Osteoarthritis is a joint disease characterized by a poorly-defined inflammatory response that does not encompass a massive immune cell infiltration yet contributes to cartilage degradation and loss of joint mobility, suggesting a chondrocyte intrinsic inflammatory response. Using primary chondrocytes from joints of osteoarthritic mice and patients, we first show that these cells express ample pro-inflammatory markers and RANKL in an NF-κB dependent manner. The inflammatory phenotype of chondrocytes was recapitulated by exposure of chondrocytes to IL-1β and bone particles, which were used to model bone matrix breakdown products revealed to be present in synovial fluid of OA patients, albeit their role was not defined. We further show that bone particles and IL-1β can promote senescent and apoptotic changes in primary chondrocytes due to oxidative stress from various cellular sources such as the mitochondria. Finally, we provide evidence that inflammation, oxidative stress and senescence converge upon IκB-ζ, the principal mediator downstream of NF-κB, which regulates expression of RANKL, inflammatory, catabolic, and SASP genes. Overall, this work highlights the capacity and mechanisms by which inflammatory cues, primarily joint degradation products, i.e., bone matrix particles in concert with IL-1β in the joint microenvironment, program chondrocytes into an “inflammatory phenotype” which inflects local tissue damage.

骨关节炎是一种关节疾病，其特征是不明确的炎症反应，不包括大量免疫细胞浸润，但会导致软骨退化和关节活动度丧失，表明软骨细胞内在炎症反应。使用来自骨关节炎小鼠和患者关节的原代软骨细胞，我们首先表明这些细胞以 NF-κB 依赖性方式表达充足的促炎标志物和 RANKL。软骨细胞的炎症表型通过将软骨细胞暴露于 IL-1β 和骨颗粒来概括，它们被用于模拟 OA 患者滑液中存在的骨基质分解产物，尽管它们的作用尚未定义。我们进一步表明，骨颗粒和 IL-1β 可以促进原代软骨细胞的衰老和凋亡变化，这是由于来自线粒体等各种细胞来源的氧化应激所致。最后，我们提供证据表明炎症、氧化应激和衰老集中在 IκB-ζ 上，IκB-ζ 是 NF-κB 下游的主要介质，它调节 RANKL、炎症、分解代谢和 SASP 基因的表达。总的来说，这项工作强调了炎症信号的能力和机制，主要是关节降解产物，即关节微环境中与 IL-1β 协同作用的骨基质颗粒，将软骨细胞编程为“炎症表型”，从而影响局部组织损伤。氧化应激和衰老集中在 IκB-ζ 上，IκB-ζ 是 NF-κB 下游的主要介质，它调节 RANKL、炎症、分解代谢和 SASP 基因的表达。总的来说，这项工作强调了炎症信号的能力和机制，主要是关节降解产物，即关节微环境中与 IL-1β 协同作用的骨基质颗粒，将软骨细胞编程为“炎症表型”，从而影响局部组织损伤。氧化应激和衰老集中在 IκB-ζ 上，IκB-ζ 是 NF-κB 下游的主要介质，它调节 RANKL、炎症、分解代谢和 SASP 基因的表达。总的来说，这项工作强调了炎症信号的能力和机制，主要是关节降解产物，即骨基质颗粒与关节微环境中的 IL-1β 协同作用，将软骨细胞编程为“炎症表型”，从而影响局部组织损伤。