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长链非编码 RNA HHIP-AS1/HHIP 通过调节 Hedgehog 信号通路调节 BM-MSCs 的成骨分化。

lncRNA HHIP-AS1/HHIP modulates osteogenic differentiation of BM-MSCs by regulating Hedgehog signaling pathway.

机构信息

Department of Spine Surgery, Hong Hui Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, China.

Physical Examination Center, Xi'an International Medical Center Hospital, Xi'an, China.

出版信息

Aging (Albany NY). 2022 Nov 14;14(21):8839-8855. doi: 10.18632/aging.204381.

DOI:10.18632/aging.204381
PMID:36375472
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9699766/
Abstract

BACKGROUND

lncRNA, a type of non-coding RNA, plays an important role in the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BM-MSCs). In this study, lncRNA and mRNA microarrays were performed to study the change of gene expression during osteogenic differentiation of BM-MSCs. We focused on Hedgehog interacting protein (HHIP), because HHIP mRNA and lncRNA HHIP-AS1 were gradually down-regulated on days 0, 7, and 14 during osteogenic differentiation. In addition, the gene coding is located on the anti-sense of gene, implying the potential interaction between lncRNA HHIP-AS1 and HHIP mRNA.

METHODS

BM-MSCs with over-expressed or silenced lncRNA HHIP-AS1 were constructed to explore the biological role of HHIP-AS1 in osteogenic differentiation. BM-MSCs were lysed to determine the alkaline phosphatase activity. Fluorescence hybridization and immunofluorescence were performed to analyze HHIP-AS1, HHIP, RUNX2 and osteocalcin.

RESULTS

Overexpression of lncRNA HHIP-AS1 increased HHIP expression, which suppressed Hedgehog signaling pathway, as indicated by the reduction of SMO, Gli1 and Gli2. The suppression of Hedgehog signal was associated with the inhibited osteogenesis. HHIP knockdown abolished the suppression of osteogenesis induced by lncRNA HHIP-AS1 overexpression. Through binding to HHIP mRNA, lncRNA HHIP-AS1 recruited ELAVL1 to HHIP mRNA, whereby increasing the mRNA stability and the protein level.

CONCLUSIONS

This study revealed that down-regulation of HHIP due to lncRNA HHIP-AS1 reduction promoted the osteogenic differentiation of BM-MSCs though removing the suppression of Hedgehog signal.

摘要

背景

lncRNA 是一种非编码 RNA，在骨髓间充质干细胞（BM-MSCs）的成骨分化中发挥重要作用。在这项研究中，通过 lncRNA 和 mRNA 微阵列研究了 BM-MSCs 成骨分化过程中基因表达的变化。我们专注于 Hedgehog 相互作用蛋白（HHIP），因为 HHIPmRNA 和 lncRNA HHIP-AS1 在成骨分化的第 0、7 和 14 天逐渐下调。此外，编码基因位于基因的反义链上，这意味着 lncRNA HHIP-AS1 和 HHIPmRNA 之间可能存在相互作用。

方法

构建了过表达或沉默 lncRNA HHIP-AS1 的 BM-MSCs，以探讨 HHIP-AS1 在成骨分化中的生物学作用。裂解 BM-MSCs 以测定碱性磷酸酶活性。进行荧光杂交和免疫荧光分析以分析 HHIP-AS1、HHIP、RUNX2 和骨钙素。

结果

过表达 lncRNA HHIP-AS1 增加 HHIP 表达，从而抑制 Hedgehog 信号通路，表现为 SMO、Gli1 和 Gli2 的减少。Hedgehog 信号的抑制与成骨抑制有关。HHIP 敲低消除了 lncRNA HHIP-AS1 过表达诱导的成骨抑制。通过与 HHIPmRNA 结合，lncRNA HHIP-AS1 将 ELAVL1 募集到 HHIPmRNA 上，从而增加 mRNA 稳定性和蛋白水平。

结论

本研究表明，由于 lncRNA HHIP-AS1 减少导致 HHIP 下调，通过去除 Hedgehog 信号的抑制，促进了 BM-MSCs 的成骨分化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/198029507052/aging-14-204381-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/40177bd59f24/aging-14-204381-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/29a134c4d907/aging-14-204381-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/39026fd7dac2/aging-14-204381-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/48b3488711c6/aging-14-204381-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/8b019cb85391/aging-14-204381-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/436e84b87104/aging-14-204381-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/198029507052/aging-14-204381-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/40177bd59f24/aging-14-204381-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/29a134c4d907/aging-14-204381-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/39026fd7dac2/aging-14-204381-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/48b3488711c6/aging-14-204381-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/8b019cb85391/aging-14-204381-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/436e84b87104/aging-14-204381-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/60ca/9699766/198029507052/aging-14-204381-g007.jpg

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