Exosomal miR‐95‐5p regulates chondrogenesis and cartilage degradation via histone deacetylase 2/8

Mao, Guping; Hu, Shu; Zhang, Ziji; Wu, Peihui; Zhao, Xiaoyi; Lin, Ru; Liao, Weiming; Kang, Yan

doi:10.1111/jcmm.13808

Cited by 93 publications

(92 citation statements)

References 46 publications

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“…For example, we observed that melatonin treatment upregulated the expression of miR-95 and downregulated the expression of miR-9 and miR-204. miR-95 has been reported to promote cartilage matrix expression by directly inhibiting histone deacetylase 2/8 (HDAC2/8) [28]. Previous studies have demonstrated that miR-9 [29] and miR-204 [30] markedly increase in OA cartilage and contribute to the disrupted matrix homeostasis via The underlying mechanisms by which melatonin regulates miR-140 expression are not fully understood.…”

Section: Discussionmentioning

confidence: 99%

Melatonin Prevents Osteoarthritis-Induced Cartilage Degradation via Targeting MicroRNA-140

Zhang

Lin

Zhou

et al. 2019

Oxidative Medicine and Cellular Longevity

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Osteoarthritis (OA) is characterized by the progressive destruction of articular cartilage, which is involved in the imbalance between extracellular matrix (ECM) synthesis and degradation. MicroRNA-140-5p (miR-140) is specifically expressed in cartilage and plays an important role in OA-induced matrix degradation. The aim of this study was to investigate (1) whether intra-articular injection of melatonin could ameliorate surgically induced OA in mice and (2) whether melatonin could regulate matrix-degrading enzymes at the posttranscriptional level by targeting miR-140. In an in vitro OA environment induced by interleukin-1 beta (IL-1β), melatonin treatment improved cell proliferation of human chondrocytes, promoted the expression of cartilage ECM proteins (e.g., type II collagen and aggrecan), and inhibited the levels of IL-1β-induced proteinases, such as matrix metalloproteinase 9 (MMP9), MMP13, ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4), and ADAMTS5. Both the microarray and polymerase chain reaction (PCR) experiments revealed that miR-140 was a melatonin-responsive microRNA and melatonin upregulated miR-140 expression, which was suppressed by IL-1β stimulation. In vivo experiments demonstrated that intra-articular injection of melatonin prevented disruptions of cartilage matrix homeostasis and successfully alleviated the progression of surgery-induced OA in mice. Transfection of miR-140 antagomir completely counteracted the antiarthritic effects of melatonin by promoting matrix destruction. Our findings demonstrate that melatonin protects the articular cartilage from OA-induced degradation by targeting miR-140, and intra-articular administration of melatonin may benefit patients suffering from OA.

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Section: Discussionmentioning

confidence: 99%

Melatonin Prevents Osteoarthritis-Induced Cartilage Degradation via Targeting MicroRNA-140

Zhang

Lin

Zhou

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…Nonetheless, the screening and confirmation of candidate factors participating in the chondrogenic enhancement observed with PCM is far from complete. In addition, the possible role of exosomal CD73-mediated adenosine activation of AKT, ERK, and AMPK signaling [14,64] and the participation of exosomal microRNAs [65,66] that have been previously implicated in regulating chondrocyte anabolic activity and cartilage degradation have yet to be examined. Further work will be required to fully decipher the paracrine mechanisms responsible for the enhanced anabolic and protective effect observed here in response to PCM administration, including the examination of the contribution of EVs to our reported PEMF-mediated secretome responses.…”

Section: Discussionmentioning

confidence: 99%

Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration

et al. 2020

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Background: The mesenchymal stem cell (MSC) secretome, via the combined actions of its plethora of biologically active factors, is capable of orchestrating the regenerative responses of numerous tissues by both eliciting and amplifying biological responses within recipient cells. MSCs are "environmentally responsive" to local micro-environmental cues and biophysical perturbations, influencing their differentiation as well as secretion of bioactive factors. We have previously shown that exposures of MSCs to pulsed electromagnetic fields (PEMFs) enhanced MSC chondrogenesis. Here, we investigate the influence of PEMF exposure over the paracrine activity of MSCs and its significance to cartilage regeneration.Methods: Conditioned medium (CM) was generated from MSCs subjected to either 3D or 2D culturing platforms, with or without PEMF exposure. The paracrine effects of CM over chondrocytes and MSC chondrogenesis, migration and proliferation, as well as the inflammatory status and induced apoptosis in chondrocytes and MSCs was assessed.Results: We show that benefits of magnetic field stimulation over MSC-derived chondrogenesis can be partly ascribed to its ability to modulate the MSC secretome. MSCs cultured on either 2D or 3D platforms displayed distinct magnetic sensitivities, whereby MSCs grown in 2D or 3D platforms responded most favorably to PEMF exposure at 2 mT and 3 mT amplitudes, respectively. Ten minutes of PEMF exposure was sufficient to substantially augment the chondrogenic potential of MSC-derived CM generated from either platform. Furthermore, PEMF-induced CM was capable of enhancing the migration of chondrocytes and MSCs as well as mitigating cellular inflammation and apoptosis. Conclusions:The findings reported here demonstrate that PEMF stimulation is capable of modulating the paracrine function of MSCs for the enhancement and re-establishment of cartilage regeneration in states of cellular stress. The PEMF-induced modulation of the MSC-derived paracrine function for directed biological responses in recipient cells or tissues has broad clinical and practical ramifications with high translational value across numerous clinical applications.

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“…Exosomes, as important paracrine components, are involved in maintaining normal physiological functions, mediating inter-cell communication, and inducing changes in cell functions and processes by delivering various types of bioactive microRNAs, proteins, and unique gene products 9,10,24 . These microRNAs might serve as vital inducers of HUCMSC differentiation into chondrocytes, such as the exosomal miR-92a-3p, exosomal miR-95-5p, exosomal miR-320c, and exosomal miR-135b, which can regulate cartilage development and homeostasis [25][26][27][28] . These ndings suggest that the active molecules in exosomes may be an important mechanism underlying their ability to promote chondrogenesis of HUCMSCs.…”

Section: Discussionmentioning

confidence: 99%

Articular chondrocyte-derived exosomes promote cartilage differentiation of human umbilical cord mesenchymal stem cells by activation of autophagy

Zhu

Wang

et al. 2020

Preprint

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Background Umbilical cord mesenchymal stem cell (HUCMSC)-based therapies were previously utilised for cartilage regeneration because of the chondrogenic potential of MSCs. However, chondrogenic differentiation of HUMSCs is limited by the administration of growth factors like TGF-β that may cause cartilage hypertrophy. It has been reported that exosomes could modulate the phenotypic expression of stem cells. However, the role of human chondrogenic-derived exosomes (C-EXOs) in chondrogenic differentiation of HUCMSCs has not been reported. Results In this study, we successfully isolated chondrocyte-derived exosomes (C-EXO) from human multi-finger cartilage and found that C-EXO efficiently promoted the proliferation and chondrogenic differentiation of HUCMSCs, evidenced by highly expressed aggrecan (ACAN), COL2A and SOX-9. Also, the expression of the fibrotic marker, COL1A and hypertrophic marker, COL10, was significantly lower than that induced by TGF-β. In vivo, stimulation of C-EXO accelerated HUCMSCs-mediated cartilage repair in rabbit models. Furthermore, C-EXO led to increasing autophagosomes during the process of chondrogenic differentiation, indicating that C-EXO promoted cartilage regeneration might be through the activation of autophagy. Conclusions C-EXOs play an essential role in fostering chondrogenic differentiation and proliferation of HUCMSCs, which may be beneficial for articular cartilage repair.

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Exosomal miR‐95‐5p regulates chondrogenesis and cartilage degradation via histone deacetylase 2/8

Cited by 93 publications

References 46 publications

Melatonin Prevents Osteoarthritis-Induced Cartilage Degradation via Targeting MicroRNA-140

Melatonin Prevents Osteoarthritis-Induced Cartilage Degradation via Targeting MicroRNA-140

Pulsed electromagnetic fields potentiate the paracrine function of mesenchymal stem cells for cartilage regeneration

Articular chondrocyte-derived exosomes promote cartilage differentiation of human umbilical cord mesenchymal stem cells by activation of autophagy

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