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    Saito et al. reported that diabetic bone has lower lysyl oxidase-derived enzymatic cross-links in collagen compared to non-diabetic bone, based on studies performed in a rat model [9]. Lysyl oxidase plays a pivotal role in bone development and function, as revealed in classical studies [10], [11]. Lysyl oxidase inhibition results in weak bones and joints known as osteolathyrism [12]. Despite evidence for reduced levels of lysyl oxidase-dependent collagen cross-links in diabetic bone, it remains to be determined whether lysyl oxidase itself is regulated under diabetic conditions in bone. In this study, we investigated a role for collagen glycation in regulating lysyl oxidase expression in primary osteoblast cultures. In light of previous work, our initial hypothesis was that AGEs would actively down-regulate lysyl oxidase by an AGE-receptor mediated mechanism [13]. By contrast, we present novel data showing that non-glycated (normal) collagen up-regulates levels of lysyl oxidase; a function we ascribe to physiological (unmodified) collagen. The two major 98 0 of collagen receptors are integrins and the discoidin domain receptors, respectively [14]. Collagen up-regulation was determined to be mediated by Discoidin Domain Receptor 2 (DDR2), with possible modulation by integrin signaling only in non-differentiating osteoblasts. Interestingly, collagen glycation was seen to attenuate its ability to both up-regulate lysyl oxidase and bind to and activate DDR2. These data have important implications regarding mechanisms which contribute to connective tissue complications of diabetes.
    Materials and methods
    Discussion Cellular and extracellular matrix complications contribute to diabetic bone fragility. Specifically, cellular complications disturb bone-remodeling homeostasis through diminished bone formation, leading to weak bones in diabetes. Furthermore, accumulation of AGE adducts on type I collagen, the prime constituent of the organic extracellular matrix of bone, interferes with bone structure and thereby reduces bone strength in diabetes. Evidence for reduced levels of lysyl oxidase-dependent collagen cross-links in rat diabetic bones has also been reported [9]. However, lysyl oxidase regulation in osteoblasts as a function of diabetic conditions has not, to our knowledge, been directly studied. Here we provide evidence for a novel mechanism, which could contribute to diabetic bone fragility. Our studies reveal that lysyl oxidase levels are increased through the interactions of osteoblasts with collagen. Collagen that has been non-enzymatically glycated, as is typical in diabetes, fails to promote lysyl oxidase production by osteoblasts. This is the first report showing that collagen regulates lysyl oxidase in osteoblasts. In order to understand the mechanism of collagen up-regulation of lysyl oxidase, we investigated roles for the major classes of collagen receptors: integrins and discoidin domain receptors. We demonstrate that DDR2, a receptor expressed on a variety of mesenchymal cells [31], functions to mediate collagen regulation of lysyl oxidase. Moreover, we show that glycated collagen made by chemical modification has a diminished ability to bind and activate DDR2. In future studies it will be of interest to study the ability of collagens derived from diabetic and non-diabetic bones to stimulate lysyl oxidase levels and activate DDR2 in osteoblasts to further assess the physiological importance of the studies presented here. Our studies investigating a role for integrins in collagen induction of lysyl oxidase may also suggest a cooperative function for integrins in DDR2-mediated up-regulation of lysyl oxidase by collagen. It is interesting to note, however, that the level of 32kDa lysyl oxidase in the presence of EDTA was partially reduced compared to its level in the no EDTA controls treated with collagen (Fig. 4A). Pro-lysyl oxidase conversion to mature lysyl oxidase is catalyzed by procollagen C-proteinases which are metalloenzymes [32], [33]. We suspect that the effect of EDTA on mature 32kDa lysyl oxidase levels may be partially due to the inhibition of pro-lysyl oxidase processing by EDTA by contrast to inhibiting integrin signaling.