Adrenomedullin inhibits MAPK pathway-dependent rheumatoid synovial fibroblast-mediated osteoclastogenesis by IL-1 and TNF-alpha.
The objective of this study is to determine the effects of adrenomedullin (AM) on IL-1- and TNF-alpha-induced rheumatoid synovial fibroblasts (RASFs)-mediated osteoclastogenesis. The formation of osteoclasts in co-cultures of RASFs and peripheral blood mononuclear cells was evaluated by tartrate-resistant acid phosphatase and resorption pit formation assay. The expression of RANKL, OPG, p-ERK, p-p38, and p-JNK was examined by immunoblotting and quantitative reverse transcription-polymerase chain reaction. AM (1-52) inhibits IL-1- and TNF-alpha-induced RASFs-mediated osteoclastogenesis. AM affected IL-1-, TNF-alpha-induced RANKL and OPG expression in RASFs. AM also inhibits IL-1 and TNF-alpha-induced phosphorylation of ERK-1/2, p38 MAPK, and JNK. Inhibitor of AM (AM 22-52) inhibits the effects of AM on the osteoclastogenesis. These results suggest that AM might be involved in the inflammatory cytokines-mediated osteoclastogenesis and thus bone damage, and indicate that it can be a new therapeutic strategy against joint destruction in RA.
Yun
Hee-Jin
HJ
Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine, Chonju, Jeonbuk, 561-712, South Korea.
Lee
Eun-Gyeong
EG
Lee
Sang-Il
SI
Chae
Han-Jung
HJ
Yoo
Wan-Hee
WH
D000135:Acid Phosphatase / Q000032:analysis; D053607:Adrenomedullin / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000378:metabolism*; D018920:Coculture Techniques; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000494:pharmacology; D007527:Isoenzymes / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000166:cytology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D010010:Osteoclasts / Q000378:metabolism*; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology*; D000071681:Tartrate-Resistant Acid Phosphatase; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology
D007375:Interleukin-1; D007527:Isoenzymes; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D053607:Adrenomedullin; D020928:Mitogen-Activated Protein Kinases; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase