How Do Extracellular Vesicles Play a Key Role in the Maintenance of Bone Homeostasis and Regeneration? A Comprehensive Review of Literature

Junxian Ren,1,* Rongcheng Yu,1,* Jingyan Xue,1 Yiqi Tang,1 Sihui Su,1 Chenxi Liao,1 Quanyi Guo,2 Weimin Guo,3 Jinxuan Zheng1 1Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, Guangzhou, 510055, People’s Republic of China; 2Institute of Orthopedics, Chinese PLA General Hospital, Key Laboratory of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma & War Injuries PLA, Beijing, 100853, People’s Republic of China; 3Department of Orthopedic Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510055, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weimin Guo, Department of Orthopedic Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, People’s Republic of China, Tel +86 20 87755766#6236, Email guowm5@mail.sysu.edu.cn Jinxuan Zheng, Hospital of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-sen University, 56 Lingyuan West Road, Guangzhou, 510055, People’s Republic of China, Tel +86 20 83802802, Email zhengjx27@mail.sysu.edu.cnAbstract: The maintenance of bone homeostasis includes both bone resorption by osteoclasts and bone formation by osteoblasts. These two processes are in dynamic balance to maintain a constant amount of bone for accomplishing its critical functions in daily life. Multiple cell type communications are involved in these two complex and continuous processes. In recent decades, an increasing number of studies have shown that osteogenic and osteoclastic extracellular vesicles play crucial roles in regulating bone homeostasis through paracrine, autosecretory and endocrine signaling. Elucidating the functional roles of extracellular vesicles in the maintenance of bone homeostasis may contribute to the design of new strategies for bone regeneration. Hence, we review the recent understandings of the classification, production process, extraction methods, structure, contents, functions and applications of extracellular vesicles in bone homeostasis. We highlight the contents of various bone-derived extracellular vesicles and their interactions with different cells in the bone microenvironment during bone homeostasis. We also summarize the recent advances in EV-loaded biomaterial scaffolds for bone regeneration and repair.Keywords: bone, homeostasis, metabolism, extracellular vesicles, regeneration