IL‐1β induces COX2, MMP‐1, ‐3 and ‐13, ADAMTS‐4, IL‐1β and IL‐6 in human tendon cells

Abstract

Overuse injuries and trauma in tendon often involve acute or chronic pain and eventual matrix destruction. Anti-inflammatory drugs have been used as a treatment, however, the cellular and molecular mechanisms of the destructive processes in tendon are not clearly understood. It is thought that an inflammatory event may be involved as an initiating factor. Mediators of the inflammatory response include cytokines released from macrophages and monocytes. Interleukin-1 beta (IL-1 p) is a candidate proinflammatory cytokine that is active in connective tissues such as bone and cartilage. We hypothesized that tendon cells would express receptors and respond to IL-1 b in an initial "molecular inflammation" cascade, that is, connective tissue cell expression of cytokines that induce matrix destructive enzymes. This cascade results in expression of matrix metalloproteinases (MMPs) and aggrecanases that may lead to matrix destruction. Normal human tendon cells from six patients were isolated, grown to quiescence and treated with human recombinant IL-lP in serum-free medium for 16 h. Total RNA was isolated and mRNA expression assessed by semiquantitative RT-PCR. IL-lP (1 nM) induced mRNAs for cyclooxygenase 2 (COX2), MMP-I, -3, -13 and aggrecanase-1 as well as IL-1 j3 and IL-6, whereas mRNAs for COX1 and MMP-2 were expressed constitutively. The IL-lj3-treated tendon cells released prostaglandin E2 (PGE2) in the medium, suggesting that the inducible COX2 catalyzed this synthesis. Induction of PGE2 was detectable at 10 pM IL-1 j3. IL-10 also stimulated MMP-1 and -3 protein secretion. Induction of MMP-1 and -3 was detectable at 10 pM IL-1 fi. Post-injury or after some other inciting events, exogenous IL-1 P released upon bleeding or as leakage of local capillaries may drive a proinflammatory response at the connective tissue cell level. The resulting induction of COX2, MMP-1 and -3 may underscore a potential for nonlymphocyte-mediated cytokine production of MMPs that causes matrix destruction and a loss of tendon biomechanical properties. Endogenous IL-1 b might contribute to the process through a positive feedback loop by stimulating expression and accumulation of MMPs in the tendon matrix.

Leukotriene B4 at low dosage negates the catabolic effect of prostaglandin E2 in human patellar tendon fibroblasts

“…Our results are consistent with the previous observation that exogenous PGE 2 up-regulates MMPs in gingival fibroblasts (Sakaki et al, 2004). Other studies have reported that PGE 2 mediates IL-1β-induced MMP-1 up-regulation in tendon and gingival fibroblasts (Domeij et al, 2002;Tsuzaki et al, 2003). It is noted that tendon consists predominantly of collagen type I with a triple helical structure that resists general proteolytic degradation but is susceptible to MMPs.…”

ADAMTS-1 and -4 are up-regulated following transient middle cerebral artery occlusion in the rat and their expression is modulated by TNF in cultured astrocytes

“…IL-1β has previously been shown to increase ADAMTS expression in other systems such as a murine colon carcinoma cell line [17] and in human tendon cells [42]. The increase in cytokine expression following stroke has previously been documented by 15 others [4], [20], [27], [36].…”

Promotion of the articular cartilage proteoglycan degradation by T-2 toxin and selenium protective effect

“…Unexpectedly, however, no detectable aggrecanase-1 mRNA expression was found in chondrocytes cultured with T-2 toxin in vitro. Previous studies have shown that aggrecanase-1 usually is an up-regulated expression in the cartilage induced by IL-1 (Liacini et al, 2005;Tsuzaki et al, 2003;Pratta et al, 2003), whereas aggrecanse-2 mRNA is expressed constitutively in cartilage, and the aggrecanase activity of aggrecanase-2 was at least 1 000-fold greater than that of aggrecanase-1 (Gendron et al, 2007). Therefore, aggrecanase-2 is a major aggrecanase in cartilage metabolism and pathology.…”