ChemerinChemR23 pathway a system beyond
Knowledge of the pathophysiology of articular carti l age is crucial in understanding the mechanisms under l ying joint diseases such as osteoarthritis (OA) and rheumatoid arthritis (RA). In a previous issue of Arthritis Research and Th erapy , Berg and colleagues [1] have provided new insights in this ? eld by showing for the ? rst time that chondrocytes express chemerin and its cognate receptor, ChemR23, and that this system may be involved in cartilage degradation.
Chemerin is a secreted protein that exerts its functions by binding the G protein-coupled receptor ChemR23. It was ? rst discovered as a chemotactic peptide directing macrophages and dendritic cells expressing ChemR23 toward sites of in? ammation, being involved in both adaptive and innate immunity [2]. As often happens, regulatory proteins have pleiotropic functions. ChemR23 is also expressed by endothelial cells, where it is
up-regulated by pro-in? ammatory cytokines, and chemerin strongly induces angiogenesis in vitro by promoting endothelial cell proliferation and remodeling through stimulation of matrix metalloproteinase (MMP ) activity [3]. Interest in chemerin has grown since it was discovered in fat tissue as a novel adipokine secreted by adipocytes, which also express ChemR23. Chemerin is up-regulated in white fat cells upon IL-1β stimulation in vitro and chemerin serum levels are increased in obese patients; thus, chemerin may be the functional link between chronic in? ammation and obesity, and obesity-related disorders such as type 2 diabetes and cardio-vascular diseases [4].Th ere is evidence that chemokines may play an important role in recruiting in? ammatory cells into the joints and contribute to chronic synovitis in OA and RA [5]. Additionally, chemokines exert catabolic e? ects on cartilage. Functional chemokine receptors (CCR-1, CCR-2, CCR-3, CCR-5, CXCR-1, and CXCR-2) are detectable on human articular chondrocytes and up-regulated in OA cartilage. Th e interactions of these receptors with their ligands activate matrix degradation by inducing MMP-3 synthesis [6]. In their study, Berg and colleagues [1] explored whether chondrocytes also express ChemR23 and investigated the metabolic e? ects of chemerin stimulation on chondrocytes. A series of experiments was performed on human native cartilage or cultured chondrocytes isolated from joints of patients undergoing knee arthroplasty for severe OA, and patients subjected to autologous chondrocyte transplantation. Cartilage from young subjects undergoing reconstruction of anterior cruciate ligament was taken as normal control. ChemR23 and prochemerin transcripts were detected in chondrocyte cultures by reverse transcriptase P CR. Furthermore, ChemR23 and chemerin proteins were detected in chondrocytes in vitro by immunocyto c hemis t ry. Th ese ? ndings were con? rmed by immunohistochemistry in cartilage biopsies, in which resident chondrocytes showed positive staining for both ChemR23 and chemerin. Th e e? ects of challenging isolated chondro-cytes with recombinant chemerin in vitro were also investigated. Chemerin binding to ChemR23 led to
Abstract
Chemerin is a chemokine that, through the
engagement of its counter-receptor, ChemR23, attracts pro-infl ammatory cells. However, chemerin has been shown to play other functions and a recent study by Berg and colleagues demonstrates that chemerin/ChemR23 is a system beyond chemokines. Human articular chondrocytes produce chemerin and express ChemR23, and upon stimulation with recombinant chemerin increase the production of pro-catabolic cytokines and metalloproteinases. The latter are up-regulated in osteoarthritic cartilage and cause extracellular matrix breakdown. Since an increase of chemerin in fat tissue and serum of obese patients has been reported, this new feature of chemerin may represent a functional link between obesity and osteoarthritis.
Chemerin/ChemR23 pathway: a system beyond chemokines
Florenzo Iannone* and Giovanni Lapadula
See related research by Berg et al ., https://www.docsj.com/doc/d310520434.html,/content/12/6/R228
E D I TOR I AL
*Correspondence: f.iannone@reumbari.uniba.it
DiMIMP-Rheumatology Unit, School of Medicine, University of Bari, 70124 Bari, Italy
Iannone and Lapadula Arthritis Research & Therapy 2011, 13:104 https://www.docsj.com/doc/d310520434.html,/content/13/2/104
? 2011 BioMed Central Ltd
increased phosphorylation of p44/42 mitogen-activated protein kinases (MAP Ks) and Akt and blocking of MEK-1/2 signaling prevented phosphorylation of p44/42 MAP Ks but not of Akt. Th is suggests that intracellular downstream events upon chemerin stimulation occur through the Akt/MEK/MAP K pathway. Th e most out-standing ? nding of this study was the demonstration that chemerin regulates the production of pro-in? ammatory cytokines and MMP s by human chondrocytes in vitro. IL-1β, TNF-α, IL-6, and IL-8 as well as MMP-13 and others MMP s were signi? cantly increased in the super-natants of chondrocyte cultures stimulated with recom-bi n ant chemerin. It is noteworthy that OA chondrocytes secreted larger amounts of cytokines than chondrocytes from healthy subjects. MMP s play a key role in the remodeling of cartilage matrix and their increase is crucial in the induction of cartilage damage in OA and RA. In OA, MMP-13 has been shown to be the most important collagenase and, together with ADAMTS-5 (a disintegrin and metalloproteinase with thrombospondin motifs-5), causes the breakdown of the collagen and aggre c an framework of the extracellular matrix and initiates the destruction of cartilage [7]. Consistent with this study, chemerin production by chondrocytes has also been reported by Conde and colleagues [8]. Th ey have shown that chondrocytes synthesize chemerin and its expression is increased by IL-1β stimulation. Further-more, dexametasone increased the e?ect of IL-1β on mRNA expression of chemerin by chondrocytes suggest-ing that intra-articular injections of steroids as treatment of OA may damage the articular cartilage.
All together, these data strongly suggest that the chemerin/ChemR23 system is involved in cartilage damage in OA, and further studies will unravel its speci? c role. However, chemerin might not be one of the many redundant mediators that activate chondrocyte catabolic pathways, but may be a crucial link between obesity and OA. For years obesity has been regarded as a risk factor for developing OA in weight-bearing joints, but a growing body of evidence is showing that obesity is a mild in? ammatory disease and that a pro-in? ammatory network links fat tissue to obesity-related disease, including OA [9]. Chemerin is produced by adipocytes as well as chondrocytes and is up-regulated in both obesity and OA, and might be a promising ? eld of research to better understand and treat these two functionally associated diseases.
Abbreviations
IL, interleukin; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; OA, osteoarthritis; RA, rheumatoid arthritis; TNF, tumor necrosis factor.
Competing interests
The authors declare that they have no competing interests
Published: 6 April 2011
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Cite this article as: Iannone F, Lapadula G: Chemerin/ChemR23 pathway:
a system beyond chemokines. Arthritis Research & Therapy 2011, 13:104.
Iannone and Lapadula Arthritis Research & Therapy 2011, 13:104
https://www.docsj.com/doc/d310520434.html,/content/13/2/104
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