes: disproportionately high AGE modification of regions of collagen which consist of DDR2 ligands would result in a strong down regulation of lysyl oxidase levels.