<i>N</i>‐acetylcysteine prevents nitric oxide‐induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis

Nakagawa, Shuji; Arai, Yuji; Mazda, Osam; Kishida, Tsunao; Takahashi, Kenji; Sakao, Kei; Saito, Motoki; Honjo, Kuniaki; Imanishi, Jirô; Kubo, Toshikazu

doi:10.1002/jor.20976

Cited by 91 publications

(70 citation statements)

References 40 publications

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“…is induced, in part, by the excess production of nitric oxide (NO) in osteoarthritic cartilage samples [11][12][13] . There is also upregulated gene and protein expression of matrix degradation enzymes MMP13 14 , a matrix metallopeptidase that cleaves type II collagen, and a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (ADAMTS5) 15 , the most common of the aggrecanases that cleave aggrecan.…”

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confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

299

340

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Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here I examined human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, I found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, Ishow in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runtrelated transcription factor-2 (Runx2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (Adamts5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.iii ACKNOWLEDGEMENTS

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mentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

299

340

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“…A substantial body of evidence exists suggesting a role for chondrocyte apoptosis in the occurrence and progression of OA 1. Multiple signalling pathways and cytokines are involved in the apoptosis of chondrocyte in OA, such as nitric oxide 2, Fas 3, p38 MAPK 4, PI3K/Akt 5, IL‐1β 6 and TNF‐α 7.…”

Section: Introductionmentioning

confidence: 99%

MiR‐29b‐3p promotes chondrocyte apoptosis and facilitates the occurrence and development of osteoarthritis by targeting PGRN

Chen

Wang

et al. 2017

J Cellular Molecular Medi

111

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This study was aimed to explore the role of miR‐29b‐3p and PGRN in chondrocyte apoptosis and the initiation and progress of osteoarthritis (OA). Both miR‐29b‐3p and PGRN were up‐regulated in cartilage tissue from patients with OA. Transfection of miR‐29b‐3p mimic into rat primary chondrocytes and SW1353 chondrosarcoma cells significantly suppressed PGRN expression and release, induced apoptosis, inhibited proliferation and scratch wound closure. By contrast, transfection of miR‐29b‐3p inhibitor exhibited the opposite effects. Moreover, the expression and secretion of cartilaginous degeneration‐related molecules were also altered by miR‐29b‐3p. Luciferase reporter gene assay showed rat GRN mRNA is directly targeted and repressed by miR‐29b‐3p. The fact that recombinant PGRN or shPGRN‐mediated PGRN interference abolished miR‐29b‐3p mimic‐induced cell apoptosis and growth inhibition suggested miR‐29b‐3p affect the cellular functions of chondrocyte through regulating PGRN expression. In vivo, joint cavity injection of miR‐29b‐3p antagomir prior to surgical induction of OA significantly suppressed the upregulation of miR‐29b‐3p, whereas further promoted the increased expression of PGRN. Articular chondrocytes apoptosis and cartilage loss in the knee joint of surgically induced OA rats were also ameliorated by the injection of miR‐29b‐3p antagomir, demonstrated by TUNEL and safranin O‐fast green staining. This work showed miR‐29b‐3p facilitates chondrocyte apoptosis and OA by targeting PGRN, and miR‐29b‐3p or PGRN may be the potential target for OA treatments.

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“…Based on previous studies on intraarticular injection in rats, a 50-μl solution was a reasonable amount in this animal model (6,34). Since normal joint cavity of rat might contain a small amount of joint fluid, after intraarticular injection of 50 μl of 1 nM apelin, the final concentration of apelin in joint cavity would be <1 nM, and might be close to 0.5 nM.…”

Section: Discussionmentioning

confidence: 99%

Apelin plays a catabolic role on articular cartilage: In vivo and in vitro studies

Chen²,

Tang³

et al. 2010

Int J Mol Med

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Abstract. Adipokines play key roles in the regulation of bone growth, obesity, diabetes mellitus type 2, and HIV infection. As a newly discovered hormone in the adipokine family, the precise role of apelin on articular cartilage metabolism is not yet clear. The aim of this study was to evaluate the role of apelin on articular cartilage. In vitro, we examined the effects of apelin on normal chondrocyte proliferation and gene expression of metalloproteinases (MMPs) and interleukin-1ß (IL-1ß). In vivo, by intra-articular injection with apelin, we examined MMP-3, -9, collagen II and IL-1ß at both gene and protein levels. Furthermore, we measured the messenger RNA (mRNA) expression of ADAMTS-4 and -5 (a disintegrin and metalloproteinase with thrombospondin motifs 4 and 5) and the proteoglycan content in articular cartilage. Apelin stimulated the proliferation of chondrocytes and significantly increased mRNA levels of MMP-1, -3, -9 and IL-1ß in vitro. Intra-articular injection with apelin in vivo up-regulated the expression of MMP-3, -9, and IL-1ß as well as decreased the level of collagen II. Additionally, after treatment with apelin, mRNA levels of ADAMTS-4 and -5 markedly increased and depletion of proteoglycan in articular cartilage was found by histological assessment. These findings suggest that apelin plays a catabolic role in cartilage metabolism and is a risk factor in the pathophysiology of osteoarthritis.

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N‐acetylcysteine prevents nitric oxide‐induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis

Cited by 91 publications

References 40 publications

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

MiR‐29b‐3p promotes chondrocyte apoptosis and facilitates the occurrence and development of osteoarthritis by targeting PGRN

Apelin plays a catabolic role on articular cartilage: In vivo and in vitro studies

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