Aging and osteoarthritis: Central role of the extracellular matrix

Rahmati, Maryam; Nalesso, Giovanna; Mobasheri, Ali; Mozafari, Masoud

doi:10.1016/j.arr.2017.07.004

Cited by 379 publications

(278 citation statements)

References 159 publications

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“…As observed byShiraishi et al (2017), MMPs/TIMPs significantly increased in ex vivo OA cartilage, but the homeostasis could be recovered by the paracrine effect of human adipose tissue-derived stem cells, which was consistent with our study. On ground of this, the protection of cartilage by CM was possibly the sequel of equilibrium between MMP-13 and TIMP-1.The ECM is primarily synthesized and secreted by chondrocytes(Toh et al, 2017), which means the intensified apoptosis of chondrocytes in OA milieu contributes the loss of ECM(Rahmati, Nalesso, Mobasheri, & Mozafari, 2017). The results of immunofluorescence in our study revealed significantly lower expression of TUNEL in CM-treated joints compared with the PBS group, indicating antiapoptosis effect of CM Shiraishi et al (2017).…”

supporting

confidence: 50%

“…The ECM is primarily synthesized and secreted by chondrocytes (Toh et al, ), which means the intensified apoptosis of chondrocytes in OA milieu contributes the loss of ECM (Rahmati, Nalesso, Mobasheri, & Mozafari, ). The results of immunofluorescence in our study revealed significantly lower expression of TUNEL in CM‐treated joints compared with the PBS group, indicating anti‐apoptosis effect of CM.…”

Section: Discussionmentioning

confidence: 99%

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Conditioned medium of mesenchymal stem cells delays osteoarthritis progression in a rat model by protecting subchondral bone, maintaining matrix homeostasis, and enhancing autophagy

Chen

Sun

et al. 2019

J Tissue Eng Regen Med

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Evidence accumulated that mesenchymal stem cell (MSC) therapy ameliorated osteoarthritis (OA) via paracrine effect, whereas conditioned medium (CM) of MSCs contains all the secretomes. In vitro studies have proved its therapeutic effect in OA, but few in vivo evidences were unveiled. This study investigated the effect of MSCs–CM in an animal model of OA. OA was induced by anterior cruciate ligament transaction and destabilization of the medial meniscus in 12 rats bilaterally. The CM group (N = 6) was administered with intraarticular injection of MSCs–CM weekly, whereas the phosphate‐buffered saline (PBS) group (N = 6) was injected with PBS. Six rats served as normal control and received sham operation with weekly PBS injection. Rats were sacrificed 8 weeks postoperatively. Gross and histological morphology were analysed. Microcomputed tomography was applied to assess the subchondral bone. Components of extracellular matrix (ECM) including type II collagen (Col II) and aggrecan, and ECM homeostasis‐related enzymes (metalloproteinase‐13 [MMP‐13] and tissue inhibitor of metalloproteinase‐1 [TIMP‐1]), as well as autophagy markers (Beclin‐1 and microtubule‐associated protein light chain 3) were evaluated immunohistochemically. Chondrocyte apoptosis was measured by terminal deoxynucleotidyl transferase dUTP nick‐end labelling staining. Gene expression of Col II, aggrecan, MMP‐13, and TIMP‐1 was confirmed by real‐time polymerase chain reaction. Morphological outcomes demonstrated remarkable articular‐protective effect of MSCs–CM. Well‐maintained subchondral bone structure, significantly more abundant cartilage matrix, notably decreased ratio of MMP‐13 to TIMP‐1, and inhibited chondrocyte apoptosis with enhanced autophagy were observed in the CM group compared with the PBS group. In conclusion, MSCs–CM demonstrated satisfactory effect in alleviating OA in rats via protecting the microarchitecture of subchondral bone, balancing the ratio of MMP‐13 to TIMP‐1 in cartilage, and enhancing autophagy, which might provide a new remedy against OA.

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supporting

confidence: 50%

Section: Discussionmentioning

confidence: 99%

Conditioned medium of mesenchymal stem cells delays osteoarthritis progression in a rat model by protecting subchondral bone, maintaining matrix homeostasis, and enhancing autophagy

Chen

Sun

et al. 2019

J Tissue Eng Regen Med

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“…Accumulation of senescent cells in various tissues could impair their normal function and is implicated in the development of several age‐related disorders. OA is known for progressive tissue remodeling and loss of joint function, and aging is the most important risk factor in its development . The chondrocyte is the sole cell type of articular cartilage in joint tissue and is responsible for the production of the extracellular matrix (ECM) and for maintaining cartilage structure and function.…”

Section: Introductionmentioning

confidence: 99%

Protective effect of vildagliptin on TNF‐α‐induced chondrocyte senescence

Cai

et al. 2019

IUBMB Life

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Osteoarthritis (OA) is a common age‐related disorder. Chondrocytes in joint tissue play a critical role in normal articular cartilage function and tissue homeostasis. Local inflammatory cytokine‐induced chondrocyte senescence contributes to the development and progression of OA. Various dipeptidyl peptidase‐4 (DPP‐4) inhibitors have been widely used to treat type 2 diabetes. Here, we report a novel pharmacological role of the DPP‐4 inhibitor vildagliptin in chondrocyte senescence. Our data indicate that DPP‐4 is an inducible factor responsive to tumor necrosis factor‐α (TNF‐α) treatment in chondrocytes. The inhibition of DPP‐4 by vildagliptin ameliorates TNF‐α‐induced chondrocyte senescence as determined by cellular senescence‐associated β‐galactosidase (SA‐β‐Gal) activity. Vildagliptin displayed protective capabilities against TNF‐α‐induced chondrocyte cell cycle arrest in the G1 phase. Moreover, vildagliptin suppresses the three major TNF‐α‐induced chondrocyte senescence proteins including p53, p21, and plasminogen activator inhibitor‐1 (PAI‐1). Vildagliptin also suppresses TNF‐α‐induced p53 acetylation at K382. Consistently, our findings demonstrate the inhibitory effect of vildagliptin on p53 acetylation, which is mediated by sirtuin 1 (SIRT1) as the inhibition of SIRT1 negated the inhibitory action of vildagliptin on p53 acetylation. Furthermore, we found that the effect of vildagliptin on SIRT1 protection is adenosine 5′‐monophosphate (AMP)‐activated protein kinase (AMPK) dependent, and the inhibition of AMPK activity negated the protection of vildagliptin against SIRT1 and chondrocytes senescence. In conclusion, our study explored the molecular mechanism and protective effect of the antidiabetic drug vildagliptin against chondrocyte senescence, and our findings imply that vildagliptin has a therapeutic potential in OA. © 2019 IUBMB Life, 1–2, 2019

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“…The approaches to counteract and avoid OA remain insufficient. Significant evidence suggests that the death of chondrocytes participates in the incidence as well as the progression of OA [7,8]. Various pathways and cytokines are involved in OA chondrocyte death, including nitrous oxide (NO), p38 MAPK, Fas, PI3K/AKT, TNF-α, as well as IL-1β [9,10].…”

Section: Introductionmentioning

confidence: 99%

MiR-34a Enhances Chondrocyte Apoptosis, Senescence and Facilitates Development of Osteoarthritis by Targeting DLL1 and Regulating PI3K/AKT Pathway

Zhang

Hsu

Zhong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Osteoarthritis (OA) is the prevalent degenerative disease caused by various factors. MicroRNAs are important regulators in the inflammation and immune response. The aim of this study was to investigate the effect of microRNA-34a (MiR-34a) on the death of chondrocytes, senescence, as well as its role in OA progression. Methods: A series of experiments involving CCK-8, flow cytometry, β-galactosidase staining and wound healing assays were conducted to determine the cellular capabilities of proliferation, cell apoptosis, senescence and the ability of cells to recover from injury, respectively. Binding sites between miR-34a and delta-like protein 1 (DLL1) were identified using a luciferase reporter system, whereas mRNA and protein expression of target genes was determined by RT-PCR and immunoblot, respectively. OA model was generated via surgery. Results: We found that miR-34a expression was increased in the cartilage of OA patients. In rat chondrocytes and chondrosarcoma cells, miR-34a transfections noticeably inhibited the expression of DLL1, triggered cell death and senescence, suppressed proliferation, and prevented scratch assay wound closure. However, transfection of a miR-34a inhibitor displayed adverse effects. Additionally, secretion and expression of factors associated with cartilage degeneration were altered via miR-34a. Moreover, miR-34a directly inhibits DLL1 mRNA. Furthermore, concentrations of DLL1, total PI3K, and p-AKT declined in chondrocytes that overexpress miR-34a. DLL1 overexpression elevated PI3K and p-AKT levels, and eliminated cell death triggered by a miR-34a mimic. In vivo, miR-34a remarkably inhibited miR-34a up-regulation, while enhanced the level of DLL1 expression. In the knee joints of surgery-induced OA rats, articular chondrocyte death and loss of cartilage were attenuated via miR-34a antagomir injection. Conclusions: These findings indicate that miR-34a contributes to chondrocyte death, causing OA progression through DLL1 and modulation of the PI3K/AKT pathway.

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Aging and osteoarthritis: Central role of the extracellular matrix

Cited by 379 publications

References 159 publications

Conditioned medium of mesenchymal stem cells delays osteoarthritis progression in a rat model by protecting subchondral bone, maintaining matrix homeostasis, and enhancing autophagy

Conditioned medium of mesenchymal stem cells delays osteoarthritis progression in a rat model by protecting subchondral bone, maintaining matrix homeostasis, and enhancing autophagy

Protective effect of vildagliptin on TNF‐α‐induced chondrocyte senescence

MiR-34a Enhances Chondrocyte Apoptosis, Senescence and Facilitates Development of Osteoarthritis by Targeting DLL1 and Regulating PI3K/AKT Pathway

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