背景
骨关节炎(OA)是一种常见的退行性关节疾病[1]。研究发现AZD8330可以抑制促炎因子的产生并阻止炎症反应[2]。鉴于炎症是 OA 的主要致病因素，推测 AZD8330 在 OA 治疗中可能表现出卓越的功效。
方法
在这项研究中，我们研究了腹腔注射 AZD8330 在手术诱导内侧半月板破坏 (DMM) 的小鼠模型中延缓骨关节炎进展的潜力。同时，我们利用 ATDC5 软骨细胞来剖析 AZD8330 通过调节 RIP1 抑制 TNF-α 诱导的 NF-κB 信号通路的机制。研究结果显示，AZD8330 减轻了软骨退化和炎症反应，导致接受 AZD8330 治疗的 DMM 小鼠的 OARSI 评分大幅降低。从机制上讲，AZD8330 通过促进 cIAP1 介导的 RIP1 的磷酸化激活，充当 TNF-α 诱导的 NF-κB/p65 信号通路的抑制剂。体内和体外实验数据的结合支持了这样的结论：AZD8330 可以通过调节 RIP1 活性来调节 NF-κB/P65 信号通路，从而减轻软骨细胞降解，从而减轻 OA。因此，AZD8330 的利用可能具有预防骨关节炎的潜力。
结果
我们的研究描述了 AZD8330 在 OA 治疗中炎症调节中的作用。此外，我们发现AZD8330对OA的抑制作用可能取决于cIAP1的激活，cIAP1反过来下调RIP1，从而抑制NF-κB/P65信号通路。这项研究证实了 AZD8330 可能是骨关节炎治疗的有希望的竞争者的观点。
结论
我们的研究提供了令人信服的证据，证明 AZD8330 在 OA 治疗领域控制炎症的能力。同样，我们的研究阐明了 AZD8330 对 OA 的减弱作用依赖于 cIAP1 的激活来抑制 RIP1，从而抑制 NF-κB 信号通路。根据我们目前的研究，我们可能已经确定了一种可行的 OA 治疗候选药物。
"点击查看英文标题和摘要"
Upregulation of cIAP1 induced by AZD8330 alleviates osteoarthritis progression by inhibiting the RIP1-associated necrosis signaling pathway
Background
Osteoarthritis (OA) is a prevalent degenerative joint disease [1]. It has come to light that AZD8330 can suppress the generation of proinflammatory factors and deter the inflammatory response [2]. Given that inflammation is a primary causative factor in OA, it is posited that AZD8330 might exhibit superior efficacy in OA management.
Methods
In this study, we investigated the potential of intraperitoneal injection of AZD8330 to retard the progression of osteoarthritis in a murine model with surgically induced medial meniscus destruction (DMM). Concurrently, we employed ATDC5 cartilage cells to dissect the mechanism through which AZD8330 inhibits the TNF-α-induced NF-κB signaling pathway via modulation of RIP1. The findings revealed that AZD8330 mitigated cartilage degradation and the inflammatory response, leading to a substantial reduction in OARSI scores among DMM mice treated with AZD8330. Mechanistically, AZD8330 functioned as a suppressor of the TNF-α-induced NF-κB/p65 signaling pathway by facilitating the phosphorylation activation of cIAP1-mediated RIP1. The combination of data from both in vivo and in vitro experiments supports the conclusion that AZD8330 can attenuate chondrocyte degradation, thereby alleviating OA, by regulating the NF-κB/P65 signaling pathway through modulation of RIP1 activity. Consequently, the utilization of AZD8330 may hold potential in the prophylaxis of osteoarthritis.
Results
Our investigation delineates the role of AZD8330 in the regulation of inflammation in the context of OA treatment. Furthermore, we have unveiled that the inhibitory impact of AZD8330 on OA may hinge upon the activation of cIAP1, which in turn downregulates RIP1, thereby restraining the NF-κB/P65 signaling pathway. This study lends credence to the notion that AZD8330 may be a promising contender for osteoarthritis therapy.
Conclusions
Our study provides compelling evidence attesting to the capacity of AZD8330 in managing inflammation within the realm of OA treatment. Likewise, our study has elucidated that the attenuation of OA by AZD8330 relies on the activation of cIAP1 to inhibit RIP1, consequently suppressing the NF-κB signaling pathway. On the strength of our present study, we may have identified a viable drug candidate for OA treatment.
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