IL-8/CXCL8 and Growth-Related Oncogene α/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 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.

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

“…IL-8 and ENA-78 are potent inducers of angiogenesis (32), which is a marked feature in our arthritis model (9,10). IL-8 also contributes to the pathologic changes observed in arthritis through p38 MAPK pathway activation (33), which can lead to hypertrophic differentiation, alteration in collagen subtype expression, and cartilage calcification. PBEF was also up-regulated, and this cytokine perpetuates inflammation since it stimulates IL-6 and IL-8 expression (34).…”

Mediation of spontaneous knee osteoarthritis by progressive chondrocyte ATP depletion in Hartley guinea pigs

“…The rise in TG activity in guinea pig OA chondrocytes holds further significance because of the major role of TG activity in promoting both cytokine-induced matrix calcification and chondrocyte hypertrophic differentiation, which results in a dysregulated matrix-reparative response in OA (48,49).…”

Osteoarthritis synovial fluid activates pro-inflammatory cytokines in primary human chondrocytes

“…Merz et al showed that IL-8 expression is associated with chondrocyte hypertrophy in OA, which possibly promotes nonphysiological calcification and matrix repair processes [23]. Matsukawa et al was able to show that IL-8 induces destruction of cartilage [24].…”