Role of HIF-1α and HIF-2α in osteoarthritis

Zhang, Fang‐Jie; Luo, Wei; Lei, Guanghua

doi:10.1016/j.jbspin.2014.10.003

Cited by 136 publications

(117 citation statements)

References 51 publications

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“…HIF-2α mediates cartilage destruction, as well as chondrocytes cell death, both contributing to the acceleration of OA progression [163]. To control cartilage degradation, HIF-2α can upregulate the expression of matrix degradative enzymes, such as MMP-1, -3, -9, -12, and -13, ADAMTS4, either directly by enhancing their promoter activities or indirectly by cooperating with CCAAT/enhancer-binding protein β (C/EBPβ) [164], or inducing IL-6 [165] or visfatin production [9].…”

Section: Autophagy In Chondrocytes and Oa Developmentmentioning

confidence: 99%

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Charlier

Relić

Deroyer

et al. 2016

IJMS

266

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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Section: Autophagy In Chondrocytes and Oa Developmentmentioning

confidence: 99%

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Charlier

Relić

Deroyer

et al. 2016

IJMS

266

220

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“…Previous studies have shown that death receptor 6 (TNFRSF21) is upregulated in OA and is targeted by miR-210, which is downregulated in OA [136, 137]. Hypoxia inducible factor-1-α (HIF-1α) regulates chondrogenesis as well as apoptosis and autophagy in chondrocytes [138]. Interestingly, miRNA-195 is highly expressed in OA samples and stimulates chondrocyte apoptosis by targeting HIF-1α [91, 139].…”

Section: Mirna Regulation Of Apoptosis and Autophagy In Oamentioning

confidence: 99%

The Role of MicroRNAs and Their Targets in Osteoarthritis

2016

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MicroRNA regulation and expression has become an emerging field in determining the mechanisms regulating a variety of inflammation-mediated diseases. Recent studies have focused on specific microRNAs that are differentially expressed in case of osteoarthritis. Furthermore, several targets of these miRNAs important in disease progression have also been identified. In this review, we focus on microRNA biogenesis, regulation, detection, and quantification with an emphasis on cellular localization and how these concepts may be linked to disease processes such as osteoarthritis. Next, we review the relationship of specific microRNAs to certain features and risk factors associated with osteoarthritis such as inflammation, obesity, autophagy, and cartilage homeostasis. We also identify selected microRNAs that are differentially expressed in osteoarthritic tissue, but have unidentified targets and functions in the disease pathogenesis. Lastly, we highlight the potential use of microRNAs for therapeutic purposes, and also point to certain remedies that regulate microRNA expression.

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“…Among predicted targets of miR-181a from these 3 databanks, 3 overlapping genes ranked as most probable targets (Figure 2). One of them, GPD1L, is implicated in hypoxia-inducible factor 1α (HIF-1α) expression and hydroxylation [15,16], and HIF-1α has been confirmed as an important regulator contributing to the synthesis of ECM and chondrocyte fate in OA [17]. Thus, we next determined whether GPD1L is a direct target of miR-181a in chondrocytes, and whether miR-181a regulates chondrocyte apoptosis by targeting GPD1L, thereby affecting the pathogenesis of OA.…”

Section: Resultsmentioning

confidence: 99%

“…GPD1L is a master regulator for the hydroxylation of HIF-1α, and its expression leads to decrease of HIF-1α expression [16]. HIF-1α was reported to protect articular cartilage by promoting the chondrocyte phenotype, maintaining chondrocyte viability, and supporting metabolic adaptation to a hypoxic environment [17]. In addition, HIF-1α-induced HSP70 overexpression increased the expression levels of ECM genes and cell viability, and protected chondrocytes from apoptosis [21], indicating that GPD1L may also be involved in modulating of chondrocytes apoptosis.…”

Section: Discussionmentioning

confidence: 99%

miR-181a Modulates Chondrocyte Apoptosis by Targeting Glycerol-3-Phosphate Dehydrogenase 1-Like Protein (GPD1L) in Osteoarthritis

Zhai

et al. 2017

Med Sci Monit

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BackgroundmiR-181a is a small non-coding RNA known to be dysregulated in osteoarthritis (OA), but the role of miR-181a in human OA remains unclear. The aim of this study was to identify its function and molecular target in chondrocytes during OA pathogenesis.Material/MethodsThe function of miR-181a was assessed by gain-of-function studies in human OA chondrocytes. Potential targets of miR-181a were predicted using series of bioinformatics and intersection analysis, then confirmed by luciferase reporter assay. Gene expression was quantified using quantitative reverse transcription PCR (qRT-PCR) assays, and protein production was quantified by Western blot analysis.ResultsThe FITC apoptosis assay results indicated that the upregulation of miR-181a led to an increase of apoptosis rate in chondrocytes. Then bioinformatic analysis identified potential target sites of the miR-181a located in the 3′ untranslated region of GPD1L. Dual-luciferase reporter assays results showed that GPD1L is a target gene of miR-181a. Furthermore, Western blot and qRT-PCR analysis demonstrated that miR-181a inhibited GPD1L gene expression. Increased GPD1L and decreased miRNA-181a were observed in tissues from osteoarthritis patients. Moreover, we found a highly negative correlation between miRNA-181a and GPD1L.ConclusionsOur results demonstrated that miR-181a may play an important role in the pathogenesis of OA through targeting GPD1L and regulating chondrocyte apoptosis.

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Role of HIF-1α and HIF-2α in osteoarthritis

Cited by 136 publications

References 51 publications

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

Insights on Molecular Mechanisms of Chondrocytes Death in Osteoarthritis

The Role of MicroRNAs and Their Targets in Osteoarthritis

miR-181a Modulates Chondrocyte Apoptosis by Targeting Glycerol-3-Phosphate Dehydrogenase 1-Like Protein (GPD1L) in Osteoarthritis

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