MicroRNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis

Yan, Shuhua; Wang, Meng; Zhao, Jian; Zhang, Hongtao; Zhou, Cheng-Pei; Jin, Lei; Zhang, Yinglong; Qiu, Xiuchun; Ma, Baoan; Fan, Qingyu

doi:10.3892/ijmm.2016.2618

Cited by 121 publications

(99 citation statements)

References 41 publications

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“…103 This study, and a previous in vitro-related study, 104 showed that silencing miR-34a could results in reduced chondrocyte apoptosis.…”

Section: Mirnas Regulating Skeletal Development and Homeostasis—evidesupporting

confidence: 54%

“…With respect to OA, a recent study showed that lentiviral delivery of anti-miR-34a could ameliorate the progression of OA following anterior cruciate ligament transection and medial meniscus resection in rats. 103 This study, and a previous in vitro-related study, 104 showed that silencing miR-34a could results in reduced chondrocyte apoptosis.…”

Section: Mirnas Regulating Skeletal Development and Homeostasis-evidesupporting

confidence: 54%

“…None of the studies referenced in this review showed over-expression or inhibition of the miRNA of interest in situ in rodent cartilage following intra-articular injection of specific lentiviral constructs. 103,121,137,157,165 However, two of these studies did did show an up-regulation of the miRNA of interest following cartilage extraction and qPCR. 121,157 To date, it is still challenging to carry out in situ hybridization for detection of miRNAs in vivo.…”

Section: Approaches To Modulate Mirna Function In Vivomentioning

confidence: 96%

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MicroRNAs in orthopaedic research: Disease associations, potential therapeutic applications, and perspectives

McAlinden

2017

Journal Orthopaedic Research

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MicroRNAs (miRNAs) are small non-coding RNAs that function to control many cellular processes by their ability to suppress expression of specific target genes. Tens to hundreds of target genes may be affected by one miRNA, thereby resulting in modulation of multiple pathways in any given cell type. Therefore, altered expression of miRNAs (i.e., during tissue development or in scenarios of disease or cellular stress) can have a profound impact on processes regulating cell differentiation, metabolism, proliferation, or apoptosis, for example. Over the past 5-10 years, thousands of reports have been published on miRNAs in cartilage and bone biology or disease, thus highlighting the significance of these non-coding RNAs in regulating skeletal development and homeostasis. For the purpose of this review, we will focus on miRNAs or miRNA families that have demonstrated function in vivo within the context of cartilage, bone or other orthopaedicrelated tissues (excluding muscle). Specifically, we will discuss studies that have utilized miRNA transgenic mouse models or in vivo approaches to target a miRNA with the aim of altering conditions such as osteoarthritis, osteoporosis and bone fractures in rodents. We will not discuss miRNAs in the context skeletal cancers since this topic is worthy of a review of its own. Overall, we aim to provide a comprehensive description of where the field currently stands with respect to the therapeutic potential of specific miRNAs to treat orthopaedic conditions and current technologies to target and modify miRNA function in vivo. KeywordsMicroRNAs (miRNAs); cartilage; bone; skeletal development; osteoarthritis MicroRNA (miRNAs) are small non-coding RNA molecules (typically 19-24 nucleotides in length) that function in RNA silencing and post-transcriptional regulation (suppression) of gene expression. 1 While the majority of miRNAs are located within the cell, some miRNAs, commonly known as circulating miRNA or extracellular miRNA, have also been detected outside the cell in the extracellular matrix, in various biological fluids, or in cell culture. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript miRNAs were first discovered over 20 years ago in the nematode Caenorhabditis elegans with the identification of the developmental regulator lin-4. 3 Since then, thousands of miRNAs have been identified and investigated, with a wide distribution in animals, plants, and viruses. 4 MicroRNAs are ubiquitously expressed in different organisms, and many of them are phylogenetically conserved. 5 To date, over 28,000 miR-NAs from various species are listed in the miRBase website (http://www.mirbase.org). Specifically, 2,588 mature miRNAs have been identified in humans and 1,915 mature miRNAs have been reported in mice.With respect to miRNA biosynthesis, transcription of miRNA genes that are located either intergenically or intragenically is mediated primarily by RNA polymerase II in eukaryotes, although RNA polymerase III has also been shown to transcrib...

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“…103 This study, and a previous in vitro-related study, 104 showed that silencing miR-34a could results in reduced chondrocyte apoptosis.…”

Section: Mirnas Regulating Skeletal Development and Homeostasis—evidesupporting

confidence: 54%

Section: Mirnas Regulating Skeletal Development and Homeostasis-evidesupporting

confidence: 54%

Section: Approaches To Modulate Mirna Function In Vivomentioning

confidence: 96%

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MicroRNAs in orthopaedic research: Disease associations, potential therapeutic applications, and perspectives

McAlinden

2017

Journal Orthopaedic Research

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“…Among these miRNAs, miR-34a, miR-122, miR-21, and miR-155 have been reported to be related to OA. [31][32][33][34][35] OA chondrocytes were transfected with the four miRNA mimics to achieve miRNA overexpression, as verified using real-time PCR assays ( Figure 5B); Cyr61 mRNA expression was significantly down-regulated by all the candidate miRNAs, especially by miR-34a-5p ( Figure 5B). Then we evaluated the role of IL-1β stimulation on miRNA expression, and found that miR-34a expression was the most strongly up-regulated by IL-1β treatment ( Figure 5C).…”

Section: Mir-34a Inhibits Cyr61 Expression Through Direct Binding Tmentioning

confidence: 76%

IL‐1β‐induced miR‐34a up‐regulation inhibits Cyr61 to modulate osteoarthritis chondrocyte proliferation through ADAMTS‐4

Yang

Long

et al. 2018

J of Cellular Biochemistry

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Osteoarthritis (OA) is the most prevalent degenerative joint disease with multifactorial etiology caused by risk factors. The degradation of aggrecan by upregulated ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is the key event in the development of OA. ADAMTS-4 contributes to aggrecan degradation in human OA. Cysteine-rich angiogenic inducer 61 (Cyr61), which is associated with diseases related to chronic inflammation, is found in articular cartilage from patients with osteoarthritis and appears to suppress ADAMTS-4 activity, possibly leading to chondrocyte cloning. Herein, we first revealed that Cyr61 and ADAMTS-4 protein levels were remarkably increased in OA cartilage tissues and OA chondrocytes, and verified Cyr61 regulation of ADAMTS-4 in normal and OA chondrocyte. Further, we revealed that Cyr61 could promote OA chondrocyte proliferation through inhibiting ADAMTS-4. Overproduction of inflammatory cytokines plays a vital role in the pathological development of OA; herein, we demonstrated that IL-1β inhibited Cyr61, while promoted ADAMTS-4 expression. By using online tools and luciferase assays, we confirmed that miR-34a, a regulatory miRNA of chondrocyte proliferation, could directly bind to the 3'-UTR of Cyr61 to inhibit its expression; further, IL-1β regulated Cyr61 and ADAMTS-4 expression through miR-34a. In OA cartilage tissues, miR-34a, and IL-1β mRNA expression was up-regulated and positively correlated; miR-34a and Cyr61 mRNA was positively correlated, further indicating that suppressing miR-34a expression might rescue IL-1β-induced Cyr61 suppression, and promote OA chondrocyte proliferation. Taken together, we provided novel experimental basis for rescuing OA chondrocyte proliferation through miR-34a/Cyr61 axis.

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“…IL-1β could also indirectly induce apoptosis through the upregulation of microRNAs (miRNAs), of which expression was reported in the pathophysiology of various diseases, such as OA [194,195]. Some miRNAs (i.e., miR-34a, miR-146a, miR-139, and miR-98) were involved in chondrocyte apoptosis: They were all overexpressed in OA vs. healthy cartilage and their expressions were induced by IL-1β in OA chondrocytes (miR-34a [196], miR-146a [197], miR-139 [198], miR-98 [199]) or in response to mechanical injury [200]. Concerning the molecular mechanisms of miRNA-induced apoptosis, a recurrent pattern is the repression of anti-apoptotic Bcl-2, as seen with miR-98 [199] and miR-139 [198], and, in some cases, the concomitant upregulation of pro-apoptotic bax [196].…”

Section: Cell Death Regulators In Chondrocytesmentioning

confidence: 99%

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Charlier

Relić

Deroyer

et al. 2016

IJMS

249

220

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Osteoarthritis (OA) is a joint pathology characterized by progressive cartilage degradation. Medical care is mainly based on alleviating pain symptoms. Compelling studies report the presence of empty lacunae and hypocellularity in cartilage with aging and OA progression, suggesting that chondrocyte cell death occurs and participates to OA development. However, the relative contribution of apoptosis per se in OA pathogenesis appears complex to evaluate. Indeed, depending on technical approaches, OA stages, cartilage layers, animal models, as well as in vivo or in vitro experiments, the percentage of apoptosis and cell death types can vary. Apoptosis, chondroptosis, necrosis, and autophagic cell death are described in this review. The question of cell death causality in OA progression is also addressed, as well as the molecular pathways leading to cell death in response to the following inducers: Fas, Interleukin-1β (IL-1β), Tumor Necrosis factor-α (TNF-α), leptin, nitric oxide (NO) donors, and mechanical stresses. Furthermore, the protective role of autophagy in chondrocytes is highlighted, as well as its decline during OA progression, enhancing chondrocyte cell death; the transition being mainly controlled by HIF-1α/HIF-2α imbalance. Finally, we have considered whether interfering in chondrocyte apoptosis or promoting autophagy could constitute therapeutic strategies to impede OA progression.

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MicroRNA-34a affects chondrocyte apoptosis and proliferation by targeting the SIRT1/p53 signaling pathway during the pathogenesis of osteoarthritis

Cited by 121 publications

References 41 publications

MicroRNAs in orthopaedic research: Disease associations, potential therapeutic applications, and perspectives

MicroRNAs in orthopaedic research: Disease associations, potential therapeutic applications, and perspectives

IL‐1β‐induced miR‐34a up‐regulation inhibits Cyr61 to modulate osteoarthritis chondrocyte proliferation through ADAMTS‐4

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

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