miR‑204‑5p inhibits the occurrence and development of osteoarthritis by targeting Runx2

Abstract

One of the hallmarks of osteoarthritis (OA) development is endochondral ossification, in which Runt-related transcription factor-2 (Runx2) is aberrantly expressed. Runx2 was previously identified to be regulated by microRNA-204-5p (miR-204-5p). The aim of the present study was to investigate the potential function of miR-204-5p regulating Runx2 during the development of OA and the underlying molecular mechanism. The expression levels of miR-204-5p and Runx2 were determined in tissue specimens. Rat OA models were established by transecting the anterior and posterior cruciate ligaments and removing the meniscus. Rats were treated with miR-204-5p agomir and miR-204-5p negative control (NC). All in vitro experiments were performed using rat primary chondrocytes and the SW-1353 human bone chondrosarcoma cell line. It was identified that the expression of miR-204-5p was significantly decreased, whereas Runx2 was significantly increased, in human OA tissues compared with in non-OA tissues, and levels were inversely associated with each other in primary chondrocytes and chondrosarcoma cells. Overexpression of miR-204-5p decreased the proliferation of chondrocytes and SW-1353 cells. Using a luciferase reporter assay, Runx2 was identified to be a direct target of miR-204-5p in chondrocytes and overexpressed miR-204-5p altered the expression of collagens II, X and matrix metalloproteinase (MMP)-1 and MMP-13 in primary chondrocytes and SW-1353 cells. Histological analysis revealed that miR-204-5p treatment ameliorated the OA-like phenotype that is reflected by assessment of cartilage thickness and Mankin's score. Runx2 expression was gradually increased as the rats increased in age. At 10 weeks of miR-204-5p agomir treatment, altered expression levels of collagens II and X, cartilage oligomeric matrix protein fragment, aggrecan, MMP-1 and MMP-13 were observed in the treatment group compared with the NC group. In conclusion, the results of the present study indicated that miR-204-5p decreases chondrocyte proliferation and ameliorates the OA-like phenotype in rats with surgically induced OA by targeting Runx2.

miR-122/SIRT1 axis regulates chondrocyte extracellular matrix degradation in osteoarthritis

“…We used chondrosarcoma cell line as cellular model, it can replace chondrocytes to a certain extent due to its easy access, strong proliferation ability and stable gene phenotype within a certain regulatory range [34]. Meanwhile, although the cell line is from tumor, it still retains the characteristics of chondrocytes, it can also avoid the possible genotype variation and chondrocytes of primary chondrocytes after long term in vitro [35].…”

Runx2 plays a central role in Osteoarthritis development

“…Although our understanding of miRNAs and their role in mesenchymal stem cells (MSCs) is scant, several transcription factors are known to modulate MSC differentiation into chondrocytes and osteoblasts. Of the transcriptional factors identified, Runx2 plays a unique multifunctional role in chondrogenesis and osteogenesis [ [102] , [103] , [104] ]. The deletion of the miRNA processing enzyme Dicer significantly reduced the expression of Runx2-related miRNAs and interrupted bone formation.…”

“…Its chondroprotective effect against OA progression has been linked to the downregulation of several proteins involved in cartilage destruction, such as Mmp13 and Admats5 [ 108 , 109 ]. Lastly, miR-204 decreased chondrocyte proliferation and ameliorated the OA-like phenotype in rodent models in a Runx2-dependent mechanism [ 102 , 104 ]. Since Runx2 protein expression was significantly increased by miR-204 Antagomir, it suggests that miR-204 is an endogenous attenuator of Runx2 in MSCs [ 102 , 104 , 110 ].…”

“…Lastly, miR-204 decreased chondrocyte proliferation and ameliorated the OA-like phenotype in rodent models in a Runx2-dependent mechanism [ 102 , 104 ]. Since Runx2 protein expression was significantly increased by miR-204 Antagomir, it suggests that miR-204 is an endogenous attenuator of Runx2 in MSCs [ 102 , 104 , 110 ]. Consistent with the in vitro findings, miR-204/miR-211 double KO mice developed severe, time-dependent OA development and progression, indicating the key role of regulation of Runx2 in OA development [ 111 ].…”

miR-296-5p inhibits IL-1β-induced apoptosis and cartilage degradation in human chondrocytes by directly targeting TGF-β1/CTGF/p38MAPK pathway

“…Accumulating studies indicate that multiple miRNAs are aberrantly regulated in cartilage degradation, and several miRNAs have been proven to act in vital regulatory roles in OA progression [3,11]. For instance, miR-93-5p, miR-204-5p and miR-221-3p are downregulated in OA tissues, and they can ameliorate OA progression via suppression of chondrocyte apoptosis and cartilage degradation [3,12,13]. miR-296-5p, a member of the miR-296 family, is located on the chromosome 20q13.32 genomic locus and regarded as a tumor angiogenesis-related miRNA [14,15].…”