YTHDF2 mediates LPS-induced osteoclastogenesis and inflammatory response via the NF-κB and MAPK signaling pathways |
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| Institution: | 1. Department of Cardiology, First Hospital of Shanxi Medical University, Taiyuan, China;2. Shanxi Medical University, Taiyuan, China;3. Department of Cardiology, the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China;1. University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam;2. Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-Do 24341, Republic of Korea;3. Kangwon Institute of Inclusive Technology, Kangwon National University, Chuncheon, Gangwon-Do 24341, Republic of Korea;4. Institute of Marine Biochemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi, Viet Nam;1. Department of Intervention, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, 1 East Banshan Road, Hangzhou, 310022, Zhejiang, China;2. Department of Intensive Care Unit, Zhejiang Medical & Health Group Hangzhou Hospital (Cooperative Hospital of Zhejiang Cancer Hospital), 1 Banshan Road, Hangzhou, 310022, Zhejiang, China;3. Department of Infectious Disease, Zhejiang Medical & Health Group Hangzhou Hospital (Cooperative Hospital of Zhejiang Cancer Hospital), 1 Banshan Road, Hangzhou, 310022, Zhejiang, China;4. Department of Respiration and Critical Care Medicine, Zhejiang Medical & Health Group Hangzhou Hospital (Cooperative Hospital of Zhejiang Cancer Hospital), 1 Banshan Road, Hangzhou, 310022, Zhejiang, China;5. Department of Intestinal Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, 1 East Banshan Road, Hangzhou, 310022, Zhejiang, China;1. Neonatal Intensive Care Unite, Children''s Hospital Affiliated to Xi''an Jiaotong University, Xi''an, Shaanxi Province, 710003, China;2. Neonatal Department, Children''s Hospital Affiliate to Xi''an Jiaotong University, Xi''an, Shaanxi Province, 710003, China |
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| Abstract: | Aberrant elevation of osteoclast differentiation and function is responsible for disrupting bone homeostasis in various inflammatory bone diseases. YTH domain family 2 (YTHDF2) is a well-known m6A-binding protein that plays an essential role in regulating cell differentiation and inflammatory processes by mediating mRNA degradation. However, the regulatory role of YTHDF2 in inflammatory osteoclast differentiation remains unelucidated. Here, we detected the expression of m6A-related genes and found that YTHDF2 was upregulated in RANKL-primed osteoclast precursors stimulated with lipopolysaccharide (LPS). Ythdf2 knockdown in RAW264.7 cells and primary bone marrow-derived macrophages (BMMs) enhanced osteoclast formation and bone resorption, which was assessed by TRAP staining assay and pit formation assay. Ythdf2 depletion upregulated osteoclast-related gene expression and proinflammatory cytokine secretion. In contrast, overexpression of Ythdf2 produced the reverse effect. Furthermore, Ythdf2 knockdown enhanced the phosphorylation of IKKα/β, IκBα, ERK, P38 and JNK. NF-κB and MAPK signaling pathway inhibitors effectively abrogated the enhanced expression of Nfact1, c-Fos, IL-1β and TNF-α caused by Ythdf2 knockdown. Mechanistically, the mRNA stability assay revealed that Ythdf2 depletion led to stabilization of Tnfrsf11a, Traf6, Map4k4, Map2k3, Map2k4 and Nfatc1 mRNA. In summary, our findings demonstrated that YTHDF2 has a negative regulatory role in LPS-induced osteoclast differentiation and the inflammatory response via the NF-κB and MAPK signaling pathways. |
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