Objective

This study aimed to investigate the biochemical effects of osteoarthritic infrapatellar fat pad (IPFP) on cartilage and the underlying mechanisms.

Methods

Human IPFP and articular cartilage were collected from end-stage osteoarthritis (OA) patients during total knee arthroplasty. IPFP-derived fat-conditioned medium (FCM) was used to stimulate human primary chondrocytes and cartilage explants. Functional effect of osteoarthritic IPFP was explored in human primary chondrocytes and articular cartilage in vitro and ex vivo. Activation of relative pathways and its effects on chondrocytes were assessed through immunoblotting and inhibition experiments, respectively. Neutralization test was performed to identify the main factors and their associated pathways responsible for the effects of IPFP.

Results

Osteoarthritic IPFP-derived FCM significantly induced extracellular matrix (ECM) degradation in both human primary chondrocytes and cartilage explants. Several pathways, such as NF-κB, mTORC1, p38MAPK, JNK, and ERK1/2 signaling, were significantly activated in human chondrocytes with osteoarthritic IPFP-derived FCM stimulation. Interestingly, inhibition of p38MAPK and ERK1/2 signaling pathway could alleviate the detrimental effects of FCM on chondrocytes, while inhibition of other signaling pathways had no similar results. In addition, IL-1β and TNF-α instead of IL-6 in osteoarthritic IPFP-derived FCM played key roles in cartilage degradation via activating p38MAPK rather than ERK1/2 signaling pathway.

Conclusion

Osteoarthritic IPFP induces the degradation and inflammation of cartilage via activation of p38MAPK and ERK1/2 pathways, in which IL-1β and TNF-α act as the key factors. Our study suggests that modulating the effects of IPFP on cartilage may be a promising strategy for knee OA intervention.

中文翻译：

---

骨关节炎髌下脂肪垫通过激活 p38MAPK 和 ERK1/2 通路加剧软骨退化

客观的

本研究旨在研究骨关节炎髌下脂肪垫 (IPFP) 对软骨的生化作用及其潜在机制。

方法

在全膝关节置换术期间从终末期骨关节炎 (OA) 患者收集人类 IPFP 和关节软骨。IPFP 衍生的脂肪条件培养基 (FCM) 用于刺激人类原代软骨细胞和软骨外植体。在体外和离体人原代软骨细胞和关节软骨中探索了骨关节炎 IPFP 的功能作用。分别通过免疫印迹和抑制实验评估相关途径的激活及其对软骨细胞的影响。进行中和测试以识别导致 IPFP 影响的主要因素及其相关途径。

结果

骨关节炎 IPFP 衍生的 FCM 显着诱导人原代软骨细胞和软骨外植体中的细胞外基质 (ECM) 降解。几种通路，如 NF-κB、mTORC1、p38MAPK、JNK 和 ERK1/2 信号传导，在骨关节炎 IPFP 衍生的 FCM 刺激下在人软骨细胞中显着激活。有趣的是，抑制 p38MAPK 和 ERK1/2 信号通路可以减轻 FCM 对软骨细胞的不利影响，而抑制其他信号通路没有类似的结果。此外，IL-1β 和 TNF-α 代替 IL-6 在骨关节炎 IPFP 衍生的 FCM 中通过激活 p38MAPK 而不是 ERK1/2 信号通路在软骨降解中起关键作用。

结论

骨关节炎 IPFP 通过激活 p38MAPK 和 ERK1/2 通路诱导软骨的降解和炎症，其中 IL-1β 和 TNF-α 作为关键因素。我们的研究表明，调节 IPFP 对软骨的影响可能是膝关节 OA 干预的一种有前途的策略。