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miR-19b 通过 WWP1/Smurf2 介导的 KLF5/β-catenin 信号通路增强间充质干细胞的成骨分化并促进骨折愈合。

miR-19b enhances osteogenic differentiation of mesenchymal stem cells and promotes fracture healing through the WWP1/Smurf2-mediated KLF5/β-catenin signaling pathway.

机构信息

Department of Orthopaedics, Hunan Provincial People's Hospital, Changsha, China.

Department of Orthopaedics, The Second Xiangya Hospital of Central South University, Changsha, China.

出版信息

Exp Mol Med. 2021 May;53(5):973-985. doi: 10.1038/s12276-021-00631-w. Epub 2021 May 25.

DOI:10.1038/s12276-021-00631-w
PMID:34035464
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8178348/
Abstract

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes have been found to enhance fracture healing. In addition, microRNAs contributing to the healing of various bone fractures have attracted widespread attention in recent years, but knowledge of the mechanisms by which they act is still very limited. In this study, we clarified the function of altered microRNA-19b (miR-19b) expression in BMSCs in fracture healing. We modulated miR-19b expression via mimics/inhibitors in BMSCs and via agomirs in mice to explore the effects of these changes on osteogenic factors, bone cell mineralization and the healing status of modeled fractures. Through gain- and loss-of function assays, the binding affinity between miR-19b and WWP1/Smurf2 was identified and characterized to explain the underlying mechanism involving the KLF5/β-catenin signaling pathway. miR-19b promoted the differentiation of human BMSCs into osteoblasts by targeting WWP1 and Smurf2. Overexpression of WWP1 or Smurf2 degraded the target protein KLF5 in BMSCs through ubiquitination to inhibit fracture healing. KLF5 knockdown delayed fracture healing by modulating the Wnt/β-catenin signaling pathway. Furthermore, miR-19b enhanced fracture healing via the KLF5/β-catenin signaling pathway by targeting WWP1 or Smurf2. Moreover, miR-19b was found to be enriched in BMSC-derived exosomes, and treatment with exosomes promoted fracture healing in vivo. Collectively, these results indicate that mesenchymal stem cell-derived exosomal miR-19b represses the expression of WWP1 or Smurf2 and elevates KLF5 expression through the Wnt/β-catenin signaling pathway, thereby facilitating fracture healing.

摘要

骨髓间充质干细胞（BMSC）衍生的外泌体已被发现可促进骨折愈合。此外，近年来，促进各种骨骨折愈合的 microRNAs 引起了广泛关注，但对其作用机制的了解仍然非常有限。在这项研究中，我们阐明了 BMSC 中 microRNA-19b（miR-19b）表达改变在骨折愈合中的功能。我们通过 mimics/inhibitors 在 BMSCs 中以及通过 agomirs 在小鼠中调节 miR-19b 的表达，以探讨这些变化对成骨因子、骨细胞矿化和模拟骨折愈合状态的影响。通过增益和损失功能测定，鉴定和表征了 miR-19b 与 WWP1/Smurf2 之间的结合亲和力，以解释涉及 KLF5/β-catenin 信号通路的潜在机制。miR-19b 通过靶向 WWP1 和 Smurf2 促进人 BMSC 向成骨细胞分化。在 BMSCs 中过表达 WWP1 或 Smurf2 通过泛素化降解靶蛋白 KLF5，从而抑制骨折愈合。KLF5 敲低通过调节 Wnt/β-catenin 信号通路延迟骨折愈合。此外，miR-19b 通过靶向 WWP1 或 Smurf2 通过 KLF5/β-catenin 信号通路增强骨折愈合。此外，发现 miR-19b 在 BMSC 衍生的外泌体中富集，并且外泌体治疗在体内促进骨折愈合。总之，这些结果表明，间充质干细胞衍生的外泌体 miR-19b 通过 Wnt/β-catenin 信号通路抑制 WWP1 或 Smurf2 的表达并上调 KLF5 表达，从而促进骨折愈合。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/93df06aaf1a3/12276_2021_631_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/b6b83c6bba37/12276_2021_631_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/7b456ba0635d/12276_2021_631_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/40f8b0168409/12276_2021_631_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/861d4c1ecd80/12276_2021_631_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/2d652c1cf249/12276_2021_631_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/93df06aaf1a3/12276_2021_631_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/b6b83c6bba37/12276_2021_631_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/7b456ba0635d/12276_2021_631_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/40f8b0168409/12276_2021_631_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/861d4c1ecd80/12276_2021_631_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/2d652c1cf249/12276_2021_631_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c25b/8178348/93df06aaf1a3/12276_2021_631_Fig6_HTML.jpg

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[10]
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本文引用的文献

[1]
[KLF5 modulates proliferation and osteogenic differentiation of human periodontal ligament cells subjected to cyclic tensile stress].

Shanghai Kou Qiang Yi Xue. 2018-2

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