Specialisation of extracellular matrix for function in tendons and ligaments (original) (raw)
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Tendon Functional Extracellular Matrix
Journal of Orthopaedic Research, 2015
The article summarising the views expressed during the functional extracellular matrix breakout sessions. All authors; Screen, Birk, Kadler, Ramirez and Young were all involved in managing the breakout sessions, and producing this manuscript based on those discussions. All authors have read and approved the final submitted manuscript.
Tendon is a dense connective tissue that connects muscle to bone. Tendon can adapt to mechanical forces passing across it, through a reciprocal relationship between its cellular components (tenocytes and tenoblasts) and the extracellular matrix (ECM). In early development, the formation of scleraxis-expressing tendon progenitor population in the sclerotome is induced by a fibroblast growth factor signal secreted by the myotome. Tendon injury has been defined as a loss of cells or ECM caused by trauma. It represents a failure of cells and matrix adaptation to mechanical loading. Injury initiates attempts of tendon to repair itself, which has been defined as replacement of damaged or lost cells and ECM by new cells or new matrices. Tendon healing generally consists of four different phases: the inflammatory, proliferation, differentiation and remodelling phases. Clinically, tendons are repaired with a variety of surgical techniques, which show various degrees of success. In order to improve the conventional tendon repair methods, current tendon tissue engineering aims to investigate a repair method which can restore tissue defects with living cells, or cell based therapy. Advances in tissue engineering techniques would potentially yield to a cell-based product that could regenerate functional tendon tissue.
Molecular interactions in extracellular matrix of tendon
Frontiers in Bioscience, 2010
Tendon is a poorly vascularized and highly specialized connective tissue containing few scattered cells that play an important role in the musculoskeletal apparatus by resisting mechanical stress. Because of the slow rate of the metabolism of its molecular components, the tendon gradually loses its mechanical properties and may rupture upon an array of physical activities. In this report, we discuss the molecular changes involved in the extracelluar matrix-tendon interactions leading to tissue degeneration and rupture.
Tendon development and musculoskeletal assembly: emerging roles for the extracellular matrix
Development (Cambridge, England), 2015
Tendons and ligaments are extracellular matrix (ECM)-rich structures that interconnect muscles and bones. Recent work has shown how tendon fibroblasts (tenocytes) interact with muscles via the ECM to establish connectivity and strengthen attachments under tension. Similarly, ECM-dependent interactions between tenocytes and cartilage/bone ensure that tendon-bone attachments form with the appropriate strength for the force required. Recent studies have also established a close lineal relationship between tenocytes and skeletal progenitors, highlighting the fact that defects in signals modulated by the ECM can alter the balance between these fates, as occurs in calcifying tendinopathies associated with aging. The dynamic fine-tuning of tendon ECM composition and assembly thus gives rise to the remarkable characteristics of this unique tissue type. Here, we provide an overview of the functions of the ECM in tendon formation and maturation that attempts to integrate findings from develop...
Changes in tendon extracellular matrix composition with age
International Journal of Experimental Pathology, 2009
and Wiley publishing. There were 132 delegates registered for the meeting, comprising 79 members of the society (including 15 graduate students) and 53 nonmembers (including 16 graduate students). There were 17 invited speakers, with three from the USA, five from the EU and five from the UK. Jean Schwarzbauer (Princeton University, USA) opened the meeting by describing her recent findings concerning the events that control fibronectin (Fn) matrix assembly. The assembly of Fn matrix fibrils is influenced by extracellular factors such as availability of Fn and other matrix molecules, and intracellular signalling pathways mediated by integrin receptors. Jean's group has investigated two kinases downstream of integrin receptors, focal adhesion kinase (FAK) and pp60-Src. Mouse fibroblasts lacking FAK were found to assemble reduced amounts of Fn fibrils. Src family kinases phosphorylate FAK, and it was found that fibroblasts without Src family kinases (SYF cells) or wild-type cells treated with an Src inhibitor (PP1) also lack Fn matrix. The extracellular influence of tenascin-C was also discussed. In fibroblasts on a 3D Fn matrix, FAK was constitutively phosphorylated, whereas in the presence of tenascin-C, FAK is transiently activated, and there is a reduction in the assembly of Fn matrix fibrils. Other aspects of integrin-Fn interactions were also described, including the stimulation of Fn matrix formation by dexamethasone in the tumourgenic cell line HT1080. Karl Kadler (University of Manchester) summarized findings on the molecular and cellular basis of collagen fibrillogenesis. The talk focussed on the sorting and secretion of type-I collagen in organ cultures of embryonic chick tendon. It was found that around 50% of newly synthesized type I procollagen is cleaved to collagen type I inside the cell with around 50% cleaved in the ECM. In a particularly striking 3D model created using serial section reconstructions and immunoEM, it was shown that cross-striated nascent collagen fibrils are enclosed within tube-like secretory vesicles within cells and are secreted via plasma membrane protusions known as nozzles. It was proposed that the nucleation phase of collagen fibrillogenesis takes place in secretory vesicles, whilst the propagation phase occurs after secretion of early fibres into tunnel-shaped extracellular spaces through nozzles. John Couchman (Imperial College, London) talked about recent work with the basement membrane molecule entactin-1, also known as nidogen-1. Entactin often originates from the mesechymal compartment as opposed to other major components that are synthesized by epithelia. The renal epithelial cell line MDCK does not express entactin-1, and the effect of recombinant entactin-1 expression in these cells was investigated. MDCK cells expressing entactin-1 constitutively or under tetracycline-responsive regulation (Ent-1 cells) adopt a flattened phenotype as opposed to the normal, cuboidal phenotype and exhibit altered integrin expression profiles and increased expression of Fn. These results indicate that entactin-1 binding to aVb3 integrin can lead to Fn matrix assembly, and that Fn ligation through aVb3 integrin promotes a flattened phenotype with prominent microfilament bundles. The relevance of this mechanism was discussed with respect to carcinomas and epithelial-mesenchymal transitions. Andrew Chantry (University of East Anglia, Norwich) discussed the regulation of TGF-b-/Smad-signalling pathways. Their work focuses on decorin-mediated Ca 2þ-dependent phosphorylation and its regulation of Smads and TGF-b. Their work shows that decorin disrupts the TGF-b-/Smaddependent transcriptional events in human mesangial cells through phosphorylation of Smad-2 at serine-240 by Ca 2þ activation of Cam kinase II. Decorin induces serine-240 phospho-Smad hetero-oligomerization with Smad-4 in the nucleus, independent of TGF-b receptor activation. Part 2 of the talk covered work on MMP/TIMP expression in Smad-3 and Smad-4 knockout cells. The response of Smad-3 and Smad-4 knockout and wild-type cells to treatment with TGF-b was analysed. TIMP-1 was induced by TGF-b and is therefore a TGF-bdependent gene. TIMP-3 was completely Smad-dependent.
Extracellular matrix adaptation of tendon and skeletal muscle to exercise
Journal of Anatomy, 2006
The extracellular matrix (ECM) of connective tissues enables linking to other tissues, and plays a key role in force transmission and tissue structure maintenance in tendons, ligaments, bone and muscle. ECM turnover is influenced by physical activity, and both collagen synthesis and metalloprotease activity increase with mechanical loading. This can be shown by determining propeptide and proteinase activity by microdialysis, as well as by verifying the incorporation of infused stable isotope amino acids in biopsies. Local tissue expression and release of growth factors for ECM such as IGF-1, TGF-beta and IL-6 is enhanced following exercise. For tendons, metabolic activity (e.g. detected by positron emission tomography scanning), circulatory responses (e.g. as measured by near-infrared spectroscopy and dye dilution) and collagen turnover are markedly increased after exercise. Tendon blood flow is regulated by cyclooxygenase-2 (COX-2)-mediated pathways, and glucose uptake is regulated by specific pathways in tendons that differ from those in skeletal muscle. Chronic loading in the form of physical training leads both to increased collagen turnover as well as to some degree of net collagen synthesis. These changes modify the mechanical properties and the viscoelastic characteristics of the tissue, decrease its stress-susceptibility and probably make it more load-resistant. The mechanical properties of tendon fascicles vary within a given human tendon, and even show gender differences. The latter is supported by findings of gender-related differences in the activation of collagen synthesis with exercise. These findings may provide the basis for understanding tissue overloading and injury in both tendons and skeletal muscle.
Quantification of Collagen Organization and Extracellular Matrix Factors within the Healing Ligament
Microscopy and Microanalysis, 2011
Ligament healing of a grade III injury (i.e. a complete tear) involves a multifaceted chain of events that forms a neoligament, which is more scar-like in character than the native tissue. The remodeling process may last months or even years with the injured ligament never fully recovering pre-injury mechanical properties. With tissue engineering and regenerative medicine, understanding the normal healing process in ligament and quantifying it provide a basis to create and assess innovative treatments. Ligament fibroblasts produce a number of ECM components, including collagen types I and III, decorin and fibromodulin. Using a combination of advanced histology, molecular biology and nonlinear optical imaging approaches, the early ECM events during ligament healing have been better characterized and defined. First, the dynamic changes in ECM factors after injury are shown. Second, the factors associated with creeping substitution are identified. Finally, a method to quantify collagen organization is developed and used. Each ECM factor described herein as well as the temporal quantification of fiber organization helps elucidate the complexity of ligament healing.
The role of the non-collagenous matrix in tendon function
International Journal of Experimental Pathology, 2013
Tendon consists of highly ordered type I collagen molecules that are grouped together to form subunits of increasing diameter. At each hierarchical level, the type I collagen is interspersed with a predominantly non-collagenous matrix (NCM) (Connect. Tissue Res., 6, 1978, 11). Whilst many studies have investigated the structure, organization and function of the collagenous matrix within tendon, relatively few have studied the non-collagenous components. However, there is a growing body of research suggesting the NCM plays an important role within tendon; adaptations to this matrix may confer the specific properties required by tendons with different functions. Furthermore, age-related alterations to non-collagenous proteins have been identified, which may affect tendon resistance to injury. This review focuses on the NCM within the tensional region of developing and mature tendon, discussing the current knowledge and identifying areas that require further study to fully understand structure-function relationships within tendon. This information will aid in the development of appropriate techniques for tendon injury prevention and treatment.
Pathobiology of Tendon and Ligament Injuries
Tendon and ligament injuries are common in athletic horses and can be difficult to treat successfully. Tendons and ligaments are characterized by sparse fibroblasts embedded in a complex structural hierarchy of collagen-rich extracellular matrix (ECM) organized along lines of tension. This precise organizational scheme imparts the necessary mechanical properties for tendons and ligaments to function under high loads. The etiology of tendon and ligament injuries remains the subject of numerous ongoing research projects; however, acute overloading and accumulated microtrauma are the two predominant theories. Under normal physiologic loading, a balance is maintained between the degeneration of ECM and its repair by the resident fibroblast population. When damage occurs faster than it can be repaired, clinical signs of tendonitis or desmitis develop. The molecular and cellular responses that occur during tendon and ligament healing are important to understand, as they provide key points of control that may be targeted for new therapies. Clin Tech Equine Pract 6:168-173