Department of Medical Research and Development, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
Department of Orthopaedics, Chiayi Chang Gung Memorial Hospital, Chiayi 613, Taiwan.
Int J Mol Sci. 2021 Jul 28;22(15):8107. doi: 10.3390/ijms22158107.
Osteoarthritis (OA) is still a recalcitrant musculoskeletal disease on account of its complex biochemistry and mechanical stimulations. Apart from stimulation by external mechanical forces, the regulation of intracellular mechanics in chondrocytes has also been linked to OA development. Recently, visfatin has received significant attention because of the clinical finding of the positive correlation between its serum/synovial level and OA progression. However, the precise mechanism involved is still unclear. This study determined the effect of visfatin on intracellular mechanics and catabolism in human primary chondrocytes isolated from patients. The intracellular stiffness of chondrocytes was analyzed by the particle-tracking microrheology method. It was shown that visfatin damages the microtubule and microfilament networks to influence intracellular mechanics to decrease the intracellular elasticity and viscosity via glycogen synthase kinase 3β (GSK3β) inactivation induced by p38 signaling. Further, microtubule network destruction in human primary chondrocytes is predominantly responsible for the catabolic effect of visfatin on the cyclooxygenase 2 upregulation. The present study shows a more comprehensive interpretation of OA development induced by visfatin through biochemical and biophysical perspectives. Finally, the role of GSK3β inactivation, and subsequent regulation of intracellular mechanics, might be considered as theranostic targets for future drug development for OA.
骨关节炎（OA）仍然是一种顽固的肌肉骨骼疾病，其原因在于其复杂的生物化学和机械刺激。除了外部机械力的刺激外，软骨细胞内的力学调节也与 OA 的发展有关。最近，内脂素因其血清/滑膜水平与 OA 进展之间的正相关关系的临床发现而受到了广泛关注。然而，其确切的机制仍不清楚。本研究旨在确定内脂素对分离自患者的人原代软骨细胞的细胞内力学和分解代谢的影响。通过粒子追踪微流变学方法分析软骨细胞的细胞内刚性。结果表明，内脂素通过 p38 信号诱导糖原合酶激酶 3β（GSK3β）失活，破坏微管和微丝网络，从而影响细胞内力学，降低细胞内弹性和粘性。此外，人原代软骨细胞中的微管网络破坏主要负责内脂素对环氧化酶 2 上调的分解代谢作用。本研究从生化和生物物理的角度更全面地解释了 OA 由内脂素引起的发展。最后，GSK3β失活及其随后对细胞内力学的调节，可能被视为 OA 未来药物开发的治疗靶点。
