Center for Orthopedic Research and Translational Sciences, Department of Orthopedics and Rehabilitation, Penn State College of Medicine, Hershey, PA 17033, USA.
Solarea Bio Inc., Cambridge, MA 02142, USA.
Sci Transl Med. 2021 Feb 10;13(580). doi: 10.1126/scitranslmed.aau8491.
Osteoarthritis (OA) is a debilitating joint disease characterized by progressive cartilage degeneration, with no available disease-modifying therapy. OA is driven by pathological chondrocyte hypertrophy (CH), the cellular regulators of which are unknown. We have recently reported the therapeutic efficacy of G protein-coupled receptor kinase 2 (GRK2) inhibition in other diseases by recovering protective G protein-coupled receptor (GPCR) signaling. However, the role of GPCR-GRK2 pathway in OA is unknown. Thus, in a surgical OA mouse model, we performed genetic GRK2 deletion in chondrocytes or pharmacological inhibition with the repurposed U.S. Food and Drug Administration (FDA)-approved antidepressant paroxetine. Both GRK2 deletion and inhibition prevented CH, abated OA progression, and promoted cartilage regeneration. Supporting experiments with cultured human OA cartilage confirmed the ability of paroxetine to mitigate CH and cartilage degradation. Our findings present elevated GRK2 signaling in chondrocytes as a driver of CH in OA and identify paroxetine as a disease-modifying drug for OA treatment.
骨关节炎（OA）是一种使人虚弱的关节疾病，其特征为渐进性软骨退化，目前尚无可改变疾病进程的治疗方法。OA 由病理性软骨细胞肥大（CH）驱动，但其细胞调节因子尚不清楚。我们最近报道了通过恢复保护性 G 蛋白偶联受体（GPCR）信号来抑制 G 蛋白偶联受体激酶 2（GRK2）对其他疾病的治疗效果。然而，GPCR-GRK2 通路在 OA 中的作用尚不清楚。因此，在一个手术诱导的 OA 小鼠模型中，我们在软骨细胞中进行了基因敲除 GRK2 或使用已获美国食品和药物管理局（FDA）批准的抗抑郁药帕罗西汀进行药理学抑制。GRK2 敲除和抑制均能防止 CH，减缓 OA 进展，并促进软骨再生。用培养的人 OA 软骨进行的支持性实验证实了帕罗西汀减轻 CH 和软骨降解的能力。我们的研究结果表明，软骨细胞中升高的 GRK2 信号是 OA 中 CH 的驱动因素，并确定帕罗西汀是治疗 OA 的一种疾病修饰药物。
