Regulation of Gelatinases Expression by Cytokines, Endotoxin, and Pharmacological Agents in the Human Osteoarthritic Knee

Chu, Shu‐Chen; Yang, Shun‐Fa; Ko, Jiunn‐Liang; Hsieh, Yih‐Shou; Wu, Chih-Lung; Lu, Ko-Hsiu

doi:10.1080/03008200490506058

Cited by 24 publications

(23 citation statements)

References 44 publications

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“…The ␦, ⑀, , and isoforms of PKC are all activated in Lyme disease (29). PKC activity is necessary for neutrophil activation in gouty arthritis (30), and linked to OA for over a decade (31)(32)(33). However, only recently has isoform-specific information, essential for informing future therapeutic design, begun to emerge.…”

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confidence: 99%

Protein Kinase C Isoforms ζ and ι Mediate Collagenase Expression and Cartilage Destruction via STAT3- and ERK-dependent c-fos Induction

Litherland

Elias

Wang

et al. 2010

Journal of Biological Chemistry

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The protein kinase C (PKC) signaling pathway is a major regulator of cellular functions and is implicated in pathologies involving extracellular matrix remodeling. Inflammatory joint disease is characterized by excessive extracellular matrix catabolism, and here we assess the role of PKC in the induction of the collagenases, matrix metalloproteinase (MMP)-1 and MMP-13, in human chondrocytes by the potent cytokine stimulus interleukin-1 (IL-1) in combination with oncostatin M (OSM). IL-1 ؉ OSM-stimulated collagenolysis and gelatinase activity were ameliorated by pharmacological PKC inhibition in bovine cartilage, as was collagenase gene induction in human chondrocytes. Small interfering RNA-mediated silencing of PKC gene expression showed that both novel (nPKC␦, nPKC) and atypical (aPKC, aPKC) isoforms were involved in collagenase induction by IL-1. However, MMP1 and MMP13 induction by IL-1 ؉ OSM was inhibited only by aPKC silencing, suggesting that only atypical isoforms play a significant role in complex inflammatory milieus. Silencing of either aPKC led to diminished IL-1 ؉ OSM-dependent extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) 3 phosphorylation, and c-fos expression. STAT3 gene silencing or ERK pathway inhibition also resulted in loss of IL-1 ؉ OSM-stimulated c-fos and collagenase expression. Silencing of c-fos and c-jun expression was sufficient to abrogate IL-1 ؉ OSM-stimulated collagenase gene induction, and overexpression of both c-fos and c-jun was sufficient to drive transcription from the MMP1 promoter in the absence of a stimulus. Our data identify atypical PKC isozymes as STAT and ERK activators that mediate c-fos and collagenase expression during IL-1 ؉ OSM synergy in human chondrocytes. aPKCs may constitute potential therapeutic targets for inflammatory joint diseases involving increased collagenase expression.Inflammation is a major characteristic of joint diseases such as rheumatoid arthritis and osteoarthritis (OA), 3 during which inflammatory mediators released by infiltrating immune cells as well as resident joint cells induce alterations in gene expression that can lead to ECM degradation (1, 2). Cytokines such as interleukin (IL-)1, IL-17, and tumor necrosis factor ␣ (TNF␣) are key mediators thought to be involved in promoting inflammatory responses in such destructive joint diseases (3, 4). We have shown that the IL-6 family cytokines oncostatin M (OSM) and IL-6 markedly exacerbate the catabolic potential of these mediators, synergistically promoting cartilage ECM catabolism both in vitro and in vivo (5-9).Chondrocytes are the only resident cell type in normal articular cartilage and function to preserve homeostasis. This is achieved by balancing the expression of ECM components with catabolic factors such as the matrix metalloproteinases (MMPs), which collectively can degrade all the ECM macromolecules. During inflammatory joint diseases, chondrocytes are stimulated to secrete elevated levels of MMPs that, once activated, media...

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confidence: 99%

Protein Kinase C Isoforms ζ and ι Mediate Collagenase Expression and Cartilage Destruction via STAT3- and ERK-dependent c-fos Induction

Litherland

Elias

Wang

et al. 2010

Journal of Biological Chemistry

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“…Pro-infl ammatory cytokines, such as tumor necrosis factor (TNF) α and interleukin (IL)-1β, and gelatinases in matrix metalloproteinases (MMPs) are involved in degradation of connective tissues (30,33,34,40), and these pro-infl ammatory cytokines and gelatinases are synthesized in tendinocytes (15,18,33). Additionally, TNF α and IL-1β are known to be initiators of the synthesis of gelatinases and of the synthesis and release of cytokines (3,7,8,10,24,28). …”

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Effect of heat on synthesis of gelatinases and pro-inflammatory cytokines in equine tendinocytes

et al. 2006

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The aim of this study was to clarify whether matrix metalloproteinases (MMP-2 and -9: gelatinases) and pro-infl ammatory cytokines [tumor necrosis factor (TNF) α and interleukin (IL)-1β] are induced by heat in tendon tissue in vitro and to test the hypothesis that heat exposure causes tendinocytes to synthesize pro-infl ammatory cytokines and that synthesis of these cytokines, in turn, leads to up-regulation of synthesis of gelatinases. Isolated tendinocytes from equine superfi cial digital fl exor tendons were cultured and all experiments were performed on cells passaged 3 or 4 times. In the cells exposed to heat (37 to 45°C, 0 to 60 min), the survival rate decreased sharply in a temperature-and time-dependent manner, especially at 42 and 45°C. Cells exposed at 40°C, however, showed little change in survival rate and morphology. Gelatin zymograms revealed that proMMP-2 and -9 were the only two MMPs remaining in the supernatant of the cultured tendinocytes, including that of untreated cells. Addition of TNFα and IL-1β to the culture medium of tendinocytes accelerated proMMP-9 synthesis considerably. Heating the tendinocytes (40°C) led to a three-fold increase in proMMP-9 synthesis in a short time. Only TNFα was detected in tendinocytes after heat exposure for 30 and 60 min. In contrast, IL-1β was under the detectable level in ELISA. Cooling of heat-exposed cells from 40°C to 37°C considerably down-regulated cellular proMMP-9 synthesis. Furthermore, proMMP-9 level was greatly reduced in cells treated at lower temperatures, 20°C and 5°C. These fi ndings support our hypothesis that hyperthermia in the horse tendon induces tendinocytes to synthesize pro-infl ammatory cytokines and that the synthesis of these cytokines results in the up-regulation of gelatinases.Tendon injury, especially in the superfi cial digital flexor tendon (SDFT), has proved to be a major problem for racehorses. Recent studies have shown that about 10-30% of racehorses suffer from tendonitis (29). Although the etiology of tendonitis has been discussed in many reports (2,19,25), there is little information on the mechanism of tendon degradation. Pro-infl ammatory cytokines, such as tumor necrosis factor (TNF) α and interleukin (IL)-1β, and gelatinases in matrix metalloproteinases (MMPs) are involved in degradation of connective tissues (30,33,34,40), and these pro-infl ammatory cytokines and gelatinases are synthesized in tendinocytes (15,18,33). Additionally, TNF α and IL-1β are known to be initiators of the synthesis of gelatinases and of the synthesis and release of cytokines (3,7,8,10,24,28).

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“…The increased expression of MMP-2 and -9 in the synovium of patients with arthritic effusions superiorly reflects the inflammatory condition of the joints, and a positive correlation between MMP-9 production and rapid destruction of the hip joint has been described in OA. 22) The zymographic profile and MMP expression can act as a useful diagnostic adjunct in patients with OA, providing precise information on the condition of the articular cartilage and the breakdown of its matrix. In the present study, high concentrations of HPE significantly lowered MMP-2 activity in osteoblastic cell line which is known to produce MMP-2 in normal condition.…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Human Placenta Extract on Cartilage Degradation in Experimental Osteoarthritis

Kim

Park

et al. 2010

Biological & Pharmaceutical Bulletin

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This study investigated the effect of human placenta extract (HPE) on cartilage degradation in vitro MG-63 cells, articular cartilage explants, and in vivo monoiodoacetate (MIA)-induced osteoarthritis (OA). Matrix metalloproteinase (MMP)-2 activity was measured in HPE-treated osteoblastic MG-63 cells. Articular cartilage explants in rabbit were cultured, and the degree of proteoglycan (PG) degradation was assessed by measuring the amount of glycosaminoglycan (GAG) released into the culture medium. Experimental osteoarthritis was induced by intra-articular injection of 3 mg MIA in rats. Beginning 14 d post-MIA injection, HPE was administered intra-articularly once a day for 14 d. The knee joints were assessed by roentgenography, histology, and gelatinase activity. HPE inhibited PG degradation in articular cartilage explants. HPE significantly reduced deformity of knee joints and suppressed the histological change in MIA-induced OA. HPE inhibited MMP-2 activity in MG-63 cells. MMP-2 and -9 activities were also reduced in the cartilages of HPE-treated knee joints. Our results indicate that HPE has therapeutic effects on OA by protecting cartilage.

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Regulation of Gelatinases Expression by Cytokines, Endotoxin, and Pharmacological Agents in the Human Osteoarthritic Knee

Cited by 24 publications

References 44 publications

Protein Kinase C Isoforms ζ and ι Mediate Collagenase Expression and Cartilage Destruction via STAT3- and ERK-dependent c-fos Induction

Protein Kinase C Isoforms ζ and ι Mediate Collagenase Expression and Cartilage Destruction via STAT3- and ERK-dependent c-fos Induction

Effect of heat on synthesis of gelatinases and pro-inflammatory cytokines in equine tendinocytes

Protective Effects of Human Placenta Extract on Cartilage Degradation in Experimental Osteoarthritis

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