Qian Zhuang, Xu Jie, Zhang Lei, Deng Qian, Fan Zhenlin, Guo Xueqiang, Liang Zhuo, Wang Weiyun, Wang Lei, Liao Xiaohua, Ren Wenjie
Clinical Medical Center of Tissue Engineering and Regeneration, Institutes of Health Central Plain, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang Medical University, Xinxiang, China.
Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Front Pharmacol. 2024 Aug 29;15:1439678. doi: 10.3389/fphar.2024.1439678. eCollection 2024.
Osteoarthritis (OA) is the most prevalent cartilage degenerative and low-grade inflammatory disease of the whole joint. However, there are currently no FDA-approved drugs or global regulatory agency-approved treatments OA disease modification. Therefore, it's essential to explore novel effective therapeutic strategies for OA. In our study, we investigated the effects of AFK-PD, a novel pyridone agent, on the development of OA induced by destabilization of the medial meniscus (DMM) , and its impact on the function of chondrocytes treated with IL-1β . Our results demonstrated AFK-PD alleviated OA progression through inhibiting cartilage degeneration, articular inflammation and osteophyte formation. Notably, AFK-PD inhibited chondrocyte inflammation and synovial macrophage M1 polarization, leading to the attenuation of articular inflammation. Additionally, AFK-PD promoted chondrocyte anabolism while mitigating catabolism and apoptosis, effectively inhibiting cartilage degeneration. Mechanistically, AFK-PD suppressed the expression of key signaling molecules involved in the MAPK pathway, such as p-ERK1/2 and p-JNK, as well as the NF-κB signaling molecule p-p65, in IL-1β-induced chondrocytes. These findings suggest AFK-PD ameliorates the development of OA by protecting chondrocyte functions and inhibiting articular inflammation in chondrocytes and synovial macrophages. Overall, our study highlights AFK-PD as a promising therapeutic candidate for the treatment of OA.
骨关节炎（OA）是全关节最常见的软骨退行性和低度炎症性疾病。然而，目前尚无美国食品药品监督管理局（FDA）批准的药物或全球监管机构批准的改善OA病情的治疗方法。因此，探索治疗OA的新型有效治疗策略至关重要。在我们的研究中，我们研究了新型吡啶酮类药物AFK-PD对内侧半月板不稳定（DMM）诱导的OA发展的影响，及其对用白细胞介素-1β（IL-1β）处理的软骨细胞功能的影响。我们的结果表明，AFK-PD通过抑制软骨退变、关节炎症和骨赘形成来减轻OA进展。值得注意的是，AFK-PD抑制软骨细胞炎症和滑膜巨噬细胞M1极化，从而减轻关节炎症。此外，AFK-PD促进软骨细胞合成代谢，同时减轻分解代谢和细胞凋亡，有效抑制软骨退变。从机制上讲，AFK-PD抑制了IL-1β诱导的软骨细胞中丝裂原活化蛋白激酶（MAPK）通路中关键信号分子的表达，如p-ERK1/2和p-JNK，以及核因子κB（NF-κB）信号分子p-p65。这些发现表明，AFK-PD通过保护软骨细胞功能和抑制软骨细胞及滑膜巨噬细胞中的关节炎症来改善OA的发展。总体而言，我们的研究突出了AFK-PD作为一种有前景的OA治疗候选药物。
