Decrease of miR-195 Promotes Chondrocytes Proliferation and Maintenance of Chondrogenic Phenotype via Targeting FGF-18 Pathway.
Decrease of miR-195 Promotes Chondrocytes Proliferation and Maintenance of Chondrogenic Phenotype via Targeting FGF-18 Pathway.
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miR-195 的减少通过靶向 FGF-18 途径促进软骨细胞增殖和软骨形成表型的维持
DOI：
10.3390/ijms18050975
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发表时间：
2017-05-04
影响因子：
5.6
通讯作者：
Zhang W
中科院分区：
文献类型：
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作者：
Wang Y;Yang T;Liu Y;Zhao W;Zhang Z;Lu M;Zhang W
慢性软骨损伤的主要问题是生长缓慢和软骨形成表型的快速丧失。microRNA-195（miR-195）在上述过程中的作用及其详细的工作机制尚不清楚。成纤维细胞生长因子18（FGF-18）在软骨稳态中起关键作用; miR-195是否能够调节FGF-18及其下游信号通路在软骨细胞增殖和维持软骨形成表型中的作用尚不清楚。本研究显示，与无软骨病变的关节液标本和CH 1 W和CH 2 W软骨细胞相比，20例慢性软骨病变患者的关节液标本和CH 1 M和CH 3 M软骨细胞中miR-195表达升高，FGF-18表达降低。以下功能丧失测试显示，通过转染miR-195抑制剂下调miR-195促进软骨细胞增殖和II型胶原α I链（Col 2a 1）/聚集蛋白聚糖的表达。通过在线信息学分析，我们从理论上预测了miR-195可以与FGF-18的3′非翻译区（3′UTR）结合，并验证了miR-195可以调控FGF-18及其下游通路。构建的双荧光素酶测定进一步证实FGF-18是miR-195的直接靶标。反义实验表明，miR-195可通过FGF-18途径调控软骨细胞增殖和Col 2a 1/aggrecan表达。最后，通过体内前交叉韧带横断（ACLT）模型，下调miR-195对慢性软骨病变具有显著的保护作用。评估当前研究的所有结果表明，miR-195的减少通过靶向FGF-18途径促进软骨细胞增殖和维持软骨形成表型来保护慢性软骨病变，并且miR-195/FGF-18轴可能是治疗软骨病变的潜在靶点。
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.