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Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea
¹ Asan Institute for Life Sciences, Seoul, Republic of Korea
² Department of Cell and Developmental Biology, Dental Research Institute, Seoul National University, Seoul, Republic of Korea
³ Department of Thoracic and Cardiovascular Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea

(Requests for offprints should be addressed to H-H Kim; Email: hhbkim{at}snu.ac.kr or G S Kim; Email: gskim3{at}amc.seoul.kr)

Growing evidence has shown a biochemical link between increased oxidative stress and reduced bone density. Although -lipoic acid (-LA) has been shown to act as a thiol antioxidant, its effect on bone cells has not been determined. Using proteomic analysis, we identified six differentially expressed proteins in the conditioned media of -LA-treated human bone marrow stromal cell line (HS-5). One of these proteins, receptor activator of nuclear factor B ligand (RANKL), was significantly up-regulated, as confirmed by immunoblotting with anti-RANKL antibody. ELISA showed that -LA stimulated RANKL production in cellular extracts (membranous RANKL) about 5-fold and in conditioned medium (soluble RANKL) about 23-fold, but had no effect on osteoprotegerin (OPG) secretion. Despite increasing the RANKL/OPG ratio, -LA showed a dose-dependent suppression of osteoclastogenesis, both in a coculture system of mouse bone marrow cells and osteoblasts and in a mouse bone marrow cell culture system, and reduced bone resorption in a dose-dependent manner. In addition, -LA-induced soluble RANKL was not inhibited by matrix metalloprotease inhibitors, indicating that soluble RANKL is produced by -LA without any posttranslational processing. In contrast, -LA had no significant effect on the proliferation and differentiation of HS-5 cells. These results suggest that -LA suppresses osteoclastogenesis by directly inhibiting RANKL–RANK mediated signals, not by mediating cellular RANKL production. In addition, our findings indicate that -LA-induced soluble RANKL is not produced by shedding of membranous RANKL.