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Huogu injection alleviates SONFH by regulating adipogenic differentiation of BMSCs via targeting the miR-34c-5p/MDM4 pathway

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机构: [1]Heilongjiang University of Traditional Chinese Medicine, Harbin 150000, Heilongjiang, China [2]Graduate School, Heilongjiang University of Traditional Chinese Medicine, Harbin 150000, Heilongjiang, China [3]College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050000, Hebei, China [4]The Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150000, Heilongjiang, China [5]Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine, Zhuhai 510000, Guangdong, China [6]National Key Laboratory of Collateral Disease Research and Innovative Chinese Medicine, Shijiazhuang 050000, Hebei, China
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关键词: Huogu injection BSMCs Adipogenic differentiation miR-34c-5p/MDM4 pathway SONFH

摘要:
Although the precise pathogenesis of steroid-induced osteonecrosis of femoral head (SONFH) is not yet fully understood, evidence shows miRNAs-mediated posttranscription control directs the adipogenesis of bone marrow mesenchymal stem cells (BMSCs) and plays a pivotal role in the SONFH processes. Huogu injection formulated according to traditional Chinese medicine (TCM) theory has been used to treat SONFH by intra-articular injection. In this study, we asked whether the therapeutic effects of Huogu injection might depend on the inhibition of adipogenic differentiation of BMSCs, and if so, the pathway might be a therapeutic target to promote bone repair. Consequently, miR-34c-5p was upregulated in the dexamethasone (DEX)-treated BMSCs and might participate in the adipogenesis of BMSCs. TargetScan database and the luciferase reporter assay showed miR-34c-5p targeted on the MDM4 and negatively regulated its expression. Huogu injection in vitro inhibited the adipogenesis in the DEX-treated BMSCs by inhibiting the expression levels of PPARγ and C/EBPα, as well as reducing miR-34c-5p to prevent the degradation of MDM4. Moreover, miR-34c-5p mimic or MDM4 knockdown using shRNA neutralized the anti-adipogenesis of Huogu injection in BMSCs. In vivo, the results of X-ray imaging confirmed that Huogu injection alleviated the bone loss in rat SONFH. Consistent with results in vitro, Huogu injection reduced the lipid accumulation, removed the suppression of MDM4 by downregulating the expression of miR-34c-5p, and inhibited the expression of C/EBPα and PPARγ in bone tissues. When the lentivirus encoding miR-34c-5p was conducted by intra-articular injection, the overexpression of miR-34c-5p antagonized the therapeutic effects of Huogu injection. Our results underline the critical importance of the miR-34c-5p/MDM4 pathway in regulating the adipogenic outcome of BMSCs, suggesting the miR-34c-5p as a potentially effective therapeutic target in SONFH. These results further reinforce the potential of Huogu injection as an alternative approach in SONFH.Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.

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出版当年[2021]版:
大类 | 3 区 生物学
小类 | 3 区 遗传学
最新[2025]版:
大类 | 3 区 生物学
小类 | 3 区 遗传学
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第一作者机构: [1]Heilongjiang University of Traditional Chinese Medicine, Harbin 150000, Heilongjiang, China
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通讯机构: [3]College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050000, Hebei, China [4]The Second Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin 150000, Heilongjiang, China [6]National Key Laboratory of Collateral Disease Research and Innovative Chinese Medicine, Shijiazhuang 050000, Hebei, China [*1]College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang 050000, Hebei, China.
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