title: Non-enzymatic glycation of bone collagen modifies osteoclastic activity and differentiation.
abstract: Type I collagen, the major organic component of bone matrix, undergoes a series of post-translational modifications that occur with aging, such as the non-enzymatic glycation. This spontaneous reaction leads to the formation of advanced glycation end products (AGEs), which accumulate in bone tissue and affect its structural and mechanical properties. We have investigated the role of matrix AGEs on bone resorption mediated by mature osteoclasts and the effects of exogenous AGEs on osteoclastogenesis. Using in vitro resorption assays performed on control- and AGE-modified bone and ivory slices, we showed that the resorption process was markedly inhibited when mature osteoclasts were seeded on slices containing matrix pentosidine, a well characterized AGE. More specifically, the total area resorbed per slice, and the area degraded per resorption lacuna created by osteoclasts, were significantly decreased in AGE-containing slices. This inhibition of bone resorption was confirmed by a marked reduction of the release of type I collagen fragments generated by the collagenolytic enzymes secreted by osteoclasts in the culture medium of AGE-modified mineralized matrices. This effect is likely to result from decreased solubility of collagen molecules in the presence of AGEs, as documented by the reduction of pepsin-mediated digestion of AGE-containing collagen. We found that AGE-modified BSA totally inhibited osteoclastogenesis in vitro, most likely by impairing the commitment of osteoclast progenitors into pre-osteoclastic cells. Although the mechanisms remain unknown, AGEs might interfere with osteoclastic differentiation and activity through their interaction with specific cell-surface receptors, because we showed that both osteoclast progenitors and mature osteoclasts expressed different AGEs receptors, including receptor for AGEs (RAGEs). These results suggest that AGEs decreased osteoclast-induced bone resorption, by altering not only the structural integrity of bone matrix proteins but also the osteoclastic differentiation process. We suggest that AGEs may play a role in the alterations of bone remodeling associated with aging and diabetes.
authors.affiliation: INSERM Research Unit 403 and Université Lyon 1, Lyon, France. u.valcourt@ibcp.fr
authors.forename: Ulrich
authors.initials: U
authors.lastname: Valcourt
authors.forename: Blandine
authors.initials: B
authors.lastname: Merle
authors.forename: Evelyne
authors.initials: E
authors.lastname: Gineyts
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Viguet-Carrin
authors.forename: Pierre D
authors.initials: PD
authors.lastname: Delmas
authors.forename: Patrick
authors.initials: P
authors.lastname: Garnero
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism; D000818:Animals; D001857:Bone Matrix / Q000378:metabolism*; D001862:Bone Resorption; D002454:Cell Differentiation; D003094:Collagen / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism; D004606:Elephants; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D010010:Osteoclasts / Q000378:metabolism*; D012710:Serum Albumin, Bovine / Q000378:metabolism* / Q000494:pharmacology; D013234:Stem Cells / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; C081628:advanced glycation end products-bovine serum albumin; D012710:Serum Albumin, Bovine; D003094:Collagen