Department of Orthopaedic Oncology, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China; Department of Orthopaedic Research Center, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China.
Department of Orthopaedic Research Center, The Third Hospital of Hebei Medical University, Shijiazhuang 050051, China; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):112948. doi: 10.1016/j.intimp.2024.112948. Epub 2024 Aug 31.
The inflammatory microenvironment, polarization of macrophages towards the M1 phenotype, and consequent matrix degradation and senescence of chondrocytes are primary contributors to the degeneration of knee joint cartilage, further exacerbating the progression of osteoarthritis (OA). Kongensin A (KA) is a recently identified natural plant extract exhibiting anti-necrotic apoptosis and anti-inflammatory properties, but the potential efficacy in alleviating OA remains uncertain. The current research lucubrated the effect of KA on the inflammatory microenvironment and macrophage polarization, as well as its regulatory function in extracellular matrix (ECM) metabolism and chondrocyte senescence. Our findings demonstrated that KA can suppress inflammatory signaling, maintain homeostasis between ECM anabolism and catabolism, and suppress chondrocytes senescence. Further investigation elucidated that the mechanism involves the suppression of the PI3K/AKT/NF-κB axis in chondrocytes under inflammatory conditions. Moreover, KA impeded M1 polarization of macrophages via inhibiting PI3K/AKT/NF-κB axis. Subsequently, we treated chondrocytes with macrophages-derived conditioned medium (CM) and revealed that KA can promote ECM anabolism and alleviate chondrocytes senescence by reprogramming macrophage polarization. Consistent with in vitro experiments, in vivo administration of KA demonstrated alleviated cartilage degeneration and delayed progression of OA. Collectively, through obstructing the PI3K/AKT/NF-κB axis, KA can reprogram macrophage polarization, promote matrix metabolism equilibrium, and alleviate chondrocytes senescence, thereby attenuating the pathology of OA. In conclusion, KA may emerge as a promising therapy for OA.
炎症微环境、巨噬细胞向 M1 表型的极化以及由此导致的软骨细胞基质降解和衰老，是膝关节软骨退变的主要原因，进一步加剧了骨关节炎（OA）的进展。Kongensin A（KA）是一种最近被鉴定出的天然植物提取物，具有抗坏死凋亡和抗炎特性，但在缓解 OA 方面的潜在疗效尚不确定。目前的研究深入探讨了 KA 对炎症微环境和巨噬细胞极化的影响，以及其对细胞外基质（ECM）代谢和软骨细胞衰老的调节作用。我们的研究结果表明，KA 可以抑制炎症信号，维持 ECM 合成代谢和分解代谢之间的平衡，并抑制软骨细胞衰老。进一步的研究表明，这种机制涉及在炎症条件下抑制软骨细胞中的 PI3K/AKT/NF-κB 轴。此外，KA 通过抑制 PI3K/AKT/NF-κB 轴来阻止巨噬细胞向 M1 极化。随后，我们用巨噬细胞来源的条件培养基（CM）处理软骨细胞，发现 KA 可以通过重编程巨噬细胞极化来促进 ECM 合成代谢和减轻软骨细胞衰老。与体外实验一致，体内给予 KA 可减轻软骨退化并延缓 OA 的进展。总之，通过阻断 PI3K/AKT/NF-κB 轴，KA 可以重编程巨噬细胞极化，促进基质代谢平衡，减轻软骨细胞衰老，从而减轻 OA 的病理。综上所述，KA 可能成为治疗 OA 的一种有前途的方法。
