Plectin promotes bone formation via phase separation and sequestering annexin A2

Kaiyuan Zheng¹, Xi He², Yang Yu³, Meng Deng², Lulu Chen⁴, Wenwen Zhou², Dan Xia², Peihong Su⁵, Ye Tian⁶, Lijuan Zhang¹, Jing Wen¹, Beilei Zeng¹, Xiaolan Guo⁷, Qi Liang⁷, Bin Guo¹, Guangrong Wang¹, Yinxu Wang¹, Qing Wu⁸, Li Jiao⁹, Airong Qian¹⁰, Chong Yin¹¹

Affiliations

¹ Department of Clinical Laboratory, Department of Rehabilitation Medicine, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, PR China.
² Department of Laboratory Medicine, Translational Medicine Research Center, North Sichuan Medical College, Nanchong, Sichuan 637000, PR China.
³ School of Pharmacy, Tianjin Medical University, Tianjin 300070, PR China.
⁴ Department of Clinical Laboratory, Zigong First People’s Hospital, Zigong, Sichuan 643000, PR China.
⁵ Lab for Bone Metabolism, Xi’an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi 710000, PR China; Shaanxi Provincial Key Laboratory of Ischemic Cardiovascular Disease, Institute of Basic and Translational Medicine, Xi’an Medical University, Xi’an, Shaanxi 710021, PR China.
⁶ Lab for Bone Metabolism, Xi’an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi 710000, PR China.
⁷ Department of Clinical Laboratory, Department of Rehabilitation Medicine, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, PR China; Department of Laboratory Medicine, Translational Medicine Research Center, North Sichuan Medical College, Nanchong, Sichuan 637000, PR China.
⁸ Department of Clinical Laboratory, Department of Rehabilitation Medicine, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, PR China. Electronic address: cbkf2017@163.com.
⁹ National Kunming High-Level Biosafety Primate Research Center, Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, Yunnan 650000, PR China. Electronic address: jiaoli87@163.com.
¹⁰ Lab for Bone Metabolism, Xi’an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi 710000, PR China. Electronic address: qianair@nwpu.edu.cn.
¹¹ Department of Clinical Laboratory, Department of Rehabilitation Medicine, Department of Oncology, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan 637000, PR China; Lab for Bone Metabolism, Xi’an Key Laboratory of Special Medicine and Health Engineering, Key Lab for Space Biosciences and Biotechnology, Research Center for Special Medicine and Health Systems Engineering, NPU-UAB Joint Laboratory for Bone Metabolism, School of Life Sciences, Northwestern Polytechnical University, Xi’an, Shaanxi 710000, PR China. Electronic address: yinchong42@nsmc.edu.cn.

PMID: 41047030
DOI: 10.1016/j.bcp.2025.117403

Abstract

Osteoporosis constitutes an emergent threat to human health, which partially caused by impaired osteoblast differentiation. Liquid-liquid phase separation (LLPS) is a cytophysiological process that regulates osteoblast differentiation. The plakin family, ubiquitously expressed in osteoblasts, interacts with multiple proteins and may mediate phase separation. However, limited reports exist regarding the involvement of the plakin family phase separation and osteoblast differentiation. In this study, we demonstrated that plectin (Plec), a plakin family member, enhances osteoblast differentiation and bone formation via its phase separation. This process is mediated by plectin’s intrinsically disordered region (IDR). Mechanistically, plectin promotes osteoblast differentiation by sequestering annexin A2 (Anxa2), an osteoblast differentiation promoter, through phase separation. Furthermore, the functional amino acid region (aa 1967-2185) of plectin exhibited therapeutic effect in mice with osteoporosis. Our findings reveal a novel regulatory mechanism by which cytoskeletal linker proteins govern osteoblast differentiation and propose a potential therapeutic strategy for osteoporosis.

Keywords: Annexin A2; Bone formation; Intrinsically disordered region; Phase separation; Plectin.

Biochem Pharmacol. 2025 Oct 3;242(Pt 4):117403.doi: 10.1016/j.bcp.2025.117403 span style=”color: red;”>(IF:5.6).

Plectin promotes bone formation via phase separation and sequestering annexin A2

Abstract

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