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受损大脑通过释放靶向成骨前体细胞的小型细胞外囊泡来加速骨愈合。

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

机构信息

Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Department of Cell Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, 510515, China.

State Key Laboratory of Organ Failure Research, Academy of Orthopedics, Guangdong Province, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510630, China.

出版信息

Nat Commun. 2021 Oct 15;12(1):6043. doi: 10.1038/s41467-021-26302-y.

DOI:10.1038/s41467-021-26302-y
PMID:34654817
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8519911/
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.

摘要

临床证据已经确立，伴随的创伤性脑损伤（TBI）会加速骨愈合，但潜在机制尚不清楚。本研究表明，TBI 后，受伤的神经元，主要是海马体中的神经元，会释放富含成骨 microRNA（miRNA）的小细胞外囊泡（sEVs），这些囊泡靶向骨中的成骨前体细胞，刺激骨形成。我们发现，TBI 后 sEVs 中富含的 miR-328a-3p 和 miR-150-5p 通过分别直接靶向 FOXO4 或 CBL 的 3'UTR 促进成骨，并且携带 miR-328a-3p 的 sEVs 的水凝胶在大鼠中有效地修复了骨缺损。重要的是，sEVs 表面纤维连接蛋白表达的增加有助于 TBI sEVs 对骨中成骨前体细胞的靶向，这意味着可以对 sEVs 表面纤维连接蛋白进行修饰，用于骨靶向药物传递。总之，我们的工作揭示了中枢调节在骨形成中的作用，以及动物和临床环境中受伤神经元和成骨细胞之间的明确联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/5234180f485e/41467_2021_26302_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/320c099de927/41467_2021_26302_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/d0f43019b9b2/41467_2021_26302_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/aa71c3573abf/41467_2021_26302_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/1397925f6fd4/41467_2021_26302_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/377be4632b0c/41467_2021_26302_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/dbc5187158ca/41467_2021_26302_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/ac10feae5920/41467_2021_26302_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/5234180f485e/41467_2021_26302_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/320c099de927/41467_2021_26302_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/d0f43019b9b2/41467_2021_26302_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/aa71c3573abf/41467_2021_26302_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/1397925f6fd4/41467_2021_26302_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/377be4632b0c/41467_2021_26302_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/dbc5187158ca/41467_2021_26302_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/ac10feae5920/41467_2021_26302_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f318/8519911/5234180f485e/41467_2021_26302_Fig8_HTML.jpg

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[2]
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[3]
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J Orthop Surg Res. 2025-7-25

[4]
Metabotissugenic citrate biomaterials orchestrate bone regeneration via citrate-mediated signaling pathways.

Sci Adv. 2025-7-25

[5]
Bidirectional Interaction Between the Brain and Bone in Traumatic Brain Injury.

Adv Sci (Weinh). 2025-8

[6]
Prevalence, risk factors, prediction of robust callus formation and accelerated fracture healing in traumatic brain injury patients: a five-year study.

J Orthop Translat. 2025-6-23

[7]
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Front Endocrinol (Lausanne). 2025-6-5

[8]
Effects of traumatic brain injury on vascular response and fracture healing: an experimental study in a rat model.

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[9]
IFI204 in microglia mediates traumatic brain injury-induced mitochondrial dysfunction and pyroptosis via SENP7 interaction.

Cell Biol Toxicol. 2025-5-23

[10]
[Isolation and proteomics analysis of cerebrospinal fluid exosome subtypes].

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