ADVANCED GLYCATION END-PRODUCTS ENHANCE OSTEOCLAST-INDUCED BONE-RESORPTION IN CULTURED MOUSE UNFRACTIONATED BONE-CELLS AND IN RATS IMPLANTED SUBCUTANEOUSLY WITH DEVITALIZED BONE PARTICLES

Advanced glycation end products (AGE) are formed in long-lived matrix proteins by a nonenzymatic reaction with sugar. The presence of AGE in beta(2)-microglobulin-amyloid fibrils of dialysis-related amyloidosis , one of the characteristic features of which is an accelerated bone r esorption around amyloid deposits, was recently demonstrated. This sug gested a potential link of AGE in bone resorption and initiated this i nvestigation of whether AGE enhance bone resorption. When mouse unfrac tionated bone cells containing osteoclasts were cultured on dentin sli ces, both AGE-modified beta(2)-microglobulin and BSA increased the num ber of resorption pits formed by osteoclasts, whereas their normal cou nterparts or those modified with the early glycation products did not. AGE proteins, however, did not increase the number of newly formed os teoclasts, even in the coculture of mouse bone marrow cells with osteo blastic cells isolated from mouse calvaria. Enhanced bone resorption w as also observed when unfractionated bone cells were cultured on AGE-m odified dentin slices. AGE-enhanced bone resorption was effectively in hibited by calcitonin and ipriflavone, both of which are inhibitors of bone resorption. AGE-enhanced bone resorption was further supported b y in vivo evidence that rat bone particles-upon incubation with glucos e for 60 days (AGE-bone particles)-when implanted subcutaneously in ra ts, were resorbed to a much greater extent than control bone particles upon parallel incubation without glucose. These findings suggest that AGE enhance osteoclast-induced bone resorption. Although the mechanis m remains unknown, AGE are unlikely to promote differentiation of oste oclast progenitors into osteoclasts, suggesting that AGE activate oste oclasts or alter microenvironments favorable for bone resorption by os teoclasts. The modification of bone matrices with AGE might play a rol e in the remodeling of senescent cent bone matrix tissues, further imp licating a pathological significance of AGE in dialysis-related amyloi dosis or osteoporosis associated with diabetes and aging.