Atorvastatin inhibits osteoclastogenesis by decreasing the expression of RANKL in the synoviocytes of rheumatoid arthritis.
BACKGROUND
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). 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.


METHODS
FLSs 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.


RESULTS
Atorvastatin 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.


CONCLUSIONS
These results suggest that atorvastatin inhibits osteoclastogenesis and bone destruction in RA patients.
Jeong Yeon
JY
Kim
Eun Young
EY
Lee
Eun Bong
EB
Lee
Yun Jong
YJ
Lee
Hyun Jung
HJ
Yoo
Jiyong
J
Choi
Yeong Wook
YW
Song
D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism*; D000069059:Atorvastatin; D002478:Cells, Cultured; D018920:Coculture Techniques; D005260:Female; D005786:Gene Expression Regulation; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013583:Synovial Membrane / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D006538:Heptanoic Acids; D011758:Pyrroles; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D000069059:Atorvastatin