Damaged brain accelerates bone healing by releasing small extracellular vesicles that target osteoprogenitors

Wei Xia,Ming Zhao,Jing Wen,Zhengtao Gu,Xiaochun Bai,Run Zhao,Qiancheng Song,Zhipeng Zou,Zhimin Zou,Zhiqing Cai,Xinru Mao,Yue Zhang,Xuhua Liu,Xiaomei Zhou,Zhong-Kai Cui,Jing Xie,Maegele Mac,Jiahui Chen

doi:10.1038/s41467-021-26302-y

Abstract

Clinical evidence has established that concomitant traumatic brain injury (TBI) accelerates bone healing, but the underlying mechanism is unclear. This study shows that after TBI, injured neurons, mainly those in the hippocampus, release osteogenic microRNA (miRNA)-enriched small extracellular vesicles (sEVs), which targeted osteoprogenitors in bone to stimulate bone formation. We show that miR-328a-3p and miR-150-5p, enriched in the sEVs after TBI, promote osteogenesis by directly targeting the 3′UTR of FOXO4 or CBL, respectively, and hydrogel carrying miR-328a-3p-containing sEVs efficiently repaires bone defects in rats. Importantly, increased fibronectin expression on sEVs surface contributes to targeting of osteoprogenitors in bone by TBI sEVs, thereby implying that modification of the sEVs surface fibronectin could be used in bone-targeted drug delivery. Together, our work unveils a role of central regulation in bone formation and a clear link between injured neurons and osteogenitors, both in animals and clinical settings.

Highlights

Clinical evidence has established that concomitant traumatic brain injury (TBI) accelerates bone healing, but the underlying mechanism is unclear
Bone volume/tissue volumes (BV/TV%), hematoxylin and eosin (H&E) staining, and the number of osteoblasts per bone perimeter showed that osteogenesis was elevated dramatically in proximal tibia defect (PTD) + TBI rats (Fig. 1d, e and Supplementary Fig. 3a)
OCN staining confirmed an increase in osteogenesis in PTD + TBI rats (Fig. 1f, g), whereas no significant change in the number of osteoclasts tartrate-resistant acid phosphatase (TRAP) positive cells and osteoclast surface per bone surface between the two groups (Supplementary Fig. 3e–g)

Summary

Introduction

Clinical evidence has established that concomitant traumatic brain injury (TBI) accelerates bone healing, but the underlying mechanism is unclear. This study shows that after TBI, injured neurons, mainly those in the hippocampus, release osteogenic microRNA (miRNA)enriched small extracellular vesicles (sEVs), which targeted osteoprogenitors in bone to stimulate bone formation. Our work unveils a role of central regulation in bone formation and a clear link between injured neurons and osteogenitors, both in animals and clinical settings. Clinical evidence over the last five decades has shown that concomitant TBI accelerates bone healing[9,10]. We showed that plasma small extracellular vesicles (sEVs) from patients and rats with TBI had much greater potential to promote osteogenesis than soluble factors. Our findings have established a clear link between the damaged brain and bone formation both in animals and clinical settings

Methods

Results

Conclusion