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

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-1beta) 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-1beta 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-1beta in serum-free medium for 16 h. Total RNA was isolated and mRNA expression assessed by semi-quantitative RT-PCR. IL-1beta (I nM) induced mRNAs for cyclooxygenase 2 (COX2), MMP-1, -3, -13 and aggrecanase-1 as well as IL-1beta and IL-6, whereas mRNAs for COX1 and MMP-2 were expressed constitutively. The IL-1beta-treated tendon cells released prostaglandin E-2 (PGE(2)) in the medium, suggesting that the inducible COX2 catalyzed this synthesis. Induction of PGE2 was detectable at 10 pM IL-1beta. IL-1beta also stimulated MMP-1 and -3 protein secretion. Induction of MMP-1 and -3 was detectable at 10 pM IL-1beta. Post-injury or after some other inciting events, exogenous IL-1beta 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-1beta might contribute to the process through a positive feedback loop by stimulating expression and accumulation of MMPs in the tendon matrix. (C) 2003 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.