MicroRNA-125b-5p regulates IL-1β induced inflammatory genes via targeting TRAF6-mediated MAPKs and NF-κB signaling in human osteoarthritic chondrocytes

Abstract

Abnormal post-transcriptional modulations in inflammatory genes by microRNAs (miRNAs) play a crucial role in human disorders including arthritis. In this study, we determined the effect of hsa-miR-125b-5p on interleukin (IL)-1β induced inflammatory genes in human osteoarthritic (OA) chondrocytes. Bioinformatics algorithms showed 3′untranslated region (3′UTR) of TRAF6 mRNA (NM_004620.3) has perfectly matched ‘seed-sequence’ for hsa-miR-125b-5p. Treatment of cells with IL-1β up-regulates TRAF6 mRNA and down-regulates hsa-miR-125b-5p expression. This negative correlation between TRAF6 and hsa-miR-125b-5p was verified by transfection with miR-125b mimic (pre-miR-125b). Moreover, transfection with miR-125b mimic caused marked inhibition of IL-1β-induced phosphorylation of p38-MAPK, JNK-MAPKs and ERK-MAPKs and also suppressed the nuclear levels of NF-κBp50, NF-κBp65 and inhibited the activation of IκBα. Furthermore, transfected chondrocytes with miR-125b mimic in the presence of IL-1β also showed marked inhibition in the secretion of several proinflammatory cytokines, chemokines and growth factors including IL-6, IL-8, INF-γ, TGF-β1, IGFBP-1 and PGDF-BB. Importantly, this transfection also significantly inhibited IL-1β- induced MMP-13 expression/production. In short, this study concludes that hsa-miR-125b-5p acts as a negative co-regulator of inflammatory genes including MMP-13 via targeting TRAF6/MAPKs/NF-κB pathway in human OA chondrocytes.

Differential Regulation of circRNA, miRNA, and piRNA during Early Osteogenic and Chondrogenic Differentiation of Human Mesenchymal Stromal Cells

“…On the contrary, miR-125b-5p, which we showed to be downregulated in early chondrogenic differentiation, has been previously indicated to be associated with the attenuation of IL-1β target gene expression in osteoarthritic chondrocytes [67,68] and LPS-induced inflammation in ATDC5 cell line [69]. Moreover, it is downregulated by the activation of the NF-κB pathway [68] and targets SP7 (Osterix), an important transcription factor in osteogenic differentiation [70]. It is not completely known what the role of miR-125b-5p downregulation is in chondrogenic differentiation, although it may point to an involvement of the NF-κB pathway and hypertrophy.…”

“…miR-5690 expression was previously shown in endothelial cells [66], but to our knowledge, it has never been associated with bone formation or cell differentiation. On the contrary, miR-125b-5p, which we showed to be downregulated in early chondrogenic differentiation, has been previously indicated to be associated with the attenuation of IL-1β target gene expression in osteoarthritic chondrocytes [67,68] and LPS-induced inflammation in ATDC5 cell line [69]. Moreover, it is downregulated by the activation of the NF-κB pathway [68] and targets SP7 (Osterix), an important transcription factor in osteogenic differentiation [70].…”

Quercetin, Epigallocatechin Gallate, Curcumin, and Resveratrol: From Dietary Sources to Human MicroRNA Modulation

“…In the same set of experiments, researcher documented that EGCG was able to decrease let-7e-5p, miR-103a-3p, miR-151a-5p, miR-195-5p, miR-222-3p, miR-23a-3p, miR-23b-3p, miR-26a-5p, miR-27a-3p, miR-29b-3p, miR-3195, miR-3651, miR-4281, miR-4459, miR-4516, miR-762, and miR-125b-5p expression [102]. The decrease of this latter miR is not positive for the prevention of cartilage breakdown in osteoarthritis [105].…”

Correlation of microRNA‐125a/b with acute respiratory distress syndrome risk and prognosis in sepsis patients

“…For instance, miR‐125a high expression is reported to contribute to the upregulation of inflammatory cytokines and chemokines, such as IL‐β, IL‐6, and TNF‐α, in lupus nephritis . As for miR‐125b, its overexpression elevated the expressions of proinflammatory factors including TNF‐α, IL‐6, IL‐1β, and p‐p65 via activating NF‐κB pathway, meanwhile its involvement in the immune response and inflammation is reported in acute lung injury . In addition, the regulatory roles of miR‐125a as well as miR‐125b in reactive oxygen species (ROS) level, which is associated with oxygen and glucose deprivation, are reported in several organs including lung .…”

“…10 As for miR-125b, its overexpression elevated the expressions of proinflammatory factors including TNF-α, IL-6, IL-1β, and p-p65 via activating NF-κB pathway, meanwhile its involvement in the immune response and inflammation is reported in acute lung injury. 11,12 In addition, the regulatory roles of miR-125a as well as miR-125b in reactive oxygen species (ROS) level, which is associated with oxygen and glucose deprivation, are reported in several organs including lung. 13,14 Considering the association of miR-125a and miR-125b with proinflammatory factors in immune, inflammation responses and their regulating roles in lung injuries, we hypothesized that they might be of value in predicting ARDS risk as well as prognosis in sepsis patients.…”