Osteoarthritis (OA) is an age‐related, chronic degenerative disease. With the increasing median age of the population, this disease has become an important public health problem. New, disease‐modifying therapies are needed. A potential novel molecular target is phospholipase Cγ1 (PLCγ1), a critical enzyme with important functions including calcium signaling regulation and cell proliferation. In rat chondrocytes treated with IL‐1β (20 ng·mL⁻¹ for 36 h), inhibition of PLCγ1 with U73122 (2 μm for 12 h) increased levels and expression of the cartilage matrix components Collagen2 and Aggrecan. This beneficial effect of PLCγ1 inhibition was counteracted by increased chondrocyte apoptosis and necroptosis, increased cell death, and increase levels of ROS, all potentially negative for OA. Combined treatment of IL‐1β + U73122‐treated chondrocytes with inhibitors of apoptosis (Z‐VAD, 10 μm) and necroptosis (Nec‐1, 30 μm) enhanced the increases in levels and expression of Collagen2 and Aggrecan, and prevented the increases in cell death and ROS levels. These results suggest that PLCγ1 inhibition may be a viable approach for an OA therapy, if combined with targeted inhibition of chondrocyte apoptosis and necroptosis.

中文翻译：

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PLCγ1 抑制联合细胞凋亡和坏死性凋亡的抑制增加了 IL-1β 处理的大鼠软骨细胞的软骨基质合成

骨关节炎（OA）是一种与年龄相关的慢性退行性疾病。随着人口中位年龄的增加，这种疾病已成为一个重要的公共卫生问题。需要新的、改善疾病的疗法。一种潜在的新型分子靶标是磷脂酶 Cγ1 (PLCγ1)，它是一种具有重要功能的关键酶，包括钙信号调节和细胞增殖。在用 IL-1β（20 ng·mL ^{-1处理 36 小时）处理的大鼠软骨细胞中，U73122（2 μ} m）抑制 PLCγ112 h) 软骨基质成分 Collagen2 和 Aggrecan 的水平和表达增加。PLCγ1 抑制的这种有益作用被增加的软骨细胞凋亡和坏死性凋亡、增加的细胞死亡和增加的 ROS 水平所抵消，所有这些都可能对 OA 不利。IL-1β + U73122 处理的软骨细胞与凋亡抑制剂 (Z-VAD, 10 μm ) 和坏死性凋亡抑制剂 (Nec-1, 30 μm ) 的联合处理增强了胶原蛋白 2 和聚集蛋白聚糖的水平和表达的增加，并阻止了细胞死亡和 ROS 水平升高。这些结果表明，如果结合靶向抑制软骨细胞凋亡和坏死性凋亡，PLCγ1 抑制可能是一种可行的 OA 治疗方法。