MicroRNA-10a-3p Improves Cartilage Degeneration by Regulating CH25H-CYP7B1-RORα Mediated Cholesterol Metabolism in Knee Osteoarthritis Rats

Abstract

Osteoarthritis (OA) is a worldwide degenerative joint disease that seriously impaired the quality of life of patients. OA has been established as a disease with metabolic disorder. Cholesterol 25-hydroxylase (CH25H) was proved to play a key role in cartilage cholesterol metabolism. However, the biological function and mechanism of CH25H in OA remains further investigation. Growing researches have proved the vital roles of miRNAs in OA progression. In this study, we screened out miR-10a-3p through high-throughput miRNA sequencing which may bind to CH25H. Molecular mechanism investigation indicated that miR-10a-3p is an upstream target of CH25H. Functional exploration revealed miR-10a-3p suppressed the inflammatory responses, cholesterol metabolism and extracellular matrix (ECM) degradation in primary chondrocytes. Moreover, rescue assays implied that miR-10a-3p reversed CH25H plasmids induced inflammatory cytokine production and ECM degradation. Furthermore, the OA rat model was established to explore the function of miR-10a-3p in vivo. The results showed that miR-10a-3p can recover the OA features through targeting CH25H/CYP7B1/RORα axis. In conclusion, these findings implied a crucial role of miR-10a-3p/CH25H/CYP7B1/RORα axis in OA, which may provide a promising therapeutic strategy for OA.

Frailty in Aging and the Search for the Optimal Biomarker: A Review

“…In a study of young people (23–35 years) and older people (≥65 years) classified as frail or robust according to Fried’s criteria [ 167 ], miRNAs derived from exosomes were analyzed, and the results show that eight miRNAs were uniquely enriched in frail patients: miR-10a-3p, miR-92a-3p, miR-185–3p, miR-194–5p, miR-326, miR-532–5p, miR-576–5p and miR-760 [ 167 ]. Regarding miR-10a-3p, it has been reported that it can regulate cholesterol metabolism in chondrocytes, while miR-92a-3p is expressed during chondrogenesis in human mesenchymal stem cells and differentially in osteoarthritis [ 169 , 170 ]. miR-185-3p has been identified as a tumor suppressor in colorectal cancer [ 171 ], whereas miR-194 is a specific miRNA in vertebrates that has a fundamental role in energy production, inflammatory inhibition, and neoplasms such as breast cancer, non-small cell lung cancer, and colorectal cancer [ 172 , 173 , 174 ].…”

Comparison between articular chondrocytes and mesenchymal stromal cells for the production of articular cartilage implants

“…Several of the canonical miRNAs upregulated in ACs, such as miR-675-3p and 5p, miR-335-5p, miR-582-5p and 3p, miR-9-5p, miR-136-3p and miR 495-3p are known to be involved in cartilage biogenesis and disease ( Tomé et al, 2011 ; Díaz-Prado et al, 2012 ; Chen et al, 2017 ; Chen et al, 2018 ; Zhong G. et al, 2019 ; Chen et al, 2019 ; Seidl and Murphy, 2019 ; Wang et al, 2019 ; Chen et al, 2020 ; Shen et al, 2020 ; Zhang et al, 2021 ). Of the highest differentially expressed canonical miRNAs in MSCs miR-10a-5p, miR-181b, miR-181a, miR-135b-5p and miR-218-5p are known to be involved in osteogenesis, cartilage hypertrophy and degeneration and OA ( Bhushan et al, 2013 ; Song et al, 2013 ; Gabler et al, 2015 ; Nakamura et al, 2016 ; Lu et al, 2017 ; Ma et al, 2019 ; Yin et al, 2019 ; Li et al, 2021 ). Hardly any of the differentially expressed isomiRs shown in Supplementary Table S4 have known functionality related to cartilage, bone or skeletal diseases.…”

“…In contrast, of the 20 most differentially expressed miRNAs expressed at higher levels in the MSC discs, many are known to be associated with cartilage hypertrophy/ossification and disease. Among the highest differentially expressed canonical miRNAs in MSCs was miR-10a-5p, which has been found to be upregulated in OA cartilage and to promote progression of OA ( Ma et al, 2019 ), and miR-10a-3p, whose overexpression has been shown to improve cartilage degeneration in a knee OA rat model ( Li et al, 2021 ). MiR-181b-5p and -3p as well as miR181a-5p and -3p are among the highly differentially expressed miRNAs in MSC discs.…”

Melatonin‐Primed Mesenchymal Stem Cells‐Derived Small Extracellular Vesicles Alleviated Neurogenic Erectile Dysfunction by Reversing Phenotypic Modulation

“…Some targets of miR-10a-3p have been reported, including homolog 11 (COX11), vascular endothelial growth factor A (VEGFA), cholesterol 25-hydroxylase (CH25H), and C-X-C motif ligand 12 (CXCL12). [39][40][41][42] We applied the online algorithm Tar-getScan to predict potential targets of miR-10a-3p. Herein, we identified and verified a direct target of miR-10a-3p in CSMC (PKIA) using dual luciferase reporter assays.…”