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J. Biol. Chem., Vol. 282, Issue 8, 5691-5703, February 23, 2007

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Non-enzymatic Glycation of Bone Collagen Modifies Osteoclastic Activity and Differentiation^*

Ulrich Valcourt¹², Blandine Merle¹, Evelyne Gineyts, Stéphanie Viguet-Carrin, Pierre D. Delmas, and Patrick Garnero

From the INSERM Research Unit 403 and Université Lyon 1, 69437 Cedex 03 Lyon and Molecular Markers, Synarc, 69003 Lyon, France

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.

Received for publication, November 13, 2006 , and in revised form, November 30, 2006.

^* This work was supported in part by an unrestricted educational grant from Eli Lilly to INSERM. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed (present address): Institut de Biologie et Chimie des Protéines, UMR 5086, CNRS, Université Lyon 1, IFR128 Biosciences Lyon-Gerland, 69367 Cedex 07 Lyon, France. Tel.: 33-4-72-72-26-59; Fax: 33-4-72-72-26-04; E-mail: u.valcourt{at}ibcp.fr.

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