Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis
Paroxetine-mediated GRK2 inhibition is a disease-modifying treatment for osteoarthritis
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DOI：
10.1126/scitranslmed.aau8491
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发表时间：
2021-02-10
影响因子：
17.1
通讯作者：
Kamal, Fadia
中科院分区：
文献类型：
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作者：
Carlson, Elijah L.;Karuppagounder, Vengadeshprabhu;Kamal, Fadia
骨关节炎（OA）是一种以进行性软骨退变为特征的使人衰弱的关节疾病，没有可用的疾病改善疗法。OA是由病理性软骨细胞肥大（CH）驱动的，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）信号传导来抑制G蛋白偶联受体激酶2（GRK 2）在其他疾病中的治疗效果。然而，GPCR-GRK 2通路在OA中的作用尚不清楚。因此，在手术OA小鼠模型中，我们在软骨细胞中进行了遗传GRK 2缺失或用美国食品和药物管理局（FDA）批准的抗抑郁药帕罗西汀进行了药理学抑制。GRK 2缺失和抑制均防止CH，减轻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GRK 2信号传导升高是OA中CH的驱动因素，并确定帕罗西汀是OA治疗的疾病缓解药物。
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.