Possible involvement of advanced glycation end-products in bone resorption

Abstract

Advanced glycation end-products (AGEs) are formed in long-lived matrix proteins by a non-enzymatic reaction with sugar. We recently demonstrated the presence of AGEs in amyloid fibrils of dialysis-related amyloidosis, one of the characteristic features of which is an accelerated bone resorption around amyloid deposits. This suggested a potential link of AGEs in bone resorption and led us to investigate whether AGEs enhance bone resorption. An immunohistochemical study using anti-AGE antibody revealed positive immunostaining for AGEs in bone tissues from elderly subjects. AGE-modified proteins were shown to stimulate monocyte/macrophage to secrete bone-resorbing cytokines such as interleukin-1β, interleukin-6 and tumour necrosis factor-α. AGE-modified proteins enhanced net calcium efflux in cultured neonatal mouse calvariae to a much greater extent than unmodified proteins. Furthermore, when mouse unfractionated bone cells containing osteoclasts were cultured on dentin slices, AGE-modified proteins increased the number of resorption pits formed by osteoclasts, whereas their normal counterparts or those modified with the early glycation products did not. These findings suggest that AGEs enhance bone resorption by osteoclasts. The modification of bone matrices with AGEs might, therefore, play a pathophysiological role not only in the remodelling of senescent bone matrix tissues, but also in dialysis-related amyloidosis or osteoporosis associated with diabetes and ageing.