Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C chemokines

Borzı̀, Rosa Maria; Mazzetti, Ilaria; Cattini, Luca; Uguccioni, Mariagrazia; Baggiolini, Marco; Facchini, Andrea

doi:10.1002/1529-0131(200008)43:8<1734::aid-anr9>3.0.co;2-b

Cited by 141 publications

(118 citation statements)

References 28 publications

(16 reference statements)

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“…Moderately increased expression of chemokines, including the C-C chemokine subfamily member RANTES, as well as IL-8 and GRO-␣, has been demonstrated in chondrocytes present in OA and RA cartilage (25)(26)(27)(28). Importantly, chemokine receptors, including CCR1, CCR2, CCR3, CCR5, CXCR1, and CXCR2, are also expressed by chondrocytes (29,30). The highly selective IL-8R (CXCR1) may be moderately increased in OA cartilage (29,31).…”

Section: Discussionmentioning

confidence: 93%

“…Importantly, chemokine receptors, including CCR1, CCR2, CCR3, CCR5, CXCR1, and CXCR2, are also expressed by chondrocytes (29,30). The highly selective IL-8R (CXCR1) may be moderately increased in OA cartilage (29,31). Therefore, the potential exists for multiple cytokine and chemokine autocrine or paracrine loops within articular cartilage, which are stimulated during the development of arthritis.…”

Section: Discussionmentioning

confidence: 99%

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NF-κB Mediates the Stimulation of Cytokine and Chemokine Expression by Human Articular Chondrocytes in Response to Fibronectin Fragments

Pulai

Chen

et al. 2005

The Journal of Immunology

194

166

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Fibronectin fragments (FN-f) that bind to the α5β1 integrin stimulate chondrocyte-mediated cartilage destruction and could play an important role in the progression of arthritis. The objective of this study was to identify potential cytokine mediators of cartilage inflammation and destruction induced by FN-f and to investigate the mechanism of their stimulation. Human articular chondrocytes, isolated from normal ankle cartilage obtained from tissue donors, were treated with a 110-kDa FN-f in serum-free culture, and expression of various cytokine genes was analyzed by cDNA microarray and by a cytokine protein array. Compared with untreated control cultures, stimulation by FN-f resulted in a >2-fold increase in IL-6, IL-8, MCP-1, and growth-related oncogene β (GRO-β). Constitutive and FN-f-inducible expression of GRO-α and GRO-γ were also noted by RT-PCR and confirmed by immunoblotting. Previous reports of IL-1β expression induced by FN-f were also confirmed, while TNF expression was found to be very low. Inhibitor studies revealed that FN-f-induced stimulation of chondrocyte chemokine expression was dependent on NF-κB activity, but independent of IL-1 autocrine signaling. The ability of FN-f to stimulate chondrocyte expression of multiple proinflammatory cytokines and chemokines suggests that damage to the cartilage matrix is capable of inducing a proinflammatory state responsible for further progressive matrix destruction, which also includes the chemoattraction of inflammatory cells. Targeting the signaling pathways activated by FN-f may be an effective means of inhibiting production of multiple mediators of cartilage destruction.

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

NF-κB Mediates the Stimulation of Cytokine and Chemokine Expression by Human Articular Chondrocytes in Response to Fibronectin Fragments

Pulai

Chen

et al. 2005

The Journal of Immunology

194

166

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“…As far as glycosidases are concerned, while chondrocytes have been shown to release ␤-D-N-acetylglucosaminidase upon stimulation (35), recruited inflammatory cells in the joint cavity are the primary candidates to release lysosomal glycosidases. The capacity for Ca 2ϩ -regulated exocytosis of lysosomal enzymes has been shown for platelets, neutrophils, mast cells, macrophages, cytotoxic T cells, and B cells (36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

Synovial fluid exoglycosidases are predictors of rheumatoid arthritis and are effective in cartilage glycosaminoglycan depletion

Ortutay

Polgar

Gömör³

et al. 2003

Arthritis & Rheumatism

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Objective. To analyze enzymes involved in joint damage by simultaneous investigation of glycosidases and matrix metalloproteinases (MMPs) in patients with various joint diseases. In joint diseases, the major clinical symptoms and disability of patients are caused by an irreversible destruction of hyaline cartilage. Enzymes capable of degrading extracellular matrix components (collagen and aggrecan) and concomitantly exposing chondrocytes to a variety of cytotoxic and/or apoptosis-inducing factors are considered to be the major effector molecules in cartilage degradation. Methods. Activities of glycosidases (␤-DRecently, significant advances have been made in our understanding of joint destruction and the mechanism of proteolytic cleavage of cartilage. Active proteases are currently implicated in the destructive processes and include matrix metalloproteinases (MMPs), the ADAM family (1), the ADAM-TS family (2), and serine proteases (elastase, cathepsins, and granzymes) (3-5). Of the 4 groups of MMPs, collagenase (MMP-1 in particular) appears to be responsible for the degradation of interstitial collagens. The gelatinases (including MMP-2 and MMP-9) degrade the denatured form of collagens, thus acting in synergy with MMP-1. The stromelysins (including MMP-3) have a broader substrate specificity for non-connective tissue components.

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“…Significantly, the highly selective IL-8R CXCR1 and the relatively promiscuous CXC chemokine receptor CXCR2 are both expressed in situ in normal cartilage, and CXCR1 expression may moderately increase in OA cartilage (16,17).…”

mentioning

confidence: 99%

IL-8/CXCL8 and Growth-Related Oncogene α/CXCL1 Induce Chondrocyte Hypertrophic Differentiation

Merz¹,

Liu²,

Johnson³

et al. 2003

The Journal of Immunology

171

150

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Foci of chondrocyte hypertrophy that commonly develop in osteoarthritic (OA) cartilage can promote dysregulated matrix repair and pathologic calcification in OA. The closely related chemokines IL-8/CXCL8 and growth-related oncogene α (GROα)/CXCL1 and their receptors are up-regulated in OA cartilage chondrocytes. Because these chemokines regulate leukocyte activation through p38 mitogen-activated protein kinase signaling, a pathway implicated in chondrocyte hypertrophic differentiation, we tested whether IL-8 and GROα promote chondrocyte hypertrophy. We observed that normal human and bovine primary articular chondrocytes expressed both IL-8Rs (CXCR1, CXCR2). IL-8 and the selective CXCR2 ligand GROα (10 ng/ml) induced tissue inhibitor of metalloproteinase-3 expression, markers of hypertrophy (type X collagen and MMP-13 expression, alkaline phosphatase activity), as well as matrix calcification. IL-8 and the selective CXCR2 ligand GROα also induced increased transamidation activity of chondrocyte transglutaminases (TGs), enzymes up-regulated in chondrocyte hypertrophy that have the potential to modulate differentiation and calcification. Under these conditions, p38 mitogen-activated protein kinase pathway signaling mediated induction of both type X collagen and TG activity. Studies using mouse knee chondrocytes lacking one of the two known articular chondrocyte-expressed TG isoenzymes (TG2) demonstrated that TG2 was essential for murine GROα homologue KC-induced TG activity and critically mediated induction by KC of type X collagen, matrix metalloproteinase-13, alkaline phosphatase, and calcification. In conclusion, IL-8 and GROα induce articular chondrocyte hypertrophy and calcification through p38 and TG2. Our results suggest a novel linkage between inflammation and altered differentiation of articular chondrocytes. Furthermore, CXCR2 and TG2 may be sites for intervention in the pathogenesis of OA.

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Human chondrocytes express functional chemokine receptors and release matrix-degrading enzymes in response to C-X-C and C-C chemokines

Abstract: Our findings suggest the existence in human chondrocytes of a novel catabolic pathway, primed by chemokines and their receptors, that leads to the breakdown of cartilage matrix components.

Cited by 141 publications

References 28 publications

NF-κB Mediates the Stimulation of Cytokine and Chemokine Expression by Human Articular Chondrocytes in Response to Fibronectin Fragments

NF-κB Mediates the Stimulation of Cytokine and Chemokine Expression by Human Articular Chondrocytes in Response to Fibronectin Fragments

Synovial fluid exoglycosidases are predictors of rheumatoid arthritis and are effective in cartilage glycosaminoglycan depletion

IL-8/CXCL8 and Growth-Related Oncogene α/CXCL1 Induce Chondrocyte Hypertrophic Differentiation

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