Qu Minghao, Chen Mingjue, Gong Weiyuan, Huo Shaochuan, Yan Qinnan, Yao Qing, Lai Yumei, Chen Di, Wu Xiaohao, Xiao Guozhi
1Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China.
2Shenzhen Hospital (Futian) of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, China.
Aging Dis. 2023 Apr 1;14(2):502-514. doi: 10.14336/AD.2022.0828.
Osteoarthritis (OA) is the most common degenerative joint disease affecting the older populations globally. Phosphatidylinositol-4-phosphate 5-kinase type-1 gamma (Pip5k1c), a lipid kinase catalyzing the synthesis of phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), is involved in various cellular processes, such as focal adhesion (FA) formation, cell migration, and cellular signal transduction. However, whether Pip5k1c plays a role in the pathogenesis of OA remains unclear. Here we show that inducible deletion of Pip5k1c in aggrecan-expressing chondrocytes (cKO) causes multiple spontaneous OA-like lesions, including cartilage degradation, surface fissures, subchondral sclerosis, meniscus deformation, synovial hyperplasia, and osteophyte formation in aged (15-month-old) mice, but not in adult (7-month-old) mice. Pip5k1c loss promotes extracellular matrix (ECM) degradation, chondrocyte hypertrophy and apoptosis, and inhibits chondrocyte proliferation in the articular cartilage of aged mice. Pip5k1c loss dramatically downregulates the expressions of several key FA proteins, including activated integrin β1, talin, and vinculin, and thus impairs the chondrocyte adhesion and spreading on ECM. Collectively, these findings suggest that Pip5k1c expression in chondrocytes plays a critical role in maintaining articular cartilage homeostasis and protecting against age-related OA.
骨关节炎（OA）是全球影响老年人群体的最常见退行性关节疾病。磷脂酰肌醇-4-磷酸 5-激酶 1γ型（Pip5k1c）是一种催化磷脂磷脂酰肌醇 4,5-二磷酸（PIP2）合成的脂质激酶，参与多种细胞过程，如粘着斑（FA）形成、细胞迁移和细胞信号转导。然而，Pip5k1c 是否在 OA 的发病机制中起作用仍不清楚。在此我们表明，在表达聚集蛋白聚糖的软骨细胞中诱导性缺失 Pip5k1c（cKO）会导致多种自发性 OA 样病变，包括老年（15 个月大）小鼠的软骨降解、表面裂隙、软骨下硬化、半月板变形、滑膜增生和骨赘形成，但成年（7 个月大）小鼠不会出现这些病变。Pip5k1c 的缺失促进老年小鼠关节软骨中的细胞外基质（ECM）降解、软骨细胞肥大和凋亡，并抑制软骨细胞增殖。Pip5k1c 的缺失显著下调几种关键 FA 蛋白的表达，包括活化的整合素β1、踝蛋白和纽蛋白，从而损害软骨细胞在 ECM 上的粘附和铺展。总体而言，这些发现表明软骨细胞中 Pip5k1c 的表达在维持关节软骨稳态和预防与年龄相关的 OA 中起关键作用。
