Vascular Pericyte-Derived Exosomes Inhibit Bone Resorption via Traf3

Abstract

Mingxiang Cai,1,* Huizhen Peng,1,* Minyi Liu,1,* Maohua Huang,2,3 Wen Zheng,1 Guilan Zhang,1 Wenjia Lai,1 Chufang Liao,1 Lizhao Cai,1 Dongmei Zhang,2,3 Xiangning Liu1 1The First Affiliated Hospital of Jinan University, School of Stomatology, Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou, 510630, People’s Republic of China; 2College of Pharmacy, Jinan University, Guangzhou, 510632, People’s Republic of China; 3Guangdong Province Key Laboratory of Pharmacodynamic Constituents of Traditional Chinese Medicine and New Drugs Research, Jinan University, Guangzhou, 510632, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangning Liu, The First Affiliated Hospital of Jinan University, School of Stomatology, Clinical Research Platform for Interdiscipline of Stomatology, Jinan University, Guangzhou, 510630, People’s Republic of China, Email [email protected] Dongmei Zhang, College of Pharmacy, Jinan University, Guangzhou, 510632, People’s Republic of China, Email [email protected]: Blood vessels distribute cells, oxygen, and nutrients throughout the body to support tissue growth and balance. Pericytes and endothelial cells form the inner wall of blood vessels, crucial for organ development and tissue homeostasis by producing paracrine signaling molecules. In the skeletal system, pericyte-derived vascular factors along with angiogenic factors released by bone cells regulate angiogenesis and bone formation. Although the involvement of angiogenic factors and skeletal blood vessels in bone homeostasis is relatively clear, the role of pericytes and the underlying mechanisms remain unknown. Here, our objective was to elucidate the significance of pericytes in regulating osteoclast differentiation.Methods: We used tissue staining to detect the coverage of pericytes and osteoclasts in femoral tissues of osteoporotic mice and mice of different ages, analyzing their correlation. We developed mice with conditionally deleted pericytes, observing changes in bone mass and osteoclast activity using micro-computer tomography and tissue staining to detect the regulatory effect of pericytes on osteoclasts. Pericytes-derived exosomes (PC-EVs) were collected and co-cultured with monocytes that induce osteoclast differentiation to detect the effect of the former on the exosomes. Finally, the specific mechanism of PC-EVs regulating osteoclast differentiation was verified using RNA sequencing and Western blotting.Results: Our study indicates a significant correlation between pericytes and age-related bone resorption. Conditional deletion of pericytes activated bone resorption and led to osteopenia in vivo. We discovered that PC-EVs inhibited the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, which is mediated by tumor necrosis factor receptor-associated factor 3 (Traf3), negatively regulating osteoclast development and bone resorption. Silencing Traf3 in PC-EVs canceled their inhibitory effect on osteoclast differentiation.Conclusion: Our study provides a novel perspective into the regulatory role of pericytes on bone resorption and may provide potential strategies for developing novel anti-bone resorption therapies. Keywords: pericytes, exosomes, bone resorption, Traf3

Keywords

• pericytes
• exosomes
• bone resorption
• traf3