The extracellular matrix (ECM), and especially the connective tissue with its collagen, links tissues of the body together and plays an important role in the force transmission and tissue structure maintenance especially in tendons, ligaments, bone, and muscle. The ECM turnover is influenced by physical activity, and both collagen synthesis and degrading metalloprotease enzymes increase with mechanical loading. Both transcription and posttranslational modifications, as well as local and systemic release of growth factors, are enhanced following exercise. For tendons, metabolic activity, circulatory responses, and collagen turnover are demonstrated to be more pronounced in humans than hitherto thought. Conversely, inactivity markedly decreases collagen turnover in both tendon and muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as, dependent on the type of collagen in question, some degree of net collagen synthesis. These changes will modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress, and likely make it more load resistant. Cross-linking in connective tissue involves an intimate, enzymatical interplay between collagen synthesis and ECM proteoglycan components during growth and maturation and influences the collagen-derived functional properties of the tissue. With aging, glycation contributes to additional cross-linking which modifies tissue stiffness. Physiological signaling pathways from mechanical loading to changes in ECM most likely involve feedback signaling that results in rapid alterations in the mechanical properties of the ECM. In developing skeletal muscle, an important interplay between muscle cells and the ECM is present, and some evidence from adult human muscle suggests common signaling pathways to stimulate contractile and ECM components. Unaccostumed overloading responses suggest an important role of ECM in the adaptation of myofibrillar structures in adult muscle. Development of overuse injury in tendons involve morphological and biochemical changes including altered collagen typing and fibril size, hypervascularization zones, accumulation of nociceptive substances, and impaired collagen degradation activity. Counteracting these phenomena requires adjusted loading rather than absence of loading in the form of immobilization. Full understanding of these physiological processes will provide the physiological basis for understanding of tissue overloading and injury seen in both tendons and muscle with repetitive work and leisure time physical activity.

Role of Extracellular Matrix in Adaptation of Tendon and Skeletal Muscle to Mechanical Loading

OBJECTIVE: To describe the functional anatomy of the ankle complex as it relates to lateral ankle instability and to describe the pathomechanics and pathophysiology of acute lateral ankle sprains and chronic ankle instability. DATA SOURCES: I searched MEDLINE (1985-2001) and CINAHL (1982-2001) using the key words ankle sprain and ankle instability. DATA SYNTHESIS: Lateral ankle sprains are among the most common injuries incurred during sports participation. The ankle functions as a complex with contributions from the talocrural, subtalar, and inferior tibiofibular joints. Each of these joints must be considered in the pathomechanics and pathophysiology of lateral ankle sprains and chronic ankle instability. Lateral ankle sprains typically occur when the rearfoot undergoes excessive supination on an externally rotated lower leg. Recurrent ankle sprain is extremely common; in fact, the most common predisposition to suffering a sprain is the history of having suffered a previous ankle sprain. Chronic ankle instability may be due to mechanical instability, functional instability, or most likely, a combination of these 2 phenomena. Mechanical instability may be due to specific insufficiencies such as pathologic laxity, arthrokinematic changes, synovial irritation, or degenerative changes. Functional instability is caused by insufficiencies in proprioception and neuromuscular control. CONCLUSIONS/RECOMMENDATIONS: Lateral ankle sprains are often inadequately treated, resulting in frequent recurrence of ankle sprains. Appreciation of the complex anatomy and mechanics of the ankle joint and the pathomechanics and pathophysiology related to acute and chronic ankle instability is integral to the process of effectively evaluating and treating ankle injuries.

Functional Anatomy, Pathomechanics, and Pathophysiology of Lateral Ankle Instability.

The repair of injured tendons remains a great challenge, largely owing to a lack of in-depth characterization of tendon cells and their precursors. We show that human and mouse tendons harbor a unique cell population, termed tendon stem/progenitor cells (TSPCs), that has universal stem cell characteristics such as clonogenicity, multipotency and self-renewal capacity. The isolated TSPCs could regenerate tendon-like tissues after extended expansion in vitro and transplantation in vivo. Moreover, we show that TSPCs reside within a unique niche predominantly comprised of an extracellular matrix, and we identify biglycan (Bgn) and fibromodulin (Fmod) as two critical components that organize this niche. Depletion of Bgn and Fmod affects the differentiation of TSPCs by modulating bone morphogenetic protein signaling and impairs tendon formation in vivo. Our results, while offering new insights into the biology of tendon cells, may assist in future strategies to treat tendon diseases.

Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche

Tendon disorders are frequent and are responsible for substantial morbidity both in sports and in the workplace. Tendinopathy, as opposed to tendinitis or tendinosis, is the best generic descriptive term for the clinical conditions in and around tendons arising from overuse. Tendinopathy is a difficult problem requiring lengthy management, and patients often respond poorly to treatment. Preexisting degeneration has been implicated as a risk factor for acute tendon rupture. Several physical modalities have been developed to treat tendinopathy. There is limited and mixed high-level evidence to support the, albeit common, clinical use of these modalities. Further research and scientific evaluation are required before biological solutions become realistic options.

http://health120years.com/cn/pdf/hd_tendonopathy_tendinosis_healing_repair.pdf

Tendon injury and tendinopathy: healing and repair.

The biochemical and biophysical properties of the extracellular matrix (ECM) dictate tissue-specific cell behaviour. The molecules that are associated with the ECM of each tissue, including collagens, proteoglycans, laminins and fibronectin, and the manner in which they are assembled determine the structure and the organization of the resultant ECM. The product is a specific ECM signature that is comprised of unique compositional and topographical features that both reflect and facilitate the functional requirements of the tissue.

/pdf/extracellular-matrix-assembly-a-multiscale-deconstruction-3ucggnbaz1.pdf

Extracellular matrix assembly: a multiscale deconstruction

Tendons consist of collagen (mostly type I collagen) and elastin embedded in a proteoglycan-water matrix with collagen accounting for 65-80% and elastin approximately 1-2% of the dry mass of the tendon. These elements are produced by tenoblasts and tenocytes, which are the elongated fibroblasts and fibrocytes that lie between the collagen fibers, and are organized in a complex hierarchical scheme to form the tendon proper. Soluble tropocollagen molecules form cross-links to create insoluble collagen molecules which then aggregate progressively into microfibrils and then into electronmicroscopically clearly visible units, the collagen fibrils. A bunch of collagen fibrils forms a collagen fiber, which is the basic unit of a tendon. A fine sheath of connective tissue called endotenon invests each collagen fiber and binds fibers together. A bunch of collagen fibers forms a primary fiber bundle, and a group of primary fiber bundles forms a secondary fiber bundle. A group of secondary fiber bundles, in turn, forms a tertiary bundle, and the tertiary bundles make up the tendon. The entire tendon is surrounded by a fine connective tissue sheath called epitenon. The three-dimensional ultrastructure of tendon fibers and fiber bundles is complex. Within one collagen fiber, the fibrils are oriented not only longitudinally but also transversely and horizontally. The longitudinal fibers do not run only parallel but also cross each other, forming spirals. Some of the individual fibrils and fibril groups form spiral-type plaits. The basic function of the tendon is to transmit the force created by the muscle to the bone, and, in this way, make joint movement possible. The complex macro- and microstructure of tendons and tendon fibers make this possible. During various phases of movements, the tendons are exposed not only to longitudinal but also to transversal and rotational forces. In addition, they must be prepared to withstand direct contusions and pressures. The above-described three-dimensional internal structure of the fibers forms a buffer medium against forces of various directions, thus preventing damage and disconnection of the fibers.

Structure of the tendon connective tissue

Treatment for acute tears of the lateral ligaments of the ankle. Operation, cast, or early controlled mobilization.

Background: The purpose of this investigation was to evaluate replacement of a torn anterior cruciate ligament with either a bone-patellar tendon-bone autograft or a two-strand semitendinosus-gracilis autograft to compare the results of clinical testing, patient satisfaction, activity level, functional status, and muscle strength.

Methods: Fifty-six patients with a torn anterior cruciate ligament were enrolled in a prospective, randomized, controlled study. Twenty-eight underwent reconstruction with a bone-patellar tendon-bone autograft, and twenty-eight were treated with a two-strand semitendinosus-gracilis autograft. Patients were followed for an average of thirty-nine months (range, thirty-six to fifty-seven months). At the time of final follow-up, twenty-two patients in each group were evaluated in terms of clinical test findings, patient satisfaction, activity level, functional status, and isokinetic muscle strength.

Results: The objective outcome of replacement of the torn anterior cruciate ligament with a bone-patellar tendon-bone graft was superior to that obtained with a two-strand semitendinosus-gracilis graft. At the three-year follow-up interval, the patients in whom a hamstring graft had been used had an average of 4.4 mm of increased anterior knee laxity compared with the laxity of the contralateral, normal knee, whereas the patients in whom a bone-patellar tendon-bone graft had been used had an average of 1.1 mm of increased knee laxity. Fourteen percent (three) of the twenty-two patients with a hamstring graft had a mild pivot shift, and 27% (six) had a moderate pivot shift. Only 14% (three) of the twenty-two patients with a bone-patellar tendon-bone graft had a mild pivot shift, and none had a moderate pivot shift. At the same follow-up interval, the patients in whom a hamstring graft had been used had significantly lower peak knee-flexion strength than those who had a bone-patellar tendon-bone graft (p = 0.039). In contrast, the two treatments produced similar outcomes in terms of patient satisfaction, activity level, and knee function (ability to perform a one-legged hop, bear weight, squat, climb stairs, run in place, and duckwalk).

Conclusions: After three years of follow-up, the objective results of anterior cruciate ligament replacement with a bone-patellar tendon-bone autograft were superior to those of replacement with a two-strand semitendinosus-gracilis graft with regard to knee laxity, pivot-shift grade, and strength of the knee flexor muscles. However, the two groups had comparable results in terms of patient satisfaction, activity level, and knee function.

Anterior cruciate ligament replacement: comparison of bone-patellar tendon-bone grafts with two-strand hamstring grafts. A prospective, randomized study.

The Achilles tendon is the strongest tendon in the human body. Because most Achilles tendon injuries take place in sports and there has been an common upsurge in sporting activities, the number and incidence of the Achilles tendon overuse injuries and complete ruptures have increased in the industrialized countries during the last decades. The most common clinical diagnosis of Achilles overuse injuries is tendinopathy, which is characterized by a combination of pain and swelling in the Achilles tendon accompanied by impaired ability to perform strenuous activities. Most patients with Achilles tendon injury respond favorably to conservative treatment and only those who fail to respond to carefully followed nonoperative treatment should undergo surgery for repair. A complete rupture of the Achilles tendon usually occurs in sports that require jumping, running, and quick turns. Although histopathologic studies have shown that ruptured Achilles tendons include clear degenerative changes before the rupture, many of the Achilles tendon ruptures occur suddenly without any preceding signs or symptoms. Neither conservative nor operative treatment is a treatment of choice for the ruptured Achilles tendon. It is generally accepted that surgery should be performed on ruptured Achilles tendons in young, physically active patients and in those patients for whom the diagnosis or the treatment of the rupture has been delayed, whereas the results of conservative treatment are an acceptable outcome in older patients with sedentary lifestyles. Many important issues still remain unanswered concerning the cause, pathogenesis, diagnosis, and management of the Achilles tendon disorders. Only when these issues have been solved by well-controlled studies can tailored treatment protocols be created.

Achilles tendon injuries.

A spontaneous rupture of a tendon may be defined as a rupture that occurs during movement and activity, that should not and usually does not damage the involved musculotendinous units (1). Spontaneous tendon ruptures were uncommon before the 1950s. Bohler found only 25 Achilles tendon ruptures in Wien between 1925 and 1948 (2). Mosender & Klatnek treated 20 Achilles tendon ruptures between 1953 and 1956, but 105 ruptures between 1964 and 1967 (3). Lawrence et al. found only 31 Achilles tendon ruptures in Boston during a period of 55 years (1900-1954) (4). During the recent decades tendon ruptures have, however, become relatively common in developed countries, especially in Europe and North America. A high incidence of tendon ruptures has been reported in Austria, Denmark, Finland, Germany. Hungary, Sweden, Switzerland and the USA; somewhat lower incidences have been reported in Canada, France, Great Britain and Spain. On the other hand, Greece, Japan, the Netherlands and Portugal have reported a clearly lower incidence. Interestingly, Achilles tendon ruptures are a rarity in developing countries, especially in Africa and East-Asia (5). In many developed countries, the increases in the rupture incidence have been dramatic. In the National Institute of Traumatology in Budapest, Hungary, the number of patients with an Achilles tendon rupture increased 285% in men and 500% in women between two successive 7-year periods, 1972-1978 and 1979-1985 (5).

P. Kannus

Papers

Structure of the tendon connective tissue

Treatment for acute tears of the lateral ligaments of the ankle. Operation, cast, or early controlled mobilization.

Anterior cruciate ligament replacement: comparison of bone-patellar tendon-bone grafts with two-strand hamstring grafts. A prospective, randomized study.

Achilles tendon injuries.

Histopathological findings in spontaneous tendon ruptures