Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes and MOE Key Laboratory of Tumor Molecular Biology, Institute of Life and Health Engineering, Jinan University, Guangzhou 510632, China.
Department of Clinical Medical Research Center, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital Southern University of Science and Technology, Shenzhen People's Hospital, Shenzhen 518020, Guangdong, China.
Aging (Albany NY). 2020 Jun 27;12(13):13297-13317. doi: 10.18632/aging.103434.
Osteoporosis (OP) is an age-related osteolytic disease and characterized by low bone mass and more prone to fracture due to active osteoclasts. Proliferating cell nuclear antigen (PCNA) has been long identified as a nuclear protein playing critical roles in the regulation of DNA replication and repair. Recently, a few studies have demonstrated the cytoplasmic localization of PCNA and its function associated with apoptosis in neutrophil and neuroblastoma cells. However, the involvement of PCNA, including the cytoplasmic PCNA, in the osteoclast differentiation remains unclear. In the present study, we show that PCNA is translocated from nucleus to cytoplasm during the RANKL-induced osteoclast differentiation, and localized in the actin belt of mature osteoclast. Knockdown of PCNA significantly affected the integrity of actin belt, the formation of multinucleated osteoclasts, the expression of osteoclast-specific genes, and the bone resorption. Interactomic study has revealed β-actin as the major interacting partner of the cytoplasmic PCNA, suggesting that cytoplasmic PCNA might play a critical role in the differentiation of osteoclast through regulation of actin-cytoskeleton remodeling. Taken together, our results demonstrate the critical role of cytoplasmic PCNA during the process of osteoclast differentiation, and provided a potential therapeutic target for treatment of osteoclast-related bone diseases.
骨质疏松症（OP）是一种与年龄相关的溶骨性疾病，其特征是骨量低，由于破骨细胞活跃，更容易发生骨折。增殖细胞核抗原（PCNA）长期以来被认为是一种核蛋白，在调节 DNA 复制和修复中发挥着关键作用。最近，有几项研究表明 PCNA 发生了细胞质定位，及其在中性粒细胞和神经母细胞瘤细胞凋亡中相关的功能。然而，PCNA 的参与，包括细胞质 PCNA，在破骨细胞分化中的作用尚不清楚。在本研究中，我们发现 PCNA 在 RANKL 诱导的破骨细胞分化过程中从核内转移到细胞质中，并定位于成熟破骨细胞的肌动蛋白带上。PCNA 的敲低显著影响了肌动蛋白带的完整性、多核破骨细胞的形成、破骨细胞特异性基因的表达和骨吸收。相互作用组学研究表明，β-肌动蛋白是细胞质 PCNA 的主要相互作用伙伴，这表明细胞质 PCNA 可能通过调节肌动蛋白细胞骨架重塑在破骨细胞分化中发挥关键作用。总之，我们的研究结果表明细胞质 PCNA 在破骨细胞分化过程中起着关键作用，并为治疗破骨细胞相关骨病提供了一个潜在的治疗靶点。
