Louis C. Almekinders

Types and epidemiology of tendinopathy

During the last few decades, the role of sports and physical activity has become more and more important in all modern communities. The risk of tendon injury has thus increased, and prevention has become important. Epidemiologic studies are important when planning prevention programs for tendon injuries. Because of individual sport cultures and different sport habits in different countries, national epidemiologic studies are of importance in each individual country.

Etiology, diagnosis, and treatment of tendonitis : an analysis of the literature

Tendonitis is a common diagnosis in sports medicine. The traditional view of tendonitis is a tendon injury resulting from repetitive mechanical load with a subsequent inflammatory response. The English literature from 1966 to the present on the etiology, diagnosis, and treatment of tendonitis was evaluated. There is some scientific support in the literature for the diagnosis of tenosynovitis and tendinosis as a pathologic entity. Actual inflammation of tendon tissue consistent with tendonitis has not been seen clearly in patho-anatomic studies. Conclusive evidence confirming that repetitive mechanical load is a major etiologic factor could not be found. Similarly, strength deficits, inflexibility, and improper equipment have not been studied in a controlled prospective manner. Other factors such as age and tendon vascularity have been consistently correlated with these injuries although their overall importance remains difficult to assess. There are no controlled studies on treatment through physical therapy aimed at flexibility and/or strengthening. Treatment with anti-inflammatory drugs has been studied extensively. However, only nine of 32 studies are prospective and placebo controlled. Some pain relief was found in five of the nine controlled studies, but healing of the tendon problem was not studied in these short follow-up studies. Twenty-three studies on steroid injections were found. Eight were prospective and placebo controlled studies, with three showing beneficial effects of the injection at follow-up. It was concluded that much of the pathology and etiology of tendonitis remains unclear. The possibility must be considered that current treatment methods may not significantly affect the natural history.

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‐1β) 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‐1β 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‐1β in serum‐free medium for 16 h. Total RNA was isolated and mRNA expression assessed by semi‐quantitative RT‐PCR. IL‐1β (1 nM) induced mRNAs for cyclooxygenase 2 (COX2), MMP‐1, ‐3, ‐13 and aggrecanase‐1 as well as IL‐1β and IL‐6, whereas mRNAs for COX1 and MMP‐2 were expressed constitutively. The IL‐1β‐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‐1β. IL‐1β also stimulated MMP‐1 and ‐3 protein secretion. Induction of MMP‐1 and ‐3 was detectable at 10 pM IL‐1β. Post‐injury or after some other inciting events, exogenous IL‐1β 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‐1β might contribute to the process through a positive feedback loop by stimulating expression and accumulation of MMPs in the tendon matrix.

PDGF-BB, IGF-I and mechanical load stimulate DNA synthesis in avian tendon fibroblasts in vitro

Resident cells in the surface epitenon and internal compartment of flexor tendons are subjected to cyclic mechanical load as muscle contracts to move limbs or digits. Tendons are largely tensile load bearing tissues and are highly matrix intensive with nondividing cells providing maintenance functions. However, when an injury occurs, tendon cells are stimulated to divide by activated endogenous growth factors and those from platelets and plasma. We hypothesize that tendon cells detect mechanical load signals but do not interpret such signals as mitogenic unless an active growth factor is present. We have used an in vitro mechanical load model, application of cyclic strain to cells cultured on flexible bottomed culture plates, to test the hypothesis that tendon cells require platelet-derived growth factor (PDGF-BB) and insulin-like growth factor-I (IGF-I) in addition to mechanical load to stimulate DNA synthesis. In addition, we demonstrate that in avian tendon cells, load and growth factors stimulate phosphorylation of tyrosine residues in multiple proteins, including pp60src, a protein kinase that phosphorylates receptor protein tyrosine kinases. A lack of mitogenic responsiveness to mechanical load alone by tendon cells may be a characteristic of a regulatory pathway that modulates cell division.

Anti-Inflammatory Treatment of Muscular Injuries in Sports

AbstractStretch-induced muscle injuries or strains, muscle contusions and delayed onset muscle soreness (DOMS) are common muscle problems in athletes. Anti-inflammatory treatment is often used for the pain and disability associated with these injuries. The most recent studies on nonsteroidal anti-inflammatory drugs (NSAIDs) in strains and contusions suggest that the use of NSAIDs can result in a modest inhibition of the initial inflammatory response and its symptoms. However, this may be associated with some small negative effects later in the healing phase. Corticosteroids have generally been shown to adversely affect the healing of these acute injuries. Animal studies have suggested that anabolic steroids may actually aid in the healing process, but clinical studies are not yet available and the exact role of these drugs has yet to be determined. Studies on anti-inflammatory treatment of DOMS have yielded conflicting results. However, the effect of NSAIDs on DOMS appears small at best. Future research may have to focus on different aspects of these injuries as the emphasis on anti-inflammatory treatment has yielded somewhat disappointing results.

An In Vitro Investigation Into the Effects of Repetitive Motion and Nonsteroidal Antiinflammatory Medication on Human Tendon Fibroblasts

Soft tissue injuries due to repetitive motion are common sports injuries and are often treated with antiinflamma tory therapies. We investigated the in vitro effects of repetitive motion and nonsteroidal antiinflammatory medication on human tendon fibroblasts. In addition, we studied the effects related to the presence of inflam matory cells. Repetitive motion was associated with an increased release of prostaglandin E2 and increased deoxyribonucleic acid (DNA) and protein synthesis. The presence of nonsteroidal antiinflammatory medication decreased prostaglandin E2 release and DNA synthe sis but increased protein synthesis. Contact with mac rophages caused a marked additional increase in pros taglandin E2 and a concomitant increase in DNA synthesis. Release of interleukin-6 by the macrophages also suggested that this cytokine plays a role in the re sponse to repetitive motion. Our results can aid in the search for a more scientific approach to the treatment of soft tissue injuries associated with repetitive motion. They suggest that nonsteroidal antiinflammatory medi cation may have potentially negative effects during the proliferative phase of a healing since it was associated with decreased DNA synthesis. However, it may be beneficial in the maturation and remodeling phase since it stimulated protein synthesis.

Effects of repetitive motion on human fibroblasts

Repetitive motion injuries such as tendonitis are common sports injuries. However, few scientific studies are available on the effects of repetitive motion on mesenchymal cells and the presumed inflammatory response. This study used a new in vitro model to study the effects of repetitive motion. Human tendon fibroblasts were subcultured and plated on culture wells with flexible bottoms. The cells were repetitively stretched using a micro-processor-controlled pressure unit that causes a cyclic deformation of the flexible bottom. The wells were divided in the following groups: group I controls without repetitive motion, group IIA repetitive motion with 0.25 strain at 0.17 Hz (10 cycles.min-1), group IIB repetitive motion with 0.25 strain and 0.17 Hz in presence of 25 microM indomethacin, and group III repetitive motion with 0.25 strain at 1 Hz (60 cycles.min-1). After 3 h of stimulation the supernatant fluids were harvested and evaluated for prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and lactate dehydrogenase (LDH). The results showed significantly (P < 0.001) increased levels of PGE2 in groups IIA (46.9 +/- 4.7 pg.0.1 ml-1) and III (65.7 +/- 8.0 pg.0.1 ml-1). This represents a 1.3- and 1.8-fold increase, respectively, compared with the control group I (36.4 +/- 5.9 pg.0.1 ml-1). LTB4 was significantly (P < 0.001) elevated in the indomethacin-treated group IIB (45.0 +/- 11.0 pg.0.1 ml-1) compared with very low levels in all other groups. LDH was not significantly different in any of the experimental groups compared with the control group I. The results indicate that repetitive motion induces production of PGE2.(ABSTRACT TRUNCATED AT 250 WORDS)

Healing of experimental muscle strains and the effects of nonsteroidal antiinflammatory medication

The healing process of muscle strains and the effect of nonsteroidal antiinflammatory medication were studied using an experimental animal model. A standardized strain of the tibialis anterior muscle in adult male rats was produced by a controlled stretch of the muscle. Groups I and II underwent a unilateral strain of the tibialis anterior muscle and were immobilized in the postinjury period. The rats in Group II were fed piroxi cam in the postinjury period. Group III underwent a sham procedure and were also immobilized. At 0, 2, 4, and 11 days postinjury both injured and contralateral control muscles were evaluated by determining tensile strength characteristics and histologic appearance. Group I showed a significant drop in maximum failure load to 25.7% of the control leg at Day 2 with a gradual return to the level of Group III at Days 4 and 11 (40.9% and 50.1 %). Group II showed a similar drop but was still stronger than Group I at 2 days with 40.8% of the control leg and continued to drop until 4 days postinjury (33.7%). Histology showed a delay in inflammatory reaction and muscle regeneration in Group II. At 11 days both Groups I and II showed regenerated muscle fibers bridging the entire defect and an increase in endomyseal fibrosis. It is concluded that muscle strains continue to weaken in the early postinjury period. Non steroidal antiinflammatory medication, such as piroxi cam, might delay muscle regeneration.

Biomechanics and pathophysiology of overuse tendon injuries: ideas on insertional tendinopathy

Tendons behave viscoelastically and exhibit adaptive responses to conditions of increased loading and disuse. High-resolution, real-time ultrasound scanning confirms the applicability of these findings in human tendons in vivo. In addition, recent biomechanical studies indicate that strain patterns in tendons may not be uniform, as tendons show stress-shielded areas and areas subjected to compressive loading at the enthesis. These areas correspond to the sites where tendinopathic characteristics are typically seen. This indicates that some tendinopathies may, paradoxically, be considered as ‘underuse’ lesions despite the common beliefs that they are overuse injuries. Classic inflammatory changes are not frequently seen in chronic athletic tendon conditions and histopathology features in tendinopathic tendons are clearly different from normal tendons, showing an exaggerated dysfunctional repair response. Tendinopathies are traditionally considered overuse injuries, involving excessive tensile loading and subsequent breakdown of the loaded tendon. Biomechanical studies show that the strains within the tendons near their insertion site are not uniform. If the material properties are similar throughout the tendon, forces transferred through the insertion site preferentially load the side of the tendon that is usually not affected initially in tendinopathy. In that case, the side affected by tendinopathy is generally ‘stress shielded’. Thus, the presence of differential strains opens the possibility of alternative biomechanical explanations for the pathology found in these regions of the tendon. The traditional concept of tensile failure may not be the essential feature of the pathomechanics of insertional tendinopathy. Certain joint positions are more likely to stress the area of the tendon commonly affected by tendinopathy. Incorporating different joint position exercises may exert more controlled stresses on these affected areas of the tendon, possibly allowing better maintenance of the mechanical strength of that tendon region and, therefore, prevent injury. Such exercises could stress a healing area of the tendon in a controlled manner and thus stimulate healing once an injury has occurred. Additional work is needed to prove whether such principles should be incorporated in current rehabilitation techniques.

ATP modulates load-inducible IL-1β, COX 2, and MMP-3 gene expression in human tendon cells

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‐1β) 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 μM) for 5 min, then stretched equibiaxially (1 Hz, 3.5% elongation) for 2 h followed by an 18‐h‐rest period. Stretching induced IL‐1β, 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‐1β, COX 2, and MMP‐3. Load‐induced endogenous IL‐1β may trigger matrix remodeling or a more destructive pathway(s) involving IL‐1β, 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.