alpha-Lipoic acid inhibits inflammatory bone resorption by suppressing prostaglandin E2 synthesis.
alpha-Lipoic acid (LA) has been intensely investigated as a therapeutic agent for several pathological conditions, including diabetic polyneuropathy. In the present study, we examined the effects of LA on osteoclastic bone loss associated with inflammation. LA significantly inhibited IL-1-induced osteoclast formation in cocultures of mouse osteoblasts and bone marrow cells, but LA had only a marginal effect on osteoclastogenesis from bone marrow macrophages induced by receptor activator of NF-kappaB ligand (RANKL). LA inhibited both the sustained up-regulation of RANKL expression and the production of PGE2 induced by IL-1 in osteoblasts. In addition, treatment with either prostaglandin E2 (PGE2) or RANKL rescued IL-1-induced osteoclast formation inhibited by LA or NS398, a specific cyclooxygenase-2 (COX-2) inhibitor, in cocultures. LA blocked IL-1-induced PGE2 production even in the presence of arachidonic acid, without affecting the expression of COX-2 and membrane-bound PGE2 synthase. Dihydrolipoic acid (the reduced form of LA), but not LA, attenuated recombinant COX-2 activity in vitro. LA also inhibited osteoclast formation and bone loss induced by IL-1 and LPS in mice. Our results suggest that the reduced form of LA inhibits COX-2 activity, PGE2 production, and sustained RANKL expression, thereby inhibiting osteoclast formation and bone loss in inflammatory conditions.
Ha
Hyunil
H
Department of Cell and Developmental Biology, DRI, BK21 Program, Seoul National University College of Dentistry, Seoul, Korea.
Lee
Jong-Ho
JH
Kim
Ha-Neui
HN
Kim
Hyun-Man
HM
Kwak
Han Bok
HB
Lee
Seungbok
S
Kim
Hong-Hee
HH
Lee
Zang Hee
ZH
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis*; D007249:Inflammation / Q000503:physiopathology; D007375:Interleukin-1 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009578:Nitrobenzenes / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000494:pharmacology; D008063:Thioctic Acid / Q000494:pharmacology*
D000975:Antioxidants; D002352:Carrier Proteins; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D009578:Nitrobenzenes; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D013449:Sulfonamides; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D008063:Thioctic Acid; D051546:Cyclooxygenase 2; D015232:Dinoprostone