transforming-growth-factor-beta and Tendinopathy

The treatment of Achilles tendinitis from conservative to minimally invasive to surgery gives patients a wide range of treatment options for this common pathology. The use and role of biologics to augment this treatment is emerging. The use of biologics may enhance the healing potential of the Achilles tendon when conservative treatment fails. There are a handful of biologics being investigated to obtain if improved outcomes can be maximized.

Topics: Achilles Tendon; Bone Marrow Transplantation; Hepatocytes; Humans; Leukocytes, Mononuclear; Platelet-Derived Growth Factor; Platelet-Rich Plasma; Tendinopathy; Tissue Scaffolds; Transforming Growth Factor beta; Ultrasonography, Interventional; Vascular Endothelial Growth Factor A; Wound Healing

Tendon disease is characterized by the development of fibrosis. Transforming growth factor beta (TGF-β), bone morphogenic proteins (BMPs) and connective tissue growth factor (CTGF) are key mediators in the pathogenesis of fibrotic disorders. The aim of this systematic review was to investigate the evidence for the expression of TGF-β, BMPs and CTGF along tendon disease progression and the response of tendon cells to these growth factors accordingly.. We conducted a systematic screen of the scientific literature using the Medline database. The search terms used were "tendon AND TGF-β," "tendon AND BMP" or "tendon AND CTGF." Studies of human samples, animal tendon injury and overuse models were included.. Thirty-three studies were included. In eight studies the expression of TGF-β, BMPs or CTGF was dysregulated in chronic tendinopathy and tendon tear patient tissues in comparison with healthy control tissues. The expression of TGF-β, BMPs and CTGF was increased and showed temporal changes in expression in tendon tissues from animal injury or overuse models compared with the healthy control (23 studies), but the pattern of upregulation was inconsistent between growth factors and also the type of animal model. No study investigated the differences in the effect of TGF-β, BMPs or CTGF treatment between patient-derived cells from healthy and diseased tendon tissues. Tendon cells derived from animal models of tendon injury showed increased expression of extracellular matrix protein genes and increased cell signaling response to TGF-β and BMP treatments compared with the control cells (two studies).. The expression of TGF-β, BMPs and CTGF in tendon tissues is altered temporally during healing in animal models of tendon injury or overuse, but the transition during the development of human tendon disease is currently unknown. Findings from this systematic review suggest a potential and compelling role for TGF-β, BMPs and CTGF in tendon disease; however, there is a paucity of studies analyzing their expression and stimulated cellular response in well-phenotyped human samples. Future work should investigate the dynamic expression of these fibrotic growth factors and their interaction with tendon cells using patient samples at different stages of human tendon disease.

Topics: Animals; Bone Morphogenetic Proteins; Connective Tissue Growth Factor; Fibrosis; Humans; Tendinopathy; Transforming Growth Factor beta

The incidence of acute and chronic conditions of the tendo Achillis appear to be increasing. Causation is multifactorial but the role of inherited genetic elements and the influence of environmental factors altering gene expression are increasingly being recognised. Certain individuals' tendons carry specific variations of genetic sequence that may make them more susceptible to injury. Alterations in the structure or relative amounts of the components of tendon and fine control of activity within the extracellular matrix affect the response of the tendon to loading with failure in certain cases. This review summarises present knowledge of the influence of genetic patterns on the pathology of the tendo Achillis, with a focus on the possible biological mechanisms by which genetic factors are involved in the aetiology of tendon pathology. Finally, we assess potential future developments with both the opportunities and risks that they may carry.

Topics: ABO Blood-Group System; Achilles Tendon; Apoptosis; Cartilage Oligomeric Matrix Protein; Collagen Type V; Epigenesis, Genetic; Extracellular Matrix Proteins; Fibrillar Collagens; Genetic Markers; Glycoproteins; Humans; Inflammation; Matrilin Proteins; Matrix Metalloproteinases; Rupture; Tenascin; Tendinopathy; Tendon Injuries; Transforming Growth Factor beta

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat tendinopathy, but evidence for this treatment is lacking, and little is known regarding effects of NSAIDs on human tendinopathic tendon. This study investigated the effects of NSAID treatment (ibuprofen) on human tendinopathic tendon, with changes in gene expression as the primary outcome, and tendon pain, function, and blood flow as secondary outcomes. Twenty-six adults (16 men, 10 women), diagnosed with chronic Achilles tendinopathy, were randomized to 1-wk treatment with ibuprofen (600 mg ×3/day) (

Topics: Activating Transcription Factor 3; Adult; Anti-Inflammatory Agents, Non-Steroidal; Collagen; Cyclooxygenase 2; Double-Blind Method; Female; Gene Expression Regulation; Humans; Ibuprofen; Male; Middle Aged; Regional Blood Flow; Tendinopathy; Transforming Growth Factor beta; Ultrasonography

Although histology data favour the view of a degenerative nature of tendinopathy, indirect support for inflammatory reactions to loading in affected tendons exists. The purpose of the present study was to elucidate whether inflammatory signalling responses after acute mechanical loading were more pronounced in tendinopathic versus healthy regions of human tendon and if treatment with non-steroidal anti-inflammatory medications (NSAID's) reduces this response. Twenty-seven tendinopathy patients (>6 months) were randomly assigned to a placebo (n = 14) or NSAID (Ibumetin NYCOMED GmbH Plant Oranienburg Germany (600 mg) × 3/day/1 week) group (n = 13) in a double-blinded-fashion. Tendon biopsies were taken from the painful and a healthy region of the same tendon 2 h after 1 h running. Gene-expression of several targets was analysed in the sampled Achilles tendon biopsies. The mRNA for TGF-β, collagen-I and collagen-III were significantly higher expressed, and decorin, CTGF, IL-6 and IL-10 were significantly lower expressed in the tendinopathic versus healthy tendon area. Only IL-10 was lower in expression in experiments with NSAID administration, while all other determined parameters were unaffected by NSAID. All ultrasonographic outcomes were unchanged in response to acute exercise and not influenced by NSAID. The signalling for collagen and TGF-beta was upregulated after acute loading in tendinopathic tendon. In contrast to the hypothesis, inflammatory signalling was not exaggerated in tendinopathic tendon 2 h after acute mechanical loading.

Topics: Achilles Tendon; Adult; Anti-Inflammatory Agents, Non-Steroidal; Collagen Type I; Collagen Type III; Connective Tissue Growth Factor; Decorin; Exercise; Female; Humans; Ibuprofen; Inflammation; Interleukin-10; Interleukin-6; Male; Middle Aged; Tendinopathy; Transcription, Genetic; Transforming Growth Factor beta; Ultrasonography

This study investigated the efficacy of sericin in treating experimental Achilles tendinopathy (AT) in rats via the transforming growth factor-beta (TGF-β)/mothers against decapentaplegic (Smad) pathway compared with diclofenac sodium (DS).. The TOS, oxidative stress index (OSI), TGF-β1, Smad2, CTGF, and decorin serum concentrations were significantly higher in AT than in C and significantly lower in ATS than in AT (P<0.05). Histopathological examination revealed that irregular fibers, degeneration, and round cell nuclei were significantly elevated in AT. Spindle-shaped fibers were similar to those in C, and degeneration was reduced in ATS. TGF-β1 and Smad2/3 expression was increased, and collagen type I alpha-1 (Col1A1) expression was decreased in AT vs. C (P=0.001). In the ATS, TGF-β1 and Smad2/3 expression decreased, and Col1A1 expression increased. The Bonar score significantly increased in the AT group (P =0.001) and significantly decreased in the ATS group (P =0.027).. Sericin shows potential efficacy in reducing oxidative stress and modulating the TGF-β/Smad pathway in experimental AT models in rats. It may be a promising therapeutic agent for AT, warranting further clinical studies for validation. Key Points • This study revealed that sericin mitigates AT-induced damage through the TGF-β/Smad pathway in an AT rat model. • ELISA and IHC investigations corroborated the effectiveness of sericin via the pivotal TGF-β/Smad pathway in tissue repair. • Evidence indicates that sericin enhances collagen synthesis,shapes tendon fiber structure, and diminishes histopathological degeneration. • Sericin's antioxidant properties were reaffirmed in its AT treatment application.

Topics: Achilles Tendon; Animals; Antioxidants; Decorin; Rats; Sericins; Tendinopathy; Transforming Growth Factor beta; Transforming Growth Factor beta1

Tendinopathy is a common tendon disorder that causes pain and impairs function. It is the most common reason for consultation with musculoskeletal specialists. The available therapies for tendinopathy are limited in number and efficacy and have unclear cellular and molecular mechanisms. Here it is shown that transforming growth factor-beta (TGF-β) activated by integrin αvβ6 promotes tendinopathy in mice. Excessive active TGF-β is found during tendinopathy progression, which led to tenocytes' phenotype transition to chondrocytes. Transgenic expression of active TGF-β in tendons induced spontaneous tendinopathy, whereas systemic injection of a TGF-β neutralizing antibody attenuated tendinopathy. Inducible knockout of the TGF-β type 2 receptor gene (Tgfbr2) in tenocytes inhibited tendinopathy progression in mice. Moreover, it is found that integrin αvβ6 induces TGF-β activation in response to mechanical load in tendons. Conditional knockout of the integrin αv gene in tendons prevented tendinopathy in mice. The study suggests that integrin αvβ6 activation of TGF-β is the mechanism of tendinopathy, and that integrin αvβ6 may be a therapeutic target in tendinopathy.

Topics: Animals; Antigens, Neoplasm; Integrins; Mice; Receptor, Transforming Growth Factor-beta Type II; Tendinopathy; Transforming Growth Factor beta

Focused extracorporeal shock waves have been found to upregulate the expression of collagen and to initiate cell proliferation in healthy tenocytes and to positively affect the metabolism of tendons, promoting the healing process. Recently, soft-focused extracorporeal shock waves have also been found to have a significant effect on tissue regeneration. However, very few in vitro reports have dealt with the application of this type of shock wave to cells, and in particular, no previous studies have investigated the response of tendon cells to this impulse. We devised an original model to investigate the in vitro effects of soft-focused shock waves on a heterogeneous population of human resident tendon cells in adherent monolayer culture. Our results indicate that soft-focused extracorporeal shock wave treatment (0.17 mJ/mm(2)) is able to induce positive modulation of cell viability, proliferation and tendon-specific marker expression, as well as release of anti-inflammatory cytokines. This could prefigure a new rationale for routine employment of soft-focused shock waves to treat the failed healing status that distinguishes tendinopathies.

Topics: Adult; Apoptosis; Biomarkers; Cell Proliferation; Cells, Cultured; Collagen Type I; Cytokines; Flow Cytometry; High-Energy Shock Waves; Humans; In Vitro Techniques; Matrix Metalloproteinases; Nitric Oxide; Tendinopathy; Tendons; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Diabetic tendinopathy is characterized by increased stiffness, thickness, and excess calcification of affected tendons. We investigated the hypothesis that proteoglycans (PGs), as key regulators of tendon structure and calcification, are altered in diabetic tendons.. Adult porcine patellar tendons were incubated in iso-osmolar media with high or normal glucose levels for 2 weeks. The PG fraction was isolated and analyzed. Protein and mRNA levels of five PGs were measured. PG production was assessed in primary tenocyte monolayers by (35)S-sulfate labeling in high and normal glucose conditions with and without exposure to advanced glycation end-products (AGEs). Levels of transforming growth factor β, which commonly mediates some effects of hyperglycemia, were also measured and the effects of free radical scavengers on (35)S-sulfate incorporation were determined.. PG levels were significantly decreased in tendons exposed to high glucose media compared with tendons in iso-osmolar control media. Relative quantities of individual PGs were unchanged by exposure to hyperglycemia and mRNAs for PGs were variably affected. High glucose media decreased PG production by tenocytes as measured by (35)S-sulfate labeling, whereas AGE-modified type I collagen and free radical scavengers had no effects. Hyperglycemic conditions increased levels of transforming growth factor β1 in an AGE-independent manner.. Hyperglycemia produces a reduction in PG levels related to decreased synthesis or sulfation of glycosaminoglycans, which may contribute to the tendon pathology observed clinically in diabetes.

Topics: Animals; Collagen Type I; Diabetes Complications; Glycation End Products, Advanced; Hyperglycemia; Organ Culture Techniques; Peptidoglycan; Swine; Tendinopathy; Tendons; Transforming Growth Factor beta

Low-level laser therapy (LLLT) has been found to produce anti-inflammatory effects in a variety of disorders. Tendinopathies are directly related to unbalance in expression of pro- and anti-inflammatory cytokines which are responsible by degeneration process of tendinocytes. In the current study, we decided to investigate if LLLT could reduce mRNA expression for TNF-α, IL-1β, IL-6, TGF-β cytokines, and COX-2 enzyme. Forty-two male Wistar rats were divided randomly in seven groups, and tendinitis was induced with a collagenase intratendinea injection. The mRNA expression was evaluated by real-time PCR in 7th and 14th days after tendinitis. LLLT irradiation with wavelength of 780 nm required for 75 s with a dose of 7.7 J/cm(2) was administered in distinct moments: 12 h and 7 days post tendinitis. At the 12 h after tendinitis, the animals were irradiated once in intercalate days until the 7th or 14th day in and them the animals were killed, respectively. In other series, 7 days after tendinitis, the animals were irradiated once in intercalated days until the 14th day and then the animals were killed. LLLT in both acute and chronic phases decreased IL-6, COX-2, and TGF-β expression after tendinitis, respectively, when compared to tendinitis groups: IL-6, COX-2, and TGF-β. The LLLT not altered IL-1β expression in any time, but reduced the TNF-α expression; however, only at chronic phase. We conclude that LLLT administered with this protocol reduces one of features of tendinopathies that is mRNA expression for pro-inflammatory mediators.

Topics: Animals; Base Sequence; Collagenases; Cyclooxygenase 2; Disease Models, Animal; DNA Primers; Gene Expression; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Low-Level Light Therapy; Male; Rats; Rats, Wistar; RNA, Messenger; Tendinopathy; Tendons; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Achilles tendon pathology is a multifactorial condition for which various risk factors, including genetic factors, have been identified. Gene transfection of two members of the TGF-β family, TGF-β1 and growth/differentiation factor-5 (GDF-5), have been shown to enhance tendon repair and mechanical strength within animal Achilles tendon injury models. The objective of this study was to investigate whether two functional 5' untranslated region (UTR) single nucleotide polymorphisms (SNPs), the TGFB1 rs1800469 variant and the GDF5 rs143383 variant, were associated with ATP within an Australian ('AUS') and a South African ('SA') case-control cohort.. One hundred and seventy-one subjects (58 AUS and 112 SA) with Achilles tendon pathology (ATP group) and 235 (142 AUS and 96 SA) asymptomatic control (CON group) subjects were genotyped for the selected SNPs using custom-designed Taqman assays. A χ(2)-analysis or Fisher's exact test was used to analyse any differences in the genotype and allele frequencies. Significance was accepted when P < 0.05.. There were no significant TGFB1 rs1800469 genotype (P = 0.491) or allele (P = 0.400) frequency differences between the ATP and CON groups. The TT genotype of the GDF5 rs143383 variant was significantly over-represented in the ATP group of the AUS cohort [P = 0.011; odds ratio (OR) = 2.24; 95% CI 1.21, 4.16], and when the AUS and SA cohorts were combined (P = 0.004; OR = 1.82; 95% CI 1.23, 2.74).. In conclusion, this study suggests that individuals with a TT genotype of the functional GDF5 rs143383 variant have twice the risk of developing ATP. This finding highlights a role of GDF-5 in the pathogenesis of Achilles tendon pathology.

Topics: Achilles Tendon; Adult; Alleles; Case-Control Studies; Cohort Studies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Growth Differentiation Factor 5; Humans; Male; Middle Aged; Risk Factors; South Africa; Tendinopathy; Transforming Growth Factor beta; Victoria

Treatment of midportion Achilles tendinopathy is hampered by limited knowledge of the pathophysiology.. Chondrogenic differentiation of tendon cells might take place in midportion Achilles tendinopathy and could be used as a target for drug treatment. An in vitro model for chondrogenic differentiation would be useful to evaluate existing and future treatment opportunities.. A controlled laboratory study.. Perioperatively harvested tissue from human midportion Achilles tendinotic lesions and healthy Achilles tendons was analyzed by microscopy and real-time reverse transcription polymerase chain reaction. In vitro chondrogenic differentiation of tendon explants was induced using transforming-growth-factor beta. This model was modulated by removing the chondrogenic stimulus or adding triamcinolone or platelet-rich plasma.. Midportion Achilles tendinotic lesions had increased glycosaminoglycan staining and more rounded cell nuclei. Chondrogenic markers (sex-determining region Y)-box9, aggrecan, collagen 2, and RUNT-related transcription factor 2 were upregulated, but collagen 10 was not. Nondegenerative tendon explants cultured on chondrogenic medium had higher expression of aggrecan, collagen 2, and collagen 10 but not (sex-determining region Y)-box9 and RUNT-related transcription factor 2. Removing the chondrogenic stimulus decreased expression of aggrecan, collagen 2, and collagen 10. Both triamcinolone and platelet-rich plasma influenced the chondrogenic gene expression pattern in the in vitro model.. Chondrogenic differentiation is present in midportion Achilles tendinopathy. An in vitro model to study this chondrogenic differentiation was developed.. This model can be used to investigate chondrogenic differentiation as a possible target for drug treatment, contributing to the development of more successful mechanism-based treatment opportunities.

Topics: Achilles Tendon; Adult; Aged; Base Sequence; Cell Differentiation; Chondrocytes; Chondrogenesis; Female; Humans; In Vitro Techniques; Male; Middle Aged; Models, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Tendinopathy; Tissue and Organ Harvesting; Transforming Growth Factor beta; Young Adult

Extracorporeal shock waves (ESW) have recently been used in resolving tendinitis. However, mechanisms by which ESW promote tendon repair is not fully understood. In this study, we reported that an optimal ESW treatment promoted healing of Achilles tendintis by inducing TGF-beta1 and IGF-I. Rats with the collagenease-induced Achilles tendinitis were given a single ESW treatment (0.16 mJ/mm(2) energy flux density) with 0, 200, 500 and 1000 impulses. Achilles tendons were subjected to biomechanical (load to failure and stiffness), biochemical properties (DNA, glycosaminoglycan and hydroxyproline content) and histological assessment. ESW with 200 impulses restored biomechanical and biochemical characteristics of healing tendons 12 weeks after treatment. However, ESW treatments with 500 and 1000 impulses elicited inhibitory effects on tendinitis repair. Histological observation demonstrated that ESW treatment resolved edema, swelling, and inflammatory cell infiltration in injured tendons. Lesion site underwent intensive tenocyte proliferation, neovascularization and progressive tendon tissue regeneration. Tenocytes at the hypertrophied cellular tissue and newly developed tendon tissue expressed strong proliferating cell nuclear antigen (PCNA) after ESW treatment, suggesting that physical ESW could increase the mitogenic responses of tendons. Moreover, the proliferation of tenocytes adjunct to hypertrophied cell aggregate and newly formed tendon tissue coincided with intensive TGF-beta1 and IGF-I expression. Increasing TGF-beta1 expression was noted in the early stage of tendon repair, and elevated IGF-I expression was persisted throughout the healing period. Together, low-energy shock wave effectively promoted tendon healing. TGF-beta1 and IGF-I played important roles in mediating ESW-stimulated cell proliferation and tissue regeneration of tendon.

Topics: Achilles Tendon; Animals; Biomechanical Phenomena; Collagenases; Disease Models, Animal; DNA; Dose-Response Relationship, Radiation; Glycosaminoglycans; High-Energy Shock Waves; Hydroxyproline; Insulin-Like Growth Factor I; Rats; Rats, Sprague-Dawley; Tendinopathy; Tendon Injuries; Transforming Growth Factor beta; Transforming Growth Factor beta1; Wound Healing

Patellar tendinosis is characterized by longstanding localized and activity-related pain, swelling and tenderness on palpation, and characteristic features on magnetic resonance imaging and ultrasonography and during surgical excision. Histologic examination of tendinosis tissues shows disrupted collagen matrix, increased cellularity, and increased proteoglycan stainability, but lack of inflammatory cell infiltration despite the clinical signs resembling inflammation. Disturbances in inflammatory response may be associated with the development of tendinosis. Expression of cyclooxygenase-2 and transforming growth factor-beta1 were detected in tendinosis, and the in vitro production of prostaglandin E2 by tendinosis and healthy tendon fibroblast cultures also was observed. Eleven patients with patellar tendinosis and 12 control subjects with healthy patellar tendons, but deficient anterior cruciate ligaments, were included in the current study. The percentages of immunopositive cells in tendinosis samples for cyclooxygenase-2 and transforming growth factor-beta1 were 66.75 and 56.40, respectively, which were significantly higher than those of the control subjects (25.15 and 23.06 respectively). Tendinosis fibroblast culture also produced more prostaglandin E2 and active transforming growth factor-beta1. These findings indicate the involvement of prostaglandins and cytokines that may explain the clinical symptoms and nonhealing features of tendinosis.

Topics: Adolescent; Adult; Dinoprostone; Female; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Knee Joint; Male; Prostaglandin-Endoperoxide Synthases; Tendinopathy; Transforming Growth Factor beta; Transforming Growth Factor beta1

In earlier studies, we have shown that pulsed electromagnetic fields (PEMFs) induce programmed cell death in cultured T cells and that rats exposed in vivo to PEMFs have decreased T-cell proliferative capacity. These data led us to hypothesize that PEMFs might be used to control proliferation of inflammatory lymphocytes and therefore beneficially affect inflammatory diseases. Tendinitis is characterized by painful inflammation of the tendon. Inflammation is characterized by massive infiltration of T lymphocytes, neutrophils and macrophages into the damaged tissue. These inflammatory cells produce a variety of cytokines, which are the cellular regulators of inflammation. The current study tests whether in vivo PEMF effects are mediated via systemic cytokine production in rat tendinitis. Inflammation was chemically induced in female Harlan Sprague Dawley rats Achilles' tendons and a wound healing PEMF (Electrobiology, Inc.) was applied for 4 hours immediately following injury. Spleens from control and experimental animals were harvested 24 hours later and total RNA was extracted from the tissues. Gene expression was analyzed by reverse transcription of mRNA, and polymerase chain reaction amplification (RT-PCR) using primers specific for the cytokines IFN-gamma, IL-1 beta, IL-6, TNF-alpha, and TGF-beta, as well as for the control beta-actin. RT-PCR products were separated on 1.5% agarose gels and band intensities were normalized to beta-actin gene expression of the same sample. TGF-beta was the only cytokine produced at high levels in rats with tendinitis in comparison to the other cytokines. PEMFs did not show an effect on any cytokine expression in the spleens, 24 hours after induction of tendinitis. Further studies need to test if cumulative exposures of PEMFs are able to regulate inflammatory cytokine expression either at the site of inflammation or at the local lymph nodes.

Topics: Achilles Tendon; Animals; Cytokines; Electromagnetic Fields; Female; Gene Expression; Hindlimb; Inflammation Mediators; Interferon-gamma; Interleukin-1; Interleukin-6; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; T-Lymphocytes; Tendinopathy; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha