Abstract
Slow growth and rapid loss of chondrogenic phenotypes are the major problems affecting chronic cartilage lesions. The role of microRNA-195 (miR-195) and its detailed working mechanism in the fore-mentioned process remains unknown. Fibroblastic growth factor 18 (FGF-18) plays a key role in cartilage homeostasis; whether miR-195 could regulate FGF-18 and its downstream signal pathway in chondrocyte proliferation and maintenance of chondrogenic phenotypes still remains unclear. The present research shows elevated miR-195 but depressed FGF-18 expressed in joint fluid specimens of 20 patients with chronic cartilage lesions and in CH1M and CH3M chondrocytes when compared with that in joint fluid specimens without cartilage lesions and in CH1W and CH2W chondrocytes, respectively. The following loss of function test revealed that downregulation of miR-195 by transfection of miR-195 inhibitors promoted chondrocyte proliferation and expression of a type II collagen α I chain (Col2a1)/aggrecan. Through the online informatics analysis we theoretically predicted that miR-195 could bind to a FGF-18 3′ untranslated region (3′UTR), also, we verified that a miR-195 could regulate the FGF-18 and its downstream pathway. The constructed dual luciferase assay further confirmed that FGF-18 was a direct target of miR-195. The executed anti-sense experiment displayed that miR-195 could regulate chondrocyte proliferation and Col2a1/aggrecan expression via the FGF-18 pathway. Finally, through an in vivo anterior cruciate ligament transection (ACLT) model, downregulation of miR-195 presented a significantly protective effect on chronic cartilage lesions. Evaluating all of the outcomes of the current research revealed that a decrease of miR-195 protected chronic cartilage lesions by promoting chondrocyte proliferation and maintenance of chondrogenic phenotypes via the targeting of the FGF-18 pathway and that the miR-195/FGF-18 axis could be a potential target in the treatment of cartilage lesions.
Highlights
It is common to see cartilage lesions caused by external factors such as sports injuries, trauma, unstable joints, and degenerative arthritis, all of which may be frequently experienced in modern society [1,2]
Through an early clinical detection trial we found that miR-195 was elevated in joint fluid specimens of patients with chronic cartilage lesions, so we wondered whether miR-195 was involved in the process of cartilage lesion formation and its repair
We revealed that miR-195 could target Fibroblastic growth factor 18 (FGF-18) and regulate the activity of Fibroblast growth factor (FGF)-18 downstream and that inhibition of miR-195 protects chronic cartilage lesion formation by promoting chondrocyte proliferation and maintenance of the chondrogenic phenotype via the targeting of the FGF-18 pathway
Summary
It is common to see cartilage lesions caused by external factors such as sports injuries, trauma, unstable joints, and degenerative arthritis, all of which may be frequently experienced in modern society [1,2]. Related reports that consider whether miRNAs could regulate chondrogenic phenotype maintenance or affect the chondrocytes dedifferentiation are even rarer. Whether miR-195 could affect chondrocyte proliferation and maintenance of chondrogenic phenotypes remains unclear. Davidson et al found that FGF-18 stimulated chondrocyte proliferation and matrix production via regulation of its downstream fibroblastic growth factor receptor 3 (FGFR3) [34]. Whether any miRNA could regulate FGF-18 to influence chondrocyte proliferation and chondrogenic phenotype maintenance remains unclear. We revealed that miR-195 could target FGF-18 and regulate the activity of FGF-18 downstream and that inhibition of miR-195 protects chronic cartilage lesion formation by promoting chondrocyte proliferation and maintenance of the chondrogenic phenotype via the targeting of the FGF-18 pathway
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