Abstract
The changed biomechanical environment of chondrocytes elicited by altered extracellular matrix is reported to accelerate the progression of OA. MicroRNAs (miRNAs or miRs) have emerged as major regulators in chondrocyte function. Hence, we explored effect of miR-23a/b-3p on OA in regulating chondrocyte growth. The medial meniscus and anterior cruciate ligaments of right knee was removed to induce a mouse model of OA. miR-23a/b-3p and Gremlin1 (Grem1) expressions in OA were determined by RT-qPCR. Dual luciferase reporter gene assay was conducted to assess their relationship in the context of OA. Loss- and gain-of-function assays were adopted to clarify their effects on OA by determining the release of pro-inflammatory proteins and the apoptosis of chondrocytes. RT-qPCR determined increased miR-23a/b-3p expression and decreased Grem1 expression in the setting OA. Inhibiting miR-23a/b-3p or overexpressing Grem1 activated transforming growth factor-β/solvated metal atom dispersed 3 (TGF-β/Smad) signaling to prevent OA development. Silencing Grem1 ablated suppressive effects of miR-23a/b-3p inhibitor on the release of pro-inflammatory proteins and the apoptosis of chondrocytes. To conclude, inhibition of miR-23a/b-3p delays OA progression through Grem1-mediated activation of TGF-β/Smad signaling, contributing to deepen understanding of the pathogenesis of OA.
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Acknowledgements
This study was funded by the National Key R&D Program of China (No. 2018YFF0301105) and the National Natural Science Foundation of China (No. 81630064 and No. 81871786).
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XL and XW designed the study. XL, ZL and BY collated the data, carried out data analyses and produced the initial draft of the manuscript. XL and YH carried out the main experiments. XW and JQ contributed to drafting the manuscript. All authors have read and approved the final submitted manuscript.
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Supplementary file2 (EPS 24292 KB) Fig. S1 The experimental images of Fig. 5. A, Western blots of TGF-β and Smad proteins and semi-quantitative analysis. B, Cell apoptosis determined by TUNEL staining (× 400). C, Western blots of collagen II, GAG and MMP-13 proteins and semi-quantitative analysis. D, Knee cartilage injury determined by safranin O staining (× 200).
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Lu, X., Weng, X., Li, Z. et al. Protective role of microRNA-23a/b-3p inhibition against osteoarthritis through Gremlin1-depenent activation of TGF-β/smad signaling in chondrocytesa. Inflammopharmacol 30, 843–853 (2022). https://doi.org/10.1007/s10787-022-00923-1
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DOI: https://doi.org/10.1007/s10787-022-00923-1