Pravastatin alleviates interleukin 1β-induced cartilage degradation by restoring impaired autophagy associated with MAPK pathway inhibition

Jin

et al. 2020

aging

Osteoarthritis (OA) is one of the most painful and widespread chronic degenerative joint diseases and is characterized by destructed articular cartilage and inflamed joints. Previously, our findings indicated that circular RNA ciRS-7 (ciRS-7)/microRNA 7 (miR-7) axis is abnormally expressed in OA, and regulates proliferation, inflammatory responses, and apoptosis of interleukin-1β (IL-1β)-stimulated chondrocytes. However, its underlying role in OA remains unknown. In this study, we first validated cartilage degradation and defection of autophagy in samples of OA patients. IL-1β initially stimulated autophagy of chondrocytes, and ultimately significantly suppressed autophagy. Upregulated ciRS-7/down-regulated miR-7 aggravated IL-1β-induced cartilage degradation, and restrained autophagy in vitro . Gene sequencing and bioinformatics analysis performed on a control group, IL-1β group, and IL-1β+miR-7-mimics group demonstrated that seven of the most significant mRNA candidates were enriched in the interleukin-17 (IL-17) signaling pathway. Increased IL-17A levels were also observed by qRT-PCR and ELISA. In addition, it was revealed that the ciRS-7/miR-7 axis ameliorated cartilage degradation and defection of autophagy by PI3K/AKT/mTOR activation in IL-1β-induced chondrocytes. Furthermore, an OA model was established in rats with medial meniscus destabilization. miR-7-siRNA-expressing lentiviruses alleviated surgical resection-induced cartilage destruction of OA mice, whereas miR-7 mimics worsened the effects. Thus, these findings revealed that the mechanism of the ciRS-7/miR-7 axis involved regulating OA progression and provided valuable directions for OA treatment.

Section: Discussionmentioning

confidence: 99%

Down-regulated ciRS-7/up-regulated miR-7 axis aggravated cartilage degradation and autophagy defection by PI3K/AKT/mTOR activation mediated by IL-17A in osteoarthritis

Jin

et al. 2020

aging

“…The MAPK signaling pathway, which is a group of serine/threonine protein kinases involved in the cellular signal transduction [60], which regulated many cellular functions, affects a large number of human diseases. Previous studies have demonstrated the effect of MAPK signals on tumor metastasis [61,62], osteogenesis [63,64], osteoarthritis [65,66], or certain inflammatory diseases [67]. For example, it can regulate the proliferation and differentiation of brain cells [68].…”

Section: Discussionmentioning

confidence: 99%

Plasma Exosome-derived MicroRNAs as Novel Biomarkers of Traumatic Brain Injury in Rats

Wang

Zhang

et al. 2020

Int. J. Med. Sci.

Self Cite

Traumatic brain injury (TBI) is a widespread central nervous system (CNS) condition and a leading cause of death, disability, and long-term disability including seizures and emotional and behavioral issues. To date, applicable diagnostic biomarkers have not been elucidated. MicroRNAs (miRNAs) are enriched and stable in exosomes in plasma. Therefore, we speculated that miRNAs in plasma exosomes might serve as novel biomarkers for TBI diagnosis and are also involved in the pathogenesis of TBI. In this study, we first isolated exosomes from peripheral blood plasma in rats with TBI and then investigated the alterations in miRNA expression in exosomes by high-throughput RNA sequencing. As a result, we identified 50 significantly differentially expressed miRNAs, including 31 upregulated and 19 downregulated miRNAs. Then, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that the most highly correlated pathways that were identified were the MAPK signaling pathway, regulation of actin cytoskeleton, Rap1 signaling pathway and Ras signaling pathway. This study provides novel perspectives on miRNAs in peripheral blood plasma exosomes, which not only could be used as biomarkers of TBI diagnosis but could also be manipulated as therapeutic targets of TBI.

“…IL-1β is a major pro-inflammatory cytokine that is involved in OA pathology by inducing inflammatory responses and catabolic effects [ 9 , 17 – 19 ]. IL-1β promotes the expression of MMPs, which are involved in the degradation of cartilage components [ 20 ]. IL-1β also induces ADAMTS-5, which promotes breakdown of aggrecan [ 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…IL-1β stimulates the expression of iNOS and COX-2, which promote the release of well known inflammatory mediators, NO and PGE2 [ 23 , 24 ]. Several studies suggest that inhibition of these pro-inflammatory mediators hinders OA progression [ 19 , 20 ].…”

Section: Discussionmentioning

confidence: 99%

Tomatidine suppresses inflammation in primary articular chondrocytes and attenuates cartilage degradation in osteoarthritic rats

Chu

Huang

et al. 2020

Aging

Self Cite

In this study, we investigated whether the anti-inflammatory effects of tomatidine alleviate osteoarthritis (OA)-related pathology in primary articular chondrocytes and a rat OA model. STITCH database analysis identified 22 tomatidine-target genes that were enriched in 78 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Moreover,39 of the 105 OA-related KEGG pathways were related to tomatidine-target genes. The top two OA-related KEGG pathways with tomatidine-target genes were the MAPK and neutrophin signaling pathways. Pretreating primary chondrocytes with tomatidine suppressed interleukin-1β (IL-1β)-induced expression of iNOS, COX-2, MMP1, MMP3, MMP13, and ADAMTS-5. Tomatidine also suppressed IL-1β-induced degradation of collagen-II and aggrecan proteins by inhibiting NF-κB and MAPK signaling. In a rat OA model, histological and immunohistochemical analyses showed significantly less cartilage degeneration in thetibiofemoral joints of rats treated for 12 weeks with tomatidine after OA induction (experimental group) than in untreated OA group rats. However, micro-computed tomography (μ-CT) showed that tomatidine did not affect remodeling of the subchondral bone at the tibial plateau. These data shows that tomatidine suppresses IL-1β-induced inflammation in primary chondrocytes by inhibiting the NF-κB and MAPK signaling pathways, and protects against cartilage destruction in a rat OA model.