PMID- 38367900 OWN - NLM STAT- MEDLINE DCOM- 20240408 LR - 20240408 IS - 1879-260X (Electronic) IS - 0925-4439 (Linking) VI - 1870 IP - 4 DP - 2024 Apr TI - Spermidine ameliorates osteoarthritis via altering macrophage polarization. PG - 167083 LID - S0925-4439(24)00072-3 [pii] LID - 10.1016/j.bbadis.2024.167083 [doi] AB - OBJECTIVE: Spermidine (SPD) is an anti-aging natural substance, and it exerts effects through anti-apoptosis and anti-inflammation. However, the specific protective mechanism of SPD in osteoarthritis (OA) remains unclear. Here, we explored the role of SPD on the articular cartilage and the synovial tissue, and tested whether the drug would regulate the polarization of synovial macrophages by in vivo and in vitro experiments. METHODS: By constructing an OA model in mice, we preliminarily explored the protective effect of SPD on the articular cartilage and the synovial tissue. Meanwhile, we isolated and cultured human primary chondrocytes and bone marrow-derived macrophages (BMDMs), and prepared a conditioned medium (CM) to explore the specific protective effect of SPD in vitro. RESULTS: We found that SPD alleviated cartilage degeneration and synovitis, increased M2 polarization and decreased M1 polarization in synovial macrophages. In vitro experiments, SPD inhibited ERK MAPK and p65/NF-kappaB signaling in macrophages, and transformed macrophages from M1 to M2 subtypes. Interestingly, SPD had no direct protective effect on chondrocytes in vitro; however, the conditioned medium (CM) from M1 macrophages treated with SPD promoted the anabolism and inhibited the catabolism of chondrocytes. Moreover, this CM markedly suppressed IL-1beta-induced p38/JNK MAPK signaling pathway activation in chondrocytes. CONCLUSIONS: This work provides new perspectives on the role of SPD in OA. SPD does not directly target chondrocytes, but can ameliorate the degradation of articular cartilage through regulating M1/M2 polarization of synovial macrophages. Hence, SPD is expected to be the potential therapy for OA. CI - Copyright (c) 2024 Elsevier B.V. All rights reserved. FAU - Ou, Qianhua AU - Ou Q AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China; Department of Intensive Care Unit, Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, China. Electronic address: oqhgao@163.com. FAU - Tang, Su'an AU - Tang S AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China. Electronic address: tangsan@mail2.sysu.edu.cn. FAU - Zhu, Jianwei AU - Zhu J AD - Department of Orthopedics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China. Electronic address: eyzhujianwei@scut.edu. FAU - Xue, Song AU - Xue S AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China; Department of Rheumatology and Immunology, Arthritis Research Institute, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China. Electronic address: freexuesong@gmail.com. FAU - Huang, Hong AU - Huang H AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China. Electronic address: honghuang7165@163.com. FAU - Zhao, Yang AU - Zhao Y AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China. Electronic address: zy19930920@smu.edu.cn. FAU - Cai, Yu AU - Cai Y AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China. Electronic address: y.cai@erasmusmc.nl. FAU - Wu, Cuixi AU - Wu C AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China. Electronic address: 18302010195@163.com. FAU - Chen, Jianmao AU - Chen J AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China. Electronic address: 18826739323@163.com. FAU - Ruan, Guangfeng AU - Ruan G AD - Clinical Research Centre, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou 510000, China. Electronic address: ruan1989.ok@163.com. FAU - Ding, Changhai AU - Ding C AD - Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510000, China; Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia. Electronic address: changhai.ding@utas.edu.au. LA - eng PT - Journal Article DEP - 20240215 PL - Netherlands TA - Biochim Biophys Acta Mol Basis Dis JT - Biochimica et biophysica acta. Molecular basis of disease JID - 101731730 RN - U87FK77H25 (Spermidine) RN - 0 (Culture Media, Conditioned) SB - IM MH - Humans MH - Mice MH - Animals MH - *Spermidine/pharmacology/metabolism/therapeutic use MH - Culture Media, Conditioned/pharmacology/metabolism MH - *Osteoarthritis/drug therapy/metabolism MH - Chondrocytes/metabolism MH - Macrophages/metabolism OTO - NOTNLM OT - Chondrocytes OT - Macrophages OT - Osteoarthritis OT - Polarization OT - Spermidine COIS- Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2024/02/18 00:42 MHDA- 2024/04/08 06:42 CRDT- 2024/02/17 19:17 PHST- 2023/08/27 00:00 [received] PHST- 2024/02/01 00:00 [revised] PHST- 2024/02/12 00:00 [accepted] PHST- 2024/04/08 06:42 [medline] PHST- 2024/02/18 00:42 [pubmed] PHST- 2024/02/17 19:17 [entrez] AID - S0925-4439(24)00072-3 [pii] AID - 10.1016/j.bbadis.2024.167083 [doi] PST - ppublish SO - Biochim Biophys Acta Mol Basis Dis. 2024 Apr;1870(4):167083. doi: 10.1016/j.bbadis.2024.167083. Epub 2024 Feb 15.