MicroRNA-146a reduces IL-1 dependent inflammatory responses in the intervertebral disc

Gu, Su Xi; Li, Xin; Hamilton, John; Chee, Ana; Kc, Ranjan; Chen, Di; An, Howard S.; Kim, Jae Sung; Oh, Chun-Do; Zheng, Yuan; Wijnen, André J. van; Im, Hee Jeong

doi:10.1016/j.gene.2014.10.024

Cited by 92 publications

(70 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result suggested a negative feedback between miR146a and inflammatory factors, considering that miR-146a was up-regulated in the RA pathology, and the administration of miR-146a may serve as a novel therapeutic target for bone destruction in RA [45]. The negative feedback of miR-146a with inflammatory factors was further confirmed in osteoarthritis fibroblast-like synoviocytes [46], osteoarthritis pain in knee joints [47], and intervertebral disc [48]. Apparently, there is still a great controversy on the role of miR-146a with two opposite conclusions, and one study reported a downregulation of miR-146 in OA cartilage, further mystifying the issue [49].…”

Section: Discussionmentioning

confidence: 73%

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2

Zhang¹,

Wang

Chu

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: There have been many studies on the etiology of osteoarthritis (OA) with regard to the function of inflammatory cytokines, the process of cartilage degradation, the function of miR-146a, hypoxia stimulation and autophagy in OA chondrocytes, but there have been no reports on the relationship between miR-146a and autophagy in cartilage, especially under hypoxia. This study aimed to confirm the relationship of miR-146a and autophagy in cartilage under hypoxia. Methods: Chondrocytes were treated by hypoxia gradients, and the main factors including HIF-1α, HIF-2α, miR-146a and Bcl-2 and autophagy markers ULK-1, ATG-5 were detected by quantitative PCR (Q-PCR) and western blotting. The autophagy marker LC-3 was detected by immunofluorescence. The reciprocal effects between miR-146a and Bcl-2 were confirmed by several combinations of shRNAs and adenovirus-gene systems followed by Q-PCR and western blot detection. Results: Hypoxia maintained the chondrocytes phenotype and promoted autophagy and miR-146a expression via HIF-1α, but not HIF-2α, while miR-146a did not reversely affect HIF-1α. The autophagy induced by hypoxia through HIF-1α, miR-146a and Bcl-2. Simply, hypoxia induced HIF-1α, and HIF-1α increased miR-146a, but miR-146a suppressed Bcl-2, an autophagy inhibitor. While Bcl-2 affected neither HIF-1α nor miR-146a. The absence of both HIF-1α and miR-146a or Bcl-2 over-expression inhibited hypoxia-induced autophagy. Conclusion: HIF-1α, miR-146a and Bcl-2 play crucial roles during hypoxia-induced autophagy, Hypoxia, HIF-1α and miR-146a promote chondrocytes autophagy via depressing Bcl-2. We conclude that miR-146a may serve as a novel therapeutic target for protecting cartilage from degeneration in OA.

show abstract

Section: Discussionmentioning

confidence: 73%

MicroRNA-146a Induced by Hypoxia Promotes Chondrocyte Autophagy through Bcl-2

Zhang¹,

Wang

Chu

et al. 2015

Cell Physiol Biochem

View full text Add to dashboard Cite

show abstract

“…These observations suggest that miR‐146a is an anti‐inflammatory microRNA that protects joints from degeneration associated with aging or trauma. This conclusion is consistent with previous studies that demonstrate an association of miR‐146a with anti‐inflammation phenotypes such as reduced pain in the joints (Gu et al., 2015; Li et al., 2011). However, we did not observe that miR‐146a gene knockout protects cartilage from degeneration in 12‐month‐old mice, as reported by a recent publication (Zhang et al., 2017).…”

Section: Discussionmentioning

confidence: 99%

“…A most recent study seemed to correlate with this hypothesis in vivo (Zhang et al., 2017). However, other study supports an opposite model in which miR‐146a plays a protective anti‐inflammatory role in OA (Gu et al., 2015; Li et al., 2011). Thus, the in vivo role of miR‐146a in OA pathogenesis is unclear.…”

Section: Introductionmentioning

confidence: 99%

Evidence that miR‐146a attenuates aging‐ and trauma‐induced osteoarthritis by inhibiting Notch1, IL‐6, and IL‐1 mediated catabolism

Guan

Yang

et al. 2018

Aging Cell

View full text Add to dashboard Cite

SummaryPrimary osteoarthritis (OA) is associated with aging, while post‐traumatic OA (PTOA) is associated with mechanical injury and inflammation. It is not clear whether the two types of osteoarthritis share common mechanisms. We found that miR‐146a, a microRNA‐associated with inflammation, is activated by cyclic load in the physiological range but suppressed by mechanical overload in human articular chondrocytes. Furthermore, miR‐146a expression is decreased in the OA lesions of human articular cartilage. To understand the role of miR‐146a in osteoarthritis, we systemically characterized mice in which miR‐146a is either deficient in whole body or overexpressed in chondrogenic cells specifically. miR‐146a‐deficient mice develop early onset of OA characterized by cartilage degeneration, synovitis, and osteophytes. Conversely, miR‐146a chondrogenic overexpressing mice are resistant to aging‐associated OA. Loss of miR‐146a exacerbates articular cartilage degeneration during PTOA, while chondrogenic overexpression of miR‐146a inhibits PTOA. Thus, miR‐146a inhibits both OA and PTOA in mice, suggesting a common protective mechanism initiated by miR‐146a. miR‐146a suppresses IL‐1β of catabolic factors, and we provide evidence that miR‐146a directly inhibits Notch1 expression. Therefore, such inhibition of Notch1 may explain suppression of inflammatory mediators by miR‐146a. Chondrogenic overexpression of miR‐146a or intra‐articular administration of a Notch1 inhibitor alleviates IL‐1β‐induced catabolism and rescues joint degeneration in miR‐146a‐deficient mice, suggesting that miR‐146a is sufficient to protect OA pathogenesis by inhibiting Notch signaling in the joint. Thus, miR‐146a may be used to counter both aging‐associated OA and mechanical injury‐/inflammation‐induced PTOA.

show abstract

“…microRNAs (miRNAs) are a class of endogenously expressed, small noncoding RNAs, which can inhibit gene expression by targeting mRNAs for translational repression and/or cleavage [81,82]. It has been reported that transfection of miR-146a mimics inhibits IL-1-induced MMP-13 expression and then increases Col II collagen content in NP cells isolated from IVD of bovine tails [83]. Conversely, when disc segments from miR-146a knockout mice were cultured ex vivo in the presence of IL-1 for 3 days, a more severe IDD is observed, with concomitant elevation of MMP-13 expression [83].…”

Section: Mmps and Iddmentioning

confidence: 99%