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.
Tendon cells receive mechanical signals from the load bearing matrices. The response to mechanical stimulation is crucial for tendon function. However, overloading tendon cells may deteriorate extracellular matrix integrity by activating intrinsic factors such as matrix metalloproteinases (MMPs) that trigger matrix destruction. We hypothesized that mechanical loading might induce interleukin-1beta (IL-1beta) in tendon cells, which can induce MMPs, and that extracellular ATP might inhibit the load-inducible gene expression. Human tendon cells isolated from flexor digitorum profundus tendons (FDPs) of four patients were made quiescent and treated with ATP (10 or 100 microM) for 5 min, then stretched equibiaxially (1 Hz, 3.5% elongation) for 2 h followed by an 18-h-rest period. Stretching induced IL-1beta, cyclooxygenase 2 (COX 2), and MMP-3 genes but not MMP-1. ATP reduced the load-inducible gene expression but had no effect alone. A medium change caused tendon cells to secrete ATP into the medium, as did exogenous UTP. The data demonstrate that mechanical loading induces ATP release in tendon cells and stimulates expression of IL-1beta, COX 2, and MMP-3. Load-induced endogenous IL-1beta may trigger matrix remodeling or a more destructive pathway(s) involving IL-1beta, COX 2, and MMP-3. Concomitant autocrine and paracrine release of ATP may serve as a negative feedback mechanism to limit activation of such an injurious pathway. Attenuation or failure of this negative feedback mechanism may result in the progression to tendinosis.
Flexor tendon sheath infections of the hand must be diagnosed and treated expeditiously to avoid poor clinical outcomes. Knowledge of the sheath's anatomy is essential for diagnosis and to help to guide treatment. The Kanavel cardinal signs are useful for differentiating conditions with similar presentations. Management of all but the earliest cases of pyogenic flexor tenosynovitis consists of intravenous antibiotics and surgical drainage of the sheath with open or closed irrigation. Closed irrigation may be continued postoperatively. Experimental data from an animal study have shown that local administration of antibiotics and/or corticosteroids can help lessen morbidity from the infection; however, additional research is required. Despite aggressive and prompt antibiotic therapy and surgical intervention, even otherwise healthy patients can expect some residual digital stiffness following flexor tendon sheath infection. Patients with medical comorbidities or those who present late with advanced infection can expect poorer outcomes, including severe digital stiffness or amputation.
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