title: IL-8/CXCL8 and growth-related oncogene alpha/CXCL1 induce chondrocyte hypertrophic differentiation.
abstract: 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 alpha (GROalpha)/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 GROalpha 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 GROalpha (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 GROalpha 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 GROalpha 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 GROalpha 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.
authors.affiliation: Veterans Affairs Medical Center, University of California at San Diego, La Jolla 92161, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Merz
authors.forename: Ru
authors.initials: R
authors.lastname: Liu
authors.forename: Kristen
authors.initials: K
authors.lastname: Johnson
authors.forename: Robert
authors.initials: R
authors.lastname: Terkeltaub
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D002417:Cattle; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D054360:Chemokine CXCL1; D018925:Chemokines / Q000502:physiology*; D019743:Chemokines, CXC / Q000378:metabolism* / Q000502:physiology*; D002630:Chemotactic Factors / Q000502:physiology*; D019902:Chondrocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D016207:Cytokines / Q000502:physiology; D019204:GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D006801:Humans; D006984:Hypertrophy; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D016209:Interleukin-8 / Q000378:metabolism / Q000502:physiology*; D008024:Ligands; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C475896:CXCL1 protein, Bos taurus; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D018925:Chemokines; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C475895:Cxcl1 protein, mouse; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D016209:Interleukin-8; D008024:Ligands; C074302:keratinocyte-derived chemokines; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins