College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
Department of Microbiology and Plant Pathology, University of California, Riverside, CA 92521, USA.
Int J Mol Sci. 2023 Jun 30;24(13):10975. doi: 10.3390/ijms241310975.
There is evidence to suggest that microRNA-140-5p (miR-140), which acts as a suppressor, is often elevated and has a role in various malignancies. Nevertheless, neither the function nor the mechanisms in chondrocytes linked with bone disorders, e.g., tibial dyschondroplasia (TD), have been satisfactorily established. The purpose of this study was to look into the role of microRNA-140-5p (miR-140) and its interaction with HDAC4 in chondrocytes, as well as the implications for tibial dyschondroplasia (TD), with a particular focus on the relationship between low miR-140 expression and poor pathologic characteristics, as well as its physiological effects on chondrocyte growth, differentiation, and chondrodysplasia. In this investigation, we discovered that TD had a reduced expression level of the miR-140. There was a correlation between low miR-140 expression, poor pathologic characteristics, and the short overall survival of chondrocytes. Our findings show an aberrant reduction in miR-140 expression, and HDAC4 overexpression caused disengagement in resting and proliferation zones. This further resulted in uncontrolled cell proliferation, differentiation, and chondrodysplasia. Mechanistically, HDAC4 inhibited the downstream transcription factors MEF2C and Runx2 and interacted with Col-Ⅱ, Col-X, and COMP. However, miR-140 binding to the 3'-UTR of HDAC4 resulted in the growth and differentiation of chondrocytes. Moreover, the expression of HDAC4 through LMK-235 was significantly decreased, and the expression was significantly increased under ITSA-1, referring to a positive feedback circuit of miR-140 and HDAC4 for endochondral bone ossification. Furthermore, as a prospective treatment, the flavonoids of Rhizoma drynariae (TFRD) therapy increased the expression of miR-140. Compared to the TD group, TFRD treatment increased the expression of growth-promoting and chondrocyte differentiation markers, implying that TFRD can promote chondrocyte proliferation and differentiation in the tibial growth plate. Hence, directing this circuit may represent a promising target for chondrocyte-related bone disorders and all associated pathological bone conditions.
有证据表明，miR-140-5p（miR-140）作为一种抑制物，其表达水平常常升高，并在各种恶性肿瘤中发挥作用。然而，miR-140 在与骨疾病相关的软骨细胞中的功能和机制，例如胫骨软骨发育不良（TD），尚未得到充分证实。本研究旨在研究 microRNA-140-5p（miR-140）及其与 HDAC4 在软骨细胞中的相互作用，以及对 TD 的影响，特别关注低 miR-140 表达与不良病理特征之间的关系，以及其对软骨细胞生长、分化和软骨发育不良的生理影响。在这项研究中，我们发现 TD 中 miR-140 的表达水平降低。miR-140 表达水平低、病理特征差与软骨细胞总生存率短之间存在相关性。我们的研究结果表明，miR-140 表达异常降低，HDAC4 过表达导致静止区和增殖区脱偶联。这进一步导致细胞增殖、分化和软骨发育不良失控。从机制上讲，HDAC4 抑制下游转录因子 MEF2C 和 Runx2，并与 Col-Ⅱ、Col-X 和 COMP 相互作用。然而，miR-140 与 HDAC4 的 3'-UTR 结合导致软骨细胞的生长和分化。此外，通过 LMK-235 降低 HDAC4 的表达，通过 ITSA-1 显著增加表达，这是 miR-140 和 HDAC4 对软骨内骨化的正反馈回路。此外，作为一种有前途的治疗方法，密骨灵（TFRD）治疗增加了 miR-140 的表达。与 TD 组相比，TFRD 治疗增加了促进生长和软骨细胞分化的标志物的表达，这表明 TFRD 可以促进胫骨生长板中的软骨细胞增殖和分化。因此，靶向该通路可能是一种有前途的治疗软骨细胞相关骨疾病和所有相关病理性骨疾病的靶点。
