alpha-Lipoic acid inhibits inflammatory bone resorption by suppressing prostaglandin E2 synthesis

J Immunol. 2006 Jan 1;176(1):111-7. doi: 10.4049/jimmunol.176.1.111.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Blotting, Western
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / drug effects
  • Bone Resorption / drug therapy*
  • Bone and Bones / drug effects*
  • Bone and Bones / metabolism
  • Carrier Proteins / drug effects
  • Carrier Proteins / metabolism
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Cyclooxygenase 2 / pharmacology
  • Cyclooxygenase Inhibitors / pharmacology
  • Dinoprostone / biosynthesis*
  • Inflammation / physiopathology
  • Interleukin-1 / metabolism
  • Macrophages / cytology
  • Macrophages / drug effects
  • Membrane Glycoproteins / drug effects
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred ICR
  • Nitrobenzenes / pharmacology
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteoclasts / drug effects*
  • Osteoclasts / metabolism
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sulfonamides / pharmacology
  • Thioctic Acid / pharmacology*


  • Antioxidants
  • Carrier Proteins
  • Cyclooxygenase Inhibitors
  • Interleukin-1
  • Membrane Glycoproteins
  • Nitrobenzenes
  • RANK Ligand
  • Receptor Activator of Nuclear Factor-kappa B
  • Sulfonamides
  • Tnfrsf11a protein, mouse
  • Tnfsf11 protein, mouse
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Thioctic Acid
  • Cyclooxygenase 2
  • Dinoprostone