Abstract
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 in vitro 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.
Highlights
With the populations of many countries aging, osteoporosis (OP) has become a major health issue of concern [1]
In those cells treated with 100 ng/mL receptor activator of nuclear factor kappa-B ligand (RANKL) during three days, a large number of Proliferating cell nuclear antigen (PCNA) has been translocated from nucleus to cytoplasm, precisely in the cell periphery, forming a ring-like structure at the proximity of plasma membrane (Figure 1A)
Compared with the control group, the nuclear PCNA was significantly reduced in RAW264.7 cells after 3-day RANKL treatment, while PCNA in the cytoplasmic and membrane fractions was significantly increased, indicating that PCNA was translocated from the nucleus to the cytoplasm and, associated with cell membrane during the process of RANKL-induced osteoclast differentiation
Summary
With the populations of many countries aging, osteoporosis (OP) has become a major health issue of concern [1]. Just in the years of 2006 and 2007, more than 200 million women in the world were affected by OP, which led to more than 8.9 million fractures every year and seriously worsened the quality of life of the patients www.aging-us.com [2]. Bone homeostasis is maintained by the balance between bone resorption and formation. OP is caused by excessive bone resorption over bone formation, resulting in reduced bone density and an increased risk of fractures [3]. Opposite to the promotive role of osteoblasts on bone formation, osteoclasts are mainly responsible for bone resorption and bone loss [4]. Revealing the mechanism of osteoclast differentiation would provide ideas for the treatment of osteoclast related or bone destruction specific diseases
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