Cleaved SPP1-rich extracellular vesicles from osteoclasts promote bone regeneration via TGFβ1/SMAD3 signaling

Abdullah Faqeer; Mengzhen Wang; Gulzar Alam; Arshad Ahmed Padhiar; Dexiu Zheng; Zhiming Luo; Irene Shuping Zhao; Guangqian Zhou; Jeroen J J P van den Beucken; Huanan Wang; Yang Zhang

doi:10.1016/j.biomaterials.2023.122367

Cleaved SPP1-rich extracellular vesicles from osteoclasts promote bone regeneration via TGFβ1/SMAD3 signaling

Biomaterials. 2023 Dec:303:122367. doi: 10.1016/j.biomaterials.2023.122367. Epub 2023 Oct 21.

Authors

Affiliations

¹ School of Dentistry, Health Science Center, Shenzhen University, Shenzhen, 518015, China; School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518015, China.
² School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518015, China.
³ School of Basic Medicine, Health Science Center, Shenzhen University, Shenzhen, 518015, China; Department of Ecology and Evoluitonary Biology, University of Connecticut, Storrs, CT, 06269-3043, USA.
⁴ School of Dentistry, Health Science Center, Shenzhen University, Shenzhen, 518015, China.
⁵ School of Basic Medicine, Health Science Center, Shenzhen University, Shenzhen, 518015, China.
⁶ Department of Dentistry - Regenerative Biomaterials, Radboudumc, Nijmegen, 6525EX, the Netherlands; Research Institute for Medical Innovation, Radboudumc, 6500HB, Nijmegen, the Netherlands. Electronic address: jeroen.vandenbeucken@radboudumc.nl.
⁷ State Key Laboratory of Fine Chemicals, School of Bioengineering, Dalian University of Technology, Dalian, 116023, China; Frontiers Science Center for Smart Materials Oriented Chemical Engineering, Dalian University of Technology, Dalian, 116024, China. Electronic address: huananwang@dlut.edu.cn.
⁸ School of Dentistry, Health Science Center, Shenzhen University, Shenzhen, 518015, China; School of Biomedical Engineering, Health Science Center, Shenzhen University, Shenzhen, 518015, China. Electronic address: yang.zhang@szu.edu.cn.

PMID: 38465579
DOI: 10.1016/j.biomaterials.2023.122367

Abstract

Bone remodeling is a tightly coupled process between bone forming osteoblasts (OBs) and bone resorbing osteoclasts (OCs) to maintain bone architecture and systemic mineral homeostasis throughout life. However, the mechanisms responsible for the coupling between OCs and OBs have not been fully elucidated. Herein, we first validate that secreted extracellular vesicles by osteoclasts (OC-EVs) promote osteogenic differentiation of mesenchymal stem cells (MSCs) and further demonstrate the efficacy of osteoclasts and their secreted EVs in treating tibial bone defects. Furthermore, we show that OC-EVs contain several osteogenesis-promoting proteins as cargo. By employing proteomic and functional analysis, we reveal that mature osteoclasts secrete thrombin cleaved phosphoprotein 1 (SPP1) through extracellular vesicles which triggers MSCs osteogenic differentiation into OBs by activating Transforming Growth Factor β1 (TGFβ1) and Smad family member 3 (SMAD3) signaling. In conclusion, our findings prove an important role of SPP1, present as cargo in OC-derived EVs, in signaling to MSCs and driving their differentiation into OBs. This biological mechanism implies a paradigm shift regarding the role of osteoclasts and their signaling toward the treatment of skeletal disorders which require bone formation.

Keywords: Bone regeneration; Extracellular vesicles; Osteoclasts; Secreted phosphoprotein 1.

MeSH terms

Bone Regeneration
Cell Differentiation
Extracellular Vesicles* / metabolism
Osteoblasts
Osteoclasts* / metabolism
Osteogenesis
Proteomics
Transforming Growth Factor beta1 / metabolism

Substances

Transforming Growth Factor beta1