Interleukin‐1 in combination with oncostatin M up‐regulates multiple genes in chondrocytes: Implications for cartilage destruction and repair

Barksby, H. E.; Wang, Hui; Wappler, Ilka; Peters, Heiko; Milner, Jennifer M; Richards, Carl D.; Cawston, Tim E.; Rowan, Andrew D.

doi:10.1002/art.21574

Cited by 91 publications

(104 citation statements)

References 49 publications

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“…In human cartilage explant culture, induction of aggrecan degradation by IL-1β alone is relatively modest. OSM was added in addition to IL-1β because both have been shown to act synergistically on human cartilage to induce aggrecan and collagen degradation (19)(20)(21). As expected, in a 10-day cartilage explant culture (media replaced every 2 days), IL-1β/OSM markedly increased the cumulative release of aggrecan into the medium ( Fig.…”

Section: Deletion Of Lxrβ Gene In Mice Increases Cartilage Matrix Catsupporting

confidence: 58%

LXR modulation blocks prostaglandin E ₂ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

Rivera-Bermudez

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Osteoarthritis (OA), the most common arthritic condition in humans, is characterized by the progressive degeneration of articular cartilage accompanied by chronic joint pain. Inflammatory mediators, such as cytokines and prostaglandin E 2 (PGE 2 ) that are elevated in OA joints, play important roles in the progression of cartilage degradation and pain-associated nociceptor sensitivity. We have found that the nuclear receptor family transcription factors Liver X Receptors (LXRα and -β) are expressed in cartilage, with LXRβ being the predominant isoform. Here we show that genetic disruption of Lxrβ gene expression in mice results in significantly increased proteoglycan (aggrecan) degradation and PGE 2 production in articular cartilage treated with IL-1β, indicating a protective role of LXRβ in cartilage. Using human cartilage explants, we found that activation of LXRs by the synthetic ligand GW3965 significantly reduced cytokine-induced degradation and loss of aggrecan from the tissue. Furthermore, LXR activation dramatically inhibited cytokine-induced PGE 2 production by human osteoarthritic cartilage as well as by a synovial sarcoma cell line. These effects were achieved at least partly by repression of the expression of ADAMTS4, a physiological cartilage aggrecanase, and of cyclooxygenase-2 and microsomal prostaglandin E synthase-1, key enzymes in the PGE 2 synthesis pathway. Consistent with our in vitro observations, oral administration of GW3965 potently alleviated joint pain in a rat meniscal tear model of osteoarthritis.cartilage | pain | prostaglandin E2 C ytokines and growth factors play significant roles in the physiology of synovial joints. Increased catabolism and/or decreased anabolism of cartilage macromolecules can result in a net loss of matrix components and deterioration of the structural and functional properties that characterize osteoarthritis (OA) (1, 2). The cartilage matrix is degraded mainly by proteases produced by chondrocytes. The destructive enzymes, such as ADAMTS4 (aggrecanase-1) and matrix metallopeptidase 13 (MMP-13, collagenase-3), are up-regulated by inflammatory cytokines such as IL-1β and oncostatin M (OSM) (2-4). Prostaglandin E 2 (PGE 2 ) is a prostanoid that is derived from arachidonic acid released from membranes by phospholipase A 2 . Elevated levels of PGE 2 in OA joints have been reported (2, 5). Cyclooxygenase-2 (COX-2) and microsomal PGE synthase 1 (mPGES-1) are the main enzymes in PGE 2 synthesis during inflammation. PGE 2 contributes to the chronic disabling pain of arthritis by increasing sensitivity of peripheral nociceptive primary afferent neurons and central nociceptive neurons (6). In addition, a major role for PGE 2 during inflammation-mediated matrix degradation has been documented using animal models (7) and human cartilage explant cultures (5, 8).The Liver X Receptors (LXRα/NR1H3 and LXRβ/NR1H2) are oxysterol-activated transcription factors of the nuclear receptor family that play an important role in the control of cellular and whole-body cholesterol homeo...

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Section: Deletion Of Lxrβ Gene In Mice Increases Cartilage Matrix Catsupporting

confidence: 58%

LXR modulation blocks prostaglandin E ₂ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

Rivera-Bermudez

Zhang

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…OSM and IL-1 increase the expression of MMP13 mRNA in articular chondrocytes through a PKR independent mechanism Several studies have shown that treatment of chondrocytes with OSM and IL-1 results in the up-regulation of MMP13 mRNA expression (Koshy et al, 2002;Barksby et al, 2006;Milner et al, 2006;Blain et al, 2010). To determine whether this increase was mediated through the PKR pathway, the expression of MMP13 mRNA was assessed by qPCR following OSM+IL-1 treatment and PKR inhibition (Fig.…”

Section: Osm and Il-1 Increase The Expression And Activation Of Mmp9 mentioning

confidence: 99%

“…partly decreased the level of ADAMTS4 and ADAMTS5 mRNAs, an additional signalling mechanism must be activated following OSM+IL-1 treatment and is likely to occur via a complex interplay of signal transduction pathways including the MAPK/ERK, PI3K/Akt, Jak/STAT, JNK1/2 and p38 kinase pathways (Blanchard et al, 2001;Catterall et al, 2001;Radtke et al, 2002;Barksby et al, 2006;El Mabrouk et al, 2007). This is the first report, to our knowledge, that OSM+IL-1 treatment of bovine articular chondrocytes also decreases the expression of cartilage matrix genes (COL2A1, COL9A1, COL11A1 and ACAN).…”

Section: Sj Gilbert Et Al Pkr Mediates Osm and Il-1 Signalling In Chmentioning

confidence: 99%

“…It is clear that a complex array of signalling interactions infl uence type II collagen breakdown following OSM treatment. These include ERK/MAPK mediated induction of ADAMTS4 and MMP13 (El Mabrouk et al, 2007), PI3K/Akt mediated induction of MMP1 and 13 (Yoshihara et al, 2000b) and the JAK/STAT, ERK1/2, JNK1/2, and p38 kinase pathways (Blanchard et al, 2001;Catterall et al, 2001;Radtke et al, 2002;Barksby et al, 2006). The nature of the cross-talk between PKR and these other signalling pathways remains to be elucidated.…”

Section: Sj Gilbert Et Al Pkr Mediates Osm and Il-1 Signalling In Chmentioning

confidence: 99%

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Protein kinase R plays a pivotal role in oncostatin M and interleukin-1 signalling in bovine articular cartilage chondrocytes

Gilbert

Blain²,

Al‐Sabah³

et al. 2012

eCM

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This study investigated whether treatment of articular cartilage chondrocytes with a combination of oncostatin M (OSM) and interleukin-1 (IL-1) could induce a degradative phenotype that was mediated through the protein kinase R (PKR) signalling pathway. High-density monolayer cultures of full depth, bovine chondrocytes were treated with a combination of OSM and IL-1 (OSM+IL-1) for 7 days. To inhibit the activation of PKR, a pharmacological inhibitor of PKR was added to duplicate cultures. Pro-and active matrix metalloproteinase-9 (MMP9) and MMP9 mRNA were signifi cantly upregulated by OSM+IL-1 through a PKR dependent mechanism. ADAMTS4 and ADAMTS5 mRNA were also upregulated by OSM+IL-1. The upregulation of ADAMTS4 and ADAMTS5 were, in part, mediated through PKR. OSM+IL-1 resulted in a loss of type II collagen, which could not be rescued by PKR inhibition. OSM+IL-1 reduced the expression of COL2A1 (type II collagen), COL9A1 (type IX collagen), COL11A1 (type XI collagen), and ACAN (aggrecan) mRNAs. Expression of type II and XI collagen and aggrecan was reduced further when PKR was inhibited. OSM+IL-1 resulted in an 11-fold increase in TNFα mRNA which was, in part, mediated through the PKR pathway. This study demonstrates, for the fi rst time, that a number of catabolic and pro-infl ammatory effects known to be important in human arthritis and induced by OSM and IL-1, are mediated by the PKR signalling pathway.Keywords: Articular cartilage, chondrocytes, protein kinase R, oncostatin M, interleukin-1, matrix metalloproteinase, aggrecanase, tumour necrosis factor alpha, type II collagen.

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“…In SW1353 chondrosarcoma cells, OSM upregulates expression of MMPs, cytokines, chemokines and extracellular matrix components. 27 Because IL-6 serum levels are increased in adult primary bone sarcoma patients and correlate with poor survival, this cytokine may have an important role in the progression of osteosarcomas, chondrosarcomas, Ewing sarcomas and giant cell tumors of bone. 15,28 However, OSM or IL-6 block osteoblasts and osteosarcoma cells in the G0/G1 phase of the cell cycle by inducing expression of the cdk inhibitor p21 WAF1 .…”

mentioning

confidence: 99%

Direct anti‐cancer effect of oncostatin M on chondrosarcoma

David

Guihard

Brounais

et al. 2011

Intl Journal of Cancer

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The cytokine Oncostatin M (OSM) is cytostatic, pro-apoptotic and induces differentiation of osteosarcoma cells into osteocytes, suggesting new adjuvant treatment for these bone-forming sarcomas. However, OSM systemic over-expression could lead to adverse side effects such as generalized inflammation, neoangiogenesis and osteolysis. We determine here the effect of OSM on chondrosarcoma, another primary bone sarcoma characterized by the production of cartilage matrix and altered bone remodelling. Chondrosarcomas are resistant to conventional chemotherapy and radiotherapy, and wide surgical excision remains the only available treatment. We found that OSM blocked the cell cycle in four of five chondrosarcoma cell lines, independently of p53 and presumably through the JAK3/STAT1 pathway. In two tested cell lines, OSM induced a hypertrophic chondrocyte differentiation, with an induced Cbfa1/SOX9 ratio and induced Coll10, matrix metalloproteinase 13 (MMP13) and RANKL expression. Adenoviral gene transfer of OSM (AdOSM) in the Swarm rat chondrosarcoma (SRC) model indicated that local intra-tumoral OSM over-expression reduces chondrosarcoma development not only with reduced tumor proliferation and enhanced apoptosis but also with enhanced RANKL expression, osteoclast formation and reduced bone volumes. Flu-like symptoms were induced by the AdOSM, but there was no effect on tumor angiogenesis. Therefore, OSM could be considered as a new adjuvant anti-cancer agent for chondrosarcomas. A local application of this cytokine is presumably needed to overcome the poor vascularization of these tumors and to limit the deleterious effect on other tissues. Its side effect on bone remodeling could be managed with anti-resorption agents, thus offering potential new lines of therapeutic interventions.

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Interleukin‐1 in combination with oncostatin M up‐regulates multiple genes in chondrocytes: Implications for cartilage destruction and repair

Cited by 91 publications

References 49 publications

LXR modulation blocks prostaglandin E ₂ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

LXR modulation blocks prostaglandin E ₂ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

Protein kinase R plays a pivotal role in oncostatin M and interleukin-1 signalling in bovine articular cartilage chondrocytes

Direct anti‐cancer effect of oncostatin M on chondrosarcoma

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Interleukin‐1 in combination with oncostatin M up‐regulates multiple genes in chondrocytes: Implications for cartilage destruction and repair

Cited by 91 publications

References 49 publications

LXR modulation blocks prostaglandin E 2 production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

LXR modulation blocks prostaglandin E 2 production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

Protein kinase R plays a pivotal role in oncostatin M and interleukin-1 signalling in bovine articular cartilage chondrocytes

Direct anti‐cancer effect of oncostatin M on chondrosarcoma

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Product

Resources

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LXR modulation blocks prostaglandin E ₂ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model

LXR modulation blocks prostaglandin E ₂ production and matrix degradation in cartilage and alleviates pain in a rat osteoarthritis model