Sympathetic influences on articular cartilage regeneration capacity and osteoarthritis manifestation

骨关节炎（OA）的发病机制涉及关节软骨与周围组织的相互作用，这些组织由交感神经支配。在早期的研究中，我们检测了创伤和OA患者滑液中的交感神经递质和应激激素去甲肾上腺素（NE），并观察了骨髓间充质干细胞培养中软骨形成的抑制。最近，我们证实NE在滑膜脂肪干细胞中的抗软骨形成作用，这是通过α 2a-肾上腺素受体依赖性ERK 1/2磷酸化介导的。此外，我们首次证明DMM手术诱导的小鼠实验性OA导致交感神经张力升高。此外，与WT小鼠相比，交感神经切除术导致软骨降解较少，但加速OA特征性软骨钙化和软骨下骨增厚。在第二个资助期，将分析OA患者的交感-副交感神经平衡及其与临床OA症状和不同关节组织细胞反应的相关性。此外，将研究实验性慢性应激对小鼠DMM模型中OA进展的影响。这些实验将揭示慢性应激在OA发病机制中的作用，并可能有助于开发针对交感神经的新型治疗方案。

Osteoarthritis (OA) pathogenesis involves the interaction of articular cartilage with surrounding tissues, which are innervated by the sympathicus. In earlier studies, we detected the sympathetic neurotransmitter and stress hormone norepinephrine (NE) in the synovial fluid of trauma and OA patients and observed the inhibition of chondrogenesis in bone marrow mesenchymal stem cell culture. Recently, we confirmed the anti-chondrogenic effect of NE in synovial adipose stem cells, which was mediated by α2a-adrenoceptor-dependent ERK1/2 phosphorylation. Furthermore, we demonstrated for the first time that DMM surgery-induced experimental OA in mice resulted in an elevated sympathetic tone. Moreover, sympathectomy led to less cartilage degradation but accelerated OA-characteristic cartilage calcification and subchondral bone thickening compared to WT mice. In the second funding period, the sympathetic-parasympathetic balance of OA patients and its correlations with clinical OA symptoms and cellular responses of different joint tissues will be analyzed. In addition, the effect of experimental chronic stress on OA progression in the murine DMM model will be investigated. These experiments will unravel the role of chronic stress in OA pathogenesis and might help to develop novel therapeutic options targeting the sympathicus.