Abstract
IntroductionStatins, hydroxymethylglutaryl-coenzyme A reductase inhibitors, have been reported to have antiinflammatory and/or immunomodulatory effects and prophylactic and therapeutic effects in collagen-induced arthritis, an experimental model of rheumatoid arthritis (RA). The authors undertook to determine the effect of atorvastatin on the expressions of osteoprotegerin (OPG) and receptor activator of nuclear factor κB ligand (RANKL) in RA fibroblast-like synoviocytes (FLSs), to identify the mechanisms responsible for these effects, and to determine whether the statin inhibits osteoclastogenesis.MethodsFLSs isolated from five RA patients were cultured in the presence of 20 ng/ml of tumor necrosis factor-α (TNF-α) with or without atorvastatin. RANKL expressions were assayed with Western blotting and enzyme-linked immunosorbent assay. RANKL, RANK, and OPG expression were assayed with reverse transcription-polymerase chain reaction (RT-PCR). Osteoclast formation was assayed by counting cells after staining for tartrate-resistant acid phosphatase in cocultures of peripheral blood mononuclear cells (PBMCs) and RA FLSs.ResultsAtorvastatin inhibited the expression of RANKL in RA FLSs in a dose-dependent manner, and the suppression of RANKL was prevented by mevalonate. However, OPG expression was not affected by atorvastatin in RA FLSs, and atorvastatin did not affect RANK expression in CD14+ cells. Conversely, atorvastatin suppressed TNF-α-induced p38 phosphorylation in RA FLSs and significantly reduced TRAP-positive multinucleated osteoclast formation in the coculture of PBMCs and RA FLSs.ConclusionThese results suggest that atorvastatin inhibits osteoclastogenesis and bone destruction in RA patients.
Highlights
Statins, hydroxymethylglutaryl-coenzyme A reductase inhibitors, have been reported to have antiinflammatory and/or immunomodulatory effects and prophylactic and therapeutic effects in collagen-induced arthritis, an experimental model of rheumatoid arthritis (RA)
We examined the effects of atorvastatin on the expressions of OPG and receptor activator of nuclear factor κB ligand (RANKL) in fibroblast-like synoviocytes (FLSs) from RA patients and the mechanisms involved, and in addition, we sought to determine whether the statin inhibits osteoclastogenesis
Effect of atorvastatin on tumor necrosis factor-a-induced signal-transduction pathways in FLSs from rheumatoid arthritis patients To investigate the mechanism by which atorvastatin suppresses the expression of TNF-a-induced RANKL, we examined its effects on the phosphorylations of p38 mitogen-activated protein kinase (MAPK), JNK, ERK, and Akt
Summary
Hydroxymethylglutaryl-coenzyme A reductase inhibitors, have been reported to have antiinflammatory and/or immunomodulatory effects and prophylactic and therapeutic effects in collagen-induced arthritis, an experimental model of rheumatoid arthritis (RA). The authors undertook to determine the effect of atorvastatin on the expressions of osteoprotegerin (OPG) and receptor activator of nuclear factor B ligand (RANKL) in RA fibroblast-like synoviocytes (FLSs), to identify the mechanisms responsible for these effects, and to determine whether the statin inhibits osteoclastogenesis. Receptor activator of nuclear factor B ligand (RANKL), and its receptor, RANK, have been found to be key factors in the stimulation of osteoclast formation, and they have been suggested to play major roles in inflammationinduced bone loss and joint destruction in arthritis [1,2]. The soluble tumor necrosis factor (TNF)-receptor molecule, osteoprotegerin (OPG), is a natural inhibitor of RANKL. Recent studies provided genetic evidence that RANKL and osteoclasts are central players in the inflammatory destruction of bone [9] and that enhanced
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