2. Academic Validation
  3. Dynamic control of mTORC1 facilitates bone healing in mice

Dynamic control of mTORC1 facilitates bone healing in mice

  • Bone. 2024 Oct 18:190:117285. doi: 10.1016/j.bone.2024.117285.
Delong Li 1,  Daozhang Cai 1,  Denghui Xie 1,  Liang Wang 1,  Yan Zhang 2,  Guangfeng Ruan 3,  Qun Zhang 4,  Bo Yan 1,  Haiyan Zhang 1,  Pinglin Lai 1,  Zhengquan Liao 1,  Yu Jiang 5,  Dianbo Yu 6,  Changhai Ding 7,  Chengliang Yang 8
Affiliations

Affiliations

  • 1 Academy of Orthopedics, Guangdong Province, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
  • 2 Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
  • 3 Clinical Research Centre, Guangzhou First People's Hospital, Guangzhou 510180, China.
  • 4 Office of Clinical Trial of Drug, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, China.
  • 5 Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • 6 Department of Sports Medicine, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, China; Guangxi Biomedical Materials Engineering Research Center for Bone and Joint Degenerative Diseases, Baise, Guangxi 533000, China.
  • 7 Clinical Research Centre, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China; Menzies Institute for Medical Research, University of Tasmania, Hobart 7000, Australia. Electronic address: changhai.ding@utas.edu.au.
  • 8 Department of Orthopedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi 533000, China; Guangxi Health Commission Key Laboratory of Biomedical Materials Research, Baise, Guangxi 533000, China. Electronic address: yangchengliang@ymcn.edu.cn.
PMID: 39426581 DOI: 10.1016/j.bone.2024.117285
Abstract

Bone healing requires well-orchestrated sequential actions of osteoblasts and osteoclasts. Previous studies have demonstrated that the mechanistic target of rapamycin complex 1 (mTORC1) plays a critical role in the metabolism of osteoblasts and osteoclasts. However, the role of mTORC1 in bone healing remains unclear. Here, we showed that a dynamic change in mTORC1 activity during the process was essential for proper healing and can be harnessed therapeutically for treatment of bone fractures. Low mTORC1 activity induced by osteoblastic Raptor knockout or rapamycin treatment promoted osteoblast-mediated osteogenesis, thus leading to better bone formation and shorter bone union time. Rapamycin treatment in vitro also revealed that low mTORC1 activity enhanced osteoblast differentiation and maturation. However, rapamycin treatment affected the recruitment of osteoclasts to new bone sites, thus resulting in delayed callus absorption in bone marrow cavity. Mechanistically, decreased mTORC1 activity inhibited the recruitment of osteoclast progenitor cells to healing sites through a decrease in osteoblastic expression of monocyte chemoattractant protein-1, thus inhibiting osteoclast-mediated remodeling. Therefore, normal mTORC1 activity was necessary for bone remodeling stage. Furthermore, through the use of sustained-release Materials at the bone defect, we confirmed that localized application of rapamycin in early stages accelerated bone healing without affecting bone remodeling. Together, these findings revealed that the activity of mTORC1 continually changed during bone healing, and staged rapamycin treatment could be used to promote bone healing.

Keywords

Bone healing; Bone remodeling; MCP-1; Rapamycin; mTORC1.

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