Department of Stomatology, Tangdu Hospital, The Fourth Military Medical University, Xi'an, China.
The College of Life Sciences, Northwest University, Xi'an, China.
Cartilage. 2024 Dec;15(4):440-452. doi: 10.1177/19476035231189841. Epub 2023 Aug 30.
Activation of sympathetic tone is important for cartilage degradation in osteoarthritis (OA). Recent studies reported that sympathetic signals can affect the mitochondrial function of target cells. It is unknown whether this effect exits in chondrocytes and affects chondrocyte catabolism. The contribution of mitochondrial dynamics in the activation of α2-adrenergic signal-mediated chondrocyte catabolism was investigated in this study.
Primary chondrocytes were stimulated with norepinephrine (NE) alone, or pretreated with an α2-adrenergic receptor (Adra2) antagonist (yohimbine) and followed by stimulation with NE. Changes in chondrocyte metabolism and their mitochondrial dynamics were investigated.
We demonstrated that NE stimulation induced increased gene and protein expressions of matrix metalloproteinase-3 and decreased level of aggrecan by chondrocytes. This was accompanied by upregulated mitochondriogenesis and the number of mitochondria, when compared with the vehicle-treated controls. Mitochondrial fusion and fission, and mitophagy also increased significantly in response to NE stimulation. Inhibition of Adra2 attenuated chondrocyte catabolism and mitochondrial dynamics induced by NE.
The present findings indicate that upregulation of mitochondrial dynamics through mitochondriogenesis, fusion, fission, and mitophagy is responsible for activation of α2-adrenergic signal-mediated chondrocyte catabolism. The hypothesis that "α2-adrenergic signal activation promotes cartilage degeneration in temporomandibular joint osteoarthritis (TMJ-OA) by upregulating mitochondrial dynamics in chondrocytes" is validated. This represents a new regulatory mechanism in the chondrocytes of TMJ-OA that inhibits abnormal activation of mitochondrial fusion and fission is a potential regulator for improving mitochondrial function and inhibiting chondrocyte injury and contrives a potentially innovative therapeutic direction for the prevention of TMJ-OA.
交感神经兴奋在骨关节炎（OA）软骨降解中起重要作用。最近的研究报道，交感信号可以影响靶细胞的线粒体功能。尚不清楚这种效应是否存在于软骨细胞中，并影响软骨细胞的分解代谢。本研究旨在探讨线粒体动力学在激活α2-肾上腺素能信号介导的软骨细胞分解代谢中的作用。
原代软骨细胞单独用去甲肾上腺素（NE）刺激，或用α2-肾上腺素能受体（Adra2）拮抗剂（育亨宾）预处理，然后用 NE 刺激。研究了软骨细胞代谢和线粒体动力学的变化。
我们证明，NE 刺激诱导软骨细胞基质金属蛋白酶-3基因和蛋白表达增加，聚集蛋白聚糖水平降低。与载体处理对照组相比，这伴随着线粒体生成和线粒体数量的增加。NE 刺激还显著增加了线粒体融合和裂变以及自噬。Adra2 抑制减弱了 NE 诱导的软骨细胞分解代谢和线粒体动力学。
本研究结果表明，通过线粒体生成、融合、裂变和自噬上调线粒体动力学是激活α2-肾上腺素能信号介导的软骨细胞分解代谢的原因。“α2-肾上腺素能信号激活通过上调软骨细胞中线粒体动力学促进颞下颌关节骨关节炎（TMJ-OA）中的软骨退化”的假设得到验证。这代表了 TMJ-OA 软骨细胞中一种新的调节机制，抑制异常的线粒体融合和裂变激活是改善线粒体功能和抑制软骨细胞损伤的潜在调节剂，并为预防 TMJ-OA 提供了一个潜在的创新治疗方向。
