Lu Jiansen, Zhang Hongbo, Pan Jianying, Hu Zhiqiang, Liu Liangliang, Liu Yanli, Yu Xiao, Bai Xiaochun, Cai Daozhang, Zhang Haiyan
Department of Joint Surgery, Center for Orthopaedic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Department of Orthopedics, Orthopedic Hospital of Guangdong Province, Academy of Orthopedics Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
Arthritis Res Ther. 2021 May 14;23(1):142. doi: 10.1186/s13075-021-02512-z.
To investigate the role and regulatory mechanisms of fargesin, one of the main components of Magnolia fargesii, in macrophage reprogramming and crosstalk across cartilage and synovium during osteoarthritis (OA) development.
Ten-week-old male C57BL/6 mice were randomized and assigned to vehicle, collagenase-induced OA (CIOA), or CIOA with intra-articular fargesin treatment groups. Articular cartilage degeneration was evaluated using the Osteoarthritis Research Society International (OARSI) score. Immunostaining and western blot analyses were conducted to detect relative protein. Raw264.7 cells were treated with LPS or IL-4 to investigate the role of polarized macrophages. ADTC5 cells were treated with IL-1β and conditioned medium was collected to investigate the crosstalk between chondrocytes and macrophages.
Fargesin attenuated articular cartilage degeneration and synovitis, resulting in substantially lower Osteoarthritis Research Society International (OARSI) and synovitis scores. In particular, significantly increased M2 polarization and decreased M1 polarization in synovial macrophages were found in fargesin-treated CIOA mice compared to controls. This was accompanied by downregulation of IL-6 and IL-1β and upregulation of IL-10 in serum. Conditioned medium (CM) from M1 macrophages treated with fargesin reduced the expression of matrix metalloproteinase-13, RUNX2, and type X collagen and increased Col2a1 and SOX9 in OA chondrocytes, but fargesin alone did not affect chondrocyte catabolic processes. Moreover, fargesin exerted protective effects by suppressing p38/ERK MAPK and p65/NF-κB signaling.
This study showed that fargesin switched the polarized phenotypes of macrophages from M1 to M2 subtypes and prevented cartilage degeneration partially by downregulating p38/ERK MAPK and p65/NF-κB signaling. Targeting macrophage reprogramming or blocking the crosstalk between macrophages and chondrocytes in early OA may be an effective preventive strategy.
研究凹叶厚朴主要成分之一的辛夷脂素在骨关节炎（OA）发展过程中巨噬细胞重编程以及软骨与滑膜间相互作用中的作用和调控机制。
将10周龄雄性C57BL/6小鼠随机分为溶剂对照组、胶原酶诱导性骨关节炎（CIOA）组或CIOA关节内注射辛夷脂素治疗组。使用国际骨关节炎研究学会（OARSI）评分评估关节软骨退变情况。进行免疫染色和蛋白质印迹分析以检测相关蛋白。用脂多糖（LPS）或白细胞介素-4（IL-4）处理Raw264.7细胞以研究极化巨噬细胞的作用。用IL-1β处理ADTC5细胞并收集条件培养基以研究软骨细胞与巨噬细胞之间的相互作用。
辛夷脂素减轻了关节软骨退变和滑膜炎，使国际骨关节炎研究学会（OARSI）评分和滑膜炎评分显著降低。特别是，与对照组相比，在辛夷脂素治疗的CIOA小鼠中发现滑膜巨噬细胞中M2极化显著增加而M1极化减少。这伴随着血清中白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）的下调以及白细胞介素-10（IL-10）的上调。用辛夷脂素处理的M1巨噬细胞的条件培养基（CM）降低了OA软骨细胞中基质金属蛋白酶-13（MMP-13）、RUNX2和X型胶原的表达，并增加了Ⅱ型胶原α1（Col2a1）和SRY-box转录因子9（SOX9）的表达，但单独的辛夷脂素不影响软骨细胞的分解代谢过程。此外，辛夷脂素通过抑制p38/细胞外信号调节激酶（ERK）丝裂原活化蛋白激酶（MAPK）和p65/核因子κB（NF-κB）信号发挥保护作用。
本研究表明，辛夷脂素将巨噬细胞的极化表型从M1亚型转变为M2亚型，并通过下调p38/ERK MAPK和p65/NF-κB信号部分预防软骨退变。在早期OA中靶向巨噬细胞重编程或阻断巨噬细胞与软骨细胞之间的相互作用可能是一种有效的预防策略。
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