Research Paper Advance Articles

Cytoplasmic PCNA is located in the actin belt and involved in osteoclast differentiation

Donge Tang1,2, *, , Xiaohui Liu1, *, , Kezhi Chen1, , Zhipeng Li1, , Yong Dai2, , Jiake Xu3, , Huan-Tian Zhang1,4, , Xuejuan Gao1, , Langxia Liu1, ,

  • 1 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
  • 2 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
  • 3 School of Pathology and Laboratory Medicine, University of Western Australia, Perth 6009, Western Australia, Australia
  • 4 Institute of Orthopedic Diseases and Department of Bone and Joint Surgery, The First Affiliated Hospital, Jinan University, Guangzhou 510630, Guangdong, China
* Equal contribution

Received: January 14, 2020       Accepted: May 25, 2020       Published: June 27, 2020      

https://doi.org/10.18632/aging.103434
How to Cite

Copyright © 2020 Tang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.

Abbreviations

ACTB: β-actin; AP-1: activator protein 1; co-IP: Co-immunoprecipitation; CRM1: Chromosome region maintenance 1; ERK: extracellular signal-regulated kinases; GO: Gene Ontology; IDCL: Included the interdomain-connecting loop; IKK: IκB kinase; JNK: c-Jun N-terminal kinase; MACF1: microtubule actin crosslinking factor 1; M-CSF: macrophage colony-stimulating factor; NFATc1: nuclear factor and activator of transcription; NF-κB: nuclear factor κB; NES: Nuclear export signal; OP: osteoporosis; PCNA: proliferating cell nuclear antigen; PIP: PCNA-interacting protein; RANKL: receptor activator of nuclear factor kappa-B ligand; TRAP: tartrate-resistant acid phosphatase.