Disordered osteoclast formation in RAGE-deficient mouse establishes an essential role for RAGE in diabetes related bone loss

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Abstract

The mechanisms underlying diabetes-mediated bone loss are not well defined. It has been reported that the advanced glycation endproducts (AGEs) and receptor for AGEs (RAGEs) are involved in diabetic complications. Here, mice deficient in RAGE were used as a model for investigating the effects of RAGE on bone mass. We found that RAGE−/− mice have a significantly increased bone mass and bone biomechanical strength and a decreased number of osteoclasts compared to wild-type mice. The serum levels of IL-6 and bone breakdown marker pyridinoline were significantly decreased in RAGE−/− mice. RAGE−/− mice maintain bone mass following ovariectomy, whereas wild-type mice lose bone mass. Furthermore, osteoclast-like cells do express RAGE mRNA. Our data therefore indicate that RAGE serves as a positive factor to regulate the osteoclast formation, directly implicates a role for RAGE in diabetes-promoted bone destruction, and documents that the AGE-RAGE interaction may account for diabetes associated bone loss.

Section snippets

Materials and methods

Mice. The RAGE targeting construct and the generation of RAGE−/− mice have been described in detail elsewhere [16]. RAGE−/− mice were backcrossed onto the C57BL/6 genetic background up to generation 8. The wild-type (WT) C57BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, Maine). All experimental procedures were performed in accordance with the guidelines of the Institutional Animal Care and Use Committee of Medical College of Georgia.

Bone densitometry and radiography. Bone

Increased bone mineral density in RAGE KO mice

To test whether RAGE is involved in bone loss in vivo, we first investigated the bone mass in RAGE−/− mice compared to sex- and age-matched WT mice at different ages. As shown in Figs. 1A and B, male RAGE−/− mice have significantly increased BMD and BMC in total body and femur at 1 and 3 months old compared to male WT mice (P < 0.001). The spine in RAGE−/− mice also shows increased BMD and BMC at 1 month of age (P < 0.01). Consistent with the increased BMD in RAGE−/− mice, contact X-rays of femora (

Acknowledgments

We thank Dr. Peter P. Nawroth for providing us RAGE−/− mice and Dr. Markowitz for carefully reviewing the manuscript. This work was supported in part by grants from Medical College of Georgia (QSM), from the VA Merit Review and National Institutes of Health (RO1DK058680) (CMI), and from the National Institutes of Health (RO1AR049717) (MWH).

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    These authors contributed equally to this work.

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