Kaempferol targeting on the fibroblast growth factor receptor 3-ribosomal S6 kinase 2 signaling axis prevents the development of rheumatoid arthritis

• DOI: 10.1038/s41419-018-0433-0
• Publication Date: 2018-03-14T16:47:50Z
• Authors: Cheol-Jung Lee; Su-Jin Moon; Jeong-Hee Jeong; Sangbae Lee; Mee-Hyun Lee; Sun-Mi Yoo; Hye Suk Lee; Han Chang Kang; Joo Young Lee; Weon Sun Lee; Hee-Jin Lee; Eun-Kyung Kim; Joo-Yeon Jhun; Mi-La Cho; Jun-Ki Min; Yong-Yeon Cho
• Keywords: Ribosomal s6 kinase

Abstract Rheumatoid arthritis (RA) is a systemic inflammatory disease that mainly affects the synovial joints. Although involvement of fibroblast growth factor (FGF) signaling pathway has been suggested as an important modulator in RA development, no clear evidence provided. In this study, we found fluid basic FGF (bFGF) concentration was significantly higher than osteoarthritis (OA) patients. bFGF stimulates proliferation and migration human fibroblast-like synoviocytes (FLSs) by activation bFGF-FGF receptor 3 (FGFR3)-ribosomal S6 kinase 2 (RSK2) axis. Moreover, molecular docking study revealed kaempferol inhibited FGFR3 activity binding to active pocket domain. Kaempferol forms hydrogen bonds with backbone oxygen Glu555 Ala558 side chain Lys508. Notably, inhibition bFGF-FGFR3–RSK2 suppresses FLSs release activated T-cell-mediated cytokines, such IL-17, IL-21, TNF-α. We further phospho-FGFR3 -RSK2 were more highly observed OA synovium. The hyperplastic lining sublining lymphoid aggregate layers synovium showed p-RSK2-expressing CD68 + macrophages high frequency, while pRSK2-expressing CD4 T-cells at lower frequency. administration collagen-induced mice relieved frequency severity arthritis. reduced osteoclast differentiation vitro vivo relative controls associated markers, tartrate-resistant acid phosphatase, integrin β3, MMP9. Conclusively, our data suggest bFGF-induced FGFR3–RSK2 may play critical role during initiation progression terms FLS enhanced osteoclastogenesis, be effective new treatment for RA.