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Melatonin inhibits human fibroblast‐like synoviocyte proliferation via extracellular signal‐regulated protein kinase/P21 CIP1 /P27 KIP1 pathways
Author(s) -
Nah SeongSu,
Won HyeJin,
Park Hae Jeong,
Ha Eunyoung,
Chung JooHo,
Cho Hong Yon,
Baik Hyung Hwan
Publication year - 2009
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/j.1600-079x.2009.00689.x
Subject(s) - melatonin , mapk/erk pathway , signal transduction , kinase , cell growth , protein kinase a , endocrinology , medicine , p38 mitogen activated protein kinases , biology , cell cycle , fibroblast , phosphorylation , microbiology and biotechnology , cancer research , apoptosis , cell culture , biochemistry , genetics
The excessive proliferation and migration of synoviocytes are well‐characterized phenomena that play key roles in the pathophysiology of rheumatoid arthritis (RA). Melatonin has been shown to have potent anti‐proliferative effect in various cancer cells such as breast and prostate cancer cells. In this study, we examined the role of melatonin on synoviocyte proliferation in primary cultured human fibroblast‐like synoviocytes (FLSs) by analyzing protein expression of P21 CIP1 (P21) and P27 KIP1 (P27), the cyclin‐dependent kinase inhibitors that are important in cell cycle control, and the phosphorylation of mitogen‐activated protein kinases (MAPKs). RA‐FLS proliferation was determined by a [ 3 H]‐thymidine incorporation assay. Western blot analysis was applied to examine the underlying mechanisms of melatonin’s effect. Melatonin inhibited RA‐FLS proliferation in a dose‐dependent manner. It reduced proliferation of passage 2 FLSs by 25% at 10 μ m and by nearly 40% at 100 μ m concentrations. The inhibitory effect of melatonin on RA‐FLS proliferation was also observed in passages 4 and 6. Melatonin upregulated the expression levels of P21 and P27 dose‐dependently (24 hr), induced the phosphorylation of extracellular signal‐regulated protein kinase (ERK) time‐dependently (10 μ m ), but did not affect phosphorylation of P38 in RA‐FLSs. In addition, the expression of P21 and P27 triggered by melatonin was inhibited by the pretreatment of the ERK inhibitor, PD98059 (10 μ m ). The anti‐proliferative action of melatonin in RA‐FLSs was also blocked by PD98059. Taken together, these results suggest that melatonin exerts the inhibitory effect of the proliferation of RA‐FLSs through the activation of P21 and P27 mediated by ERK. Hence we suggest that melatonin could be used as a therapeutic agent for the treatment of RA.