The Effect of miR-140-5p with HDAC4 towards Growth and Differentiation Signaling of Chondrocytes in Thiram-Induced Tibial Dyschondroplasia.

Abstract

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.

• Authors: Wangyuan Yao, Muhammad Fakhar-E-Alam Kulyar, Yanmei Ding, Haitao Du, Jiajia Hong, Kyein San Loon, Shah Nawaz, Jiakui Li
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 13 (Jun 30 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 37446153 (Publication Type: Journal Article)

Chemical References

• Thiram
• MicroRNAs
• HDAC4 protein, human
• Histone Deacetylases
• Repressor Proteins
• Mirn140 microRNA, human

Topics

• Humans
• Chondrocytes (metabolism)
• Thiram
• Osteochondrodysplasias (metabolism)
• Cell Differentiation (genetics)
• MicroRNAs (metabolism)
• Histone Deacetylases (genetics, metabolism)
• Repressor Proteins (metabolism)