Exploring the burden, prevalence and associated factors of chronic musculoskeletal pain in migrants from North Africa and Middle East living in Europe: a scoping review.

BACKGROUND: Immigrants are exposed to numerous risk factors that may contribute to the development of chronic musculoskeletal pain. Recent political and environmental crises in North Africa and the Middle East have led to an increase in immigration to Europe that has challenged the healthcare system and especially the management of chronic conditions. OBJECTIVE: The aims of this scoping review are to investigate the burden, prevalence, and associated factors of chronic musculoskeletal pain in immigrants from North Africa and the Middle East in Europe during the last decade. The intentions of the review are to inform healthcare policymakers, to identify gaps in the literature, and aid the planning of future research. DESIGN: Online databases Medline, Embase, PubMed and Web of Science were used to identify epidemiological studies published from2012-2022 examining chronic pain in populations from North Africa and the Middle East with a migration background residing in Europe. RESULTS: In total eleven studies were identified conducted in Norway (n = 3), Denmark (n = 3), Germany (n = 1), Austria (n = 1), Sweden (n = 1), and Switzerland (n = 1). Among the identified studies, eight studies were cross-sectional (n = 8), two were prospective cohort studies (n = 2) and one was a retrospective cohort study (n = 1). Data suggested that chronic pain is more prevalent, more widespread, and more severe in people with than without a migration background. Furthermore, immigrants who have resided in the destination country for a longer period experience a higher prevalence of chronic pain compared to those in the early phases of migration. The following factors were found to be associated with chronic pain in this population: female gender, lower education, financial hardship, being underweight or obese, time in transit during migration, experience of trauma, immigration status, anxiety, depression, and post-traumatic stress disorder. CONCLUSION: Several gaps in the literature were identified. Research is limited in terms of quantity and quality, does not reflect actual immigration trends, and does not account for immigration factors. Prospective cohort studies with long follow-ups would aid in improving prevention and management of chronic pain in populations with a migration background. In particular, they should reflect actual immigration trajectories, account for immigration factors, and have valid comparison groups in the countries of origin, transit and destination.

A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution.

Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.

Cellular characterisation of advanced osteoarthritis knee synovium.

OBJECTIVES: Osteoarthritis (OA) is increasingly recognised as a whole joint disease, with an important role for synovium. However, the repertoire of immune cells and fibroblasts that constitute OA synovium remains understudied. This study aims to characterise the cellular composition of advanced OA synovium and to explore potential correlations between different cell types and patient demographics or clinical scores. METHODS: Synovium, collected from 10 patients with advanced OA during total knee replacement surgery, was collagenase-digested, and cells were stained for flow cytometry analysis. Formalin-fixed paraffin-embedded synovium was sectioned, stained with immunofluorescence, and imaged using the multiplex Cell DIVE platform. Patient demographics and clinical scores were also collected. RESULTS: The proportion of immune cells in OA synovium varied between patients (8-38% of all cells). Macrophages and T cells were the dominant immune cell populations, together representing 76% of immune cells. Age positively correlated with the proportion of macrophages, and negatively correlated with T cells. CCR6+ T cells were found in 6/10 patients; these patients had a higher mean Kellgren-Lawrence grade across the three knee compartments. Immunofluorescence staining showed that macrophages were present in the lining as well as distributed throughout the sublining, while T and B cells were mainly localised near vessels in the sublining. Fibroblast subsets (CD45-PDPN+) based on the expression of CD34/CD90 or FAP/CD90 were identified in all patient samples, and some populations correlate with the percentage of immune cells or clinical scores. Immunofluorescence staining showed that FAP expression was particularly strong in the lining layer, but also present throughout the sublining layer. CD90 expression was exclusively found around vessels in the sublining, while CD34 was mostly found in the sublining but also occasionally in the lining layer. CONCLUSIONS: There are significant differences in the relative proportions and subsets of immune cells in OA synovium; exploratory correlative analyses suggest that these differences might be correlated with age, clinical scores, or fibroblast subsets. Additional studies are required to understand how different cell types affect OA pathobiology, and if the presence or proportion of cell subsets relates to disease phenotypes.

Osteoarthritis: a narrative review of molecular approaches to disease management.

Osteoarthritis (OA) is a chronic, progressive degenerative whole joint disease that affects the articular cartilage, subchondral bone, ligaments, capsule, and synovium. While it is still believed to be a mechanically driven disease, the role of underlying co-existing inflammatory processes and mediators in the onset of OA and its progression is now more appreciated. Post-traumatic osteoarthritis (PTOA) is a subtype of OA that occurs secondary to traumatic joint insults and is widely used in pre-clinical models to help understand OA in general. There is an urgent need to develop new treatments as the global burden is considerable and expanding. In this review, we focus on the recent pharmacological advances in the treatment of OA and summarize the most significant promising agents based on their molecular effects. Those are classified here into broad categories: anti-inflammatory, modulation of the activity of matrix metalloproteases, anabolic, and unconventional pleiotropic agents. We provide a comprehensive analysis of the pharmacological advances in each of these areas and highlight future insights and directions in the OA field.

Impact of age on unicompartmental knee arthroplasty outcomes: a systematic review and meta-analysis.

PURPOSE: Unicompartmental knee arthroplasty (UKA) is an effective treatment for late knee osteoarthritis (OA). Young age (< 60 years) has been associated with worse outcomes. The goal of this systematic review and meta-analysis is to study the effect of age on UKA outcomes. METHODS: The primary objective was to compare the UKA revision rate in young patients with that of old patients, using the age thresholds of 60 and 55 years. Secondary objectives were patient-reported outcome measures (PROMs) and implant design. Five databases were searched in December 2021 for original comparative studies with a minimum of 1-year follow-up. No restrictions were placed on the type of UKA prosthesis. RESULTS: A total of 11 observational studies with 6130 knees were included. A mean MINORS score of 19 was assigned to the review. The mean age of patients was 64 years, with average follow-up of 7.5 ± 2.98 years. There was no significant difference in revision rate, incident or PROMs between young and old patients in the analysis for each age threshold. Further sub-analysis adjusting for implant type in mobile- and fixed-bearing prostheses also showed similar results between those above and under 60 and 55 years. CONCLUSION: Young age was not associated with a higher revision rate or lower functional scores. Thus, this review provides evidence that age alone is not a contraindication to UKA, but the surgical choice must be based on several elements, and this finding should be applied in context, given the binary division and heterogeneity of patients. LEVEL OF EVIDENCE: III.

The role of the microbiome in rheumatoid arthritis: a review.

The close bidirectional relationship between the microbiome and the immune system is well supported, and a role of gut dysbiosis has been implied in many systemic autoimmune diseases. This review aims to provide a critical summary and appraisal of 6 murine studies and 16 clinical studies. The findings of the literature review suggest that gut dysbiosis precedes arthritis and that local intestinal inflammation leads to systemic inflammation in genetically predisposed individuals. However, the exact mechanism by which microorganisms provoke immune responses at distal sites remains to be elucidated. Although a characteristic RA microbiome was not identified, there were some common findings among studies: overabundance of Prevotella copri in early RA patients, and proliferation of the genus Collinsela and some Lactobacillus species. Three mechanisms by which microbiota might contribute to RA pathogenesis were proposed: inflammatory responses (P. copri and Lactobacillus), molecular mimicry (P. copri) and loss of intestinal barrier integrity (Collinsella). Larger longitudinal studies are required in order to shed light on the mechanisms involved and unravel the therapeutic potential of the microbiome, and clinical trials are needed to evaluate the safety and efficacy of the implied therapeutic interventions.

Three-dimensional, in-vitro approaches for modelling soft-tissue joint diseases.

Diseases affecting the soft tissues of the joint represent a considerable global health burden, causing pain and disability and increasing the likelihood of developing metabolic comorbidities. Current approaches to investigating the cellular basis of joint diseases, including osteoarthritis, rheumatoid arthritis, tendinopathy, and arthrofibrosis, involve well phenotyped human tissues, animal disease models, and in-vitro tissue culture models. Inherent challenges in preclinical drug discovery have driven the development of state-of-the-art, in-vitro human tissue models to rapidly advance therapeutic target discovery. The clinical potential of such models has been substantiated through successful recapitulation of the pathobiology of cancers, generating accurate predictions of patient responses to therapeutics and providing a basis for equivalent musculoskeletal models. In this Review, we discuss the requirement to develop physiologically relevant three-dimensional (3D) culture systems that could advance understanding of the cellular and molecular basis of diseases that affect the soft tissues of the joint. We discuss the practicalities and challenges associated with modelling the complex extracellular matrix of joint tissues-including cartilage, synovium, tendon, and ligament-highlighting the importance of considering the joint as a whole organ to encompass crosstalk across tissues and between diverse cell types. The design of bespoke in-vitro models for soft-tissue joint diseases has the potential to inform functional studies of the cellular and molecular mechanisms underlying disease onset, progression, and resolution. Use of these models could inform precision therapeutic targeting and advance the field towards personalised medicine for patients with common musculoskeletal diseases.

Pathological Tendon Histology in Early and Chronic Human Patellar Tendinopathy.

The present pilot study investigated the extent of histological tissue changes in both chronic tendinopathy and in individuals that display early clinical signs of tendinopathy. The study included 8 individuals of whom 3 were healthy without any tendon symptoms, 2 had early symptoms (1-2 months), and 3 had chronic symptoms (>3 months) from their patellar tendons. Percutaneous needle biopsy samples were obtained from the affected tendon tissue region. Biopsy samples were stained with Haematoxylin & Eosin, and multiplex immunofluorescence staining was performed for markers of inflammation and resolution. Both early and chronic stage patellar tendon biopsy samples from this small patient cohort exhibited expansion of the interfascicular matrix (IFM) and endotenon regions together with increased cellularity and vascularity. These histological observations were moderate in early tendinopathy, whereas they were more pronounced and associated with marked disruption of tissue architecture in chronic tendinopathy. Early stage tendinopathic patellar tendons expressed markers associated with an activated phenotype of fibroblasts (CD90, CD34), macrophages (S100A8), and endothelial cells (ICAM1, VCAM1). These tissues also expressed enzymes implicated in inflammation (PTGS2, 15PGDH) and resolution (ALOX12) and the proresolving receptor ERV1. Immunopositive staining for these markers was predominantly located in the IFM regions. These preliminary findings suggest that mild to moderate structural histological changes including expansion of IFM and endotenon regions are pathological features of early tendinopathy, and support inflammatory and resolving processes are active in early-stage disease. Further investigation of the cellular and molecular basis of early-stage tendinopathy is required to inform therapeutic strategies that prevent the development of irreversible chronic tendon disease.

Comparison of Cellular Responses to TGF-ß1 and BMP-2 Between Healthy and Torn Tendons.

BACKGROUND: Tendons heal by fibrotic repair, increasing the likelihood of reinjury. Animal tendon injury and overuse models have identified transforming growth factor beta (TGF-ß) and bone morphogenetic proteins (BMPs) as growth factors actively involved in the development of fibrosis, by mediating extracellular matrix synthesis and cell differentiation. PURPOSE: To understand how TGF-ß and BMPs contribute to fibrotic processes using tendon-derived cells isolated from healthy and diseased human tendons. STUDY DESIGN: Controlled laboratory study. METHODS: Tendon-derived cells were isolated from patients with a chronic rotator cuff tendon tear (large to massive, diseased) and healthy hamstring tendons of patients undergoing anterior cruciate ligament repair. Isolated cells were incubated with TGF-ß1 (10 ng/mL) or BMP-2 (100 ng/mL) for 3 days. Gene expression was measured by real-time quantitative polymerase chain reaction. Cell signaling pathway activation was determined by Western blotting. RESULTS: TGF-ß1 treatment induced ACAN mRNA expression in both cell types but less in the diseased compared with healthy cells (P < .05). BMP-2 treatment induced BGN mRNA expression in healthy but not diseased cells (P < .01). In the diseased cells, TGF-ß1 treatment induced increased ACTA2 mRNA expression (P < .01) and increased small mothers against decapentaplegic (SMAD) signaling (P < .05) compared with those of healthy cells. Moreover, BMP-2 treatment induced ACTA2 mRNA expression in the diseased cells only (P < .05). CONCLUSION: Diseased tendon-derived cells show reduced expression of the proteoglycans aggrecan and biglycan in response to TGF-ß1 and BMP-2 treatments. These same treatments induced enhanced fibrotic differentiation and canonical SMAD cell signaling in diseased compared with healthy cells. CLINICAL RELEVANCE: Findings from this study suggest that diseased tendon-derived cells respond differently than healthy cells in the presence of TGF-ß1 and BMP-2. The altered responses of diseased cells may influence fibrotic repair processes during tendon healing.

Interleukin-17A Causes Osteoarthritis-Like Transcriptional Changes in Human Osteoarthritis-Derived Chondrocytes and Synovial Fibroblasts In Vitro.

Increased interleukin (IL)-17A has been identified in joints affected by osteoarthritis (OA), but it is unclear how IL-17A, and its family members IL-17AF and IL-17F, can contribute to human OA pathophysiology. Therefore, we aimed to evaluate the gene expression and signalling pathway activation effects of the different IL-17 family members in chondrocytes and synovial fibroblasts derived from cartilage and synovium of patients with end-stage knee OA. Immunohistochemistry staining confirmed that IL-17 receptor A (IL-17RA) and IL-17RC are expressed in end-stage OA-derived cartilage and synovium. Chondrocytes and synovial fibroblasts derived from end-stage OA patients were treated with IL-17A, IL-17AF, or IL-17F, and gene expression was assessed with bulk RNA-Seq. Hallmark pathway analysis showed that IL-17 cytokines regulated several OA pathophysiology-related pathways including immune-, angiogenesis-, and complement-pathways in both chondrocytes and synovial fibroblasts derived from end-stage OA patients. While overall IL-17A induced the strongest transcriptional response, followed by IL-17AF and IL-17F, not all genes followed this pattern. Disease-Gene Network analysis revealed that IL-17A-related changes in gene expression in these cells are associated with experimental arthritis, knee arthritis, and musculoskeletal disease gene-sets. Western blot analysis confirmed that IL-17A significantly activates p38 and p65 NF-κB. Incubation of chondrocytes and synovial fibroblasts with anti-IL-17A monoclonal antibody secukinumab significantly inhibited IL-17A-induced gene expression. In conclusion, the association of IL-17-induced transcriptional changes with arthritic gene-sets supports a role for IL-17A in OA pathophysiology. Future studies should further investigate the role of IL-17A in the OA joint to establish whether anti-IL-17 treatment could be a potential therapeutic option in OA patients with an inflammatory phenotype.

Interleukin-17 Cytokines and Receptors: Potential Amplifiers of Tendon Inflammation.

Interleukin (IL)-17A, a pro-inflammatory cytokine that is linked to the pathology of several inflammatory diseases, has been shown to be upregulated in early human tendinopathy and to mediate inflammatory and tissue remodelling events. However, it remains unclear which cells in tendons can respond to IL-17A, and how IL-17A, and its family members IL-17F and IL-17AF, can affect intracellular signalling activation and mRNA expression in healthy and diseased tendon-derived fibroblasts. Using well-phenotyped human tendon samples, we show that IL-17A and its receptors IL-17RA and IL-17RC are present in healthy hamstring, and tendinopathic and torn supraspinatus tendon tissue. Next, we investigated the effects of IL-17A, IL-17F, or IL-17AF on cultured patient-derived healthy and diseased tendon-derived fibroblasts. In these experiments, IL-17A treatment significantly upregulated IL6, MMP3, and PDPN mRNA expression in diseased tendon-derived fibroblasts. IL-17AF treatment induced moderate increases in these target genes, while little change was observed with IL-17F. These trends were reflected in the activation of intracellular signalling proteins p38 and NF- κ B p65, which were significantly increased by IL-17A, modestly increased by IL-17AF, and not increased by IL-17F. In combination with TNF-α, all three IL-17 cytokines induced IL6 and MMP3 mRNA expression to similar levels. Therefore, this study confirms that healthy and diseased tendon-derived fibroblasts are responsive to IL-17 cytokines and that IL-17A induces the most profound intracellular signalling activation and mRNA expression of inflammatory genes, followed by IL-17AF, and finally IL-17F. The ability of IL-17 cytokines to induce a direct response and activate diverse pro-inflammatory signalling pathways through synergy with other inflammatory mediators suggests a role for IL-17 family members as amplifiers of tendon inflammation and as potential therapeutic targets in tendinopathy.

Electrospun Scaffold Micro-Architecture Induces an Activated Transcriptional Phenotype within Tendon Fibroblasts.

Biomaterial augmentation of surgically repaired rotator cuff tendon tears aims to improve the high failure rates (∼40%) of traditional repairs. Biomaterials that can alter cellular phenotypes through the provision of microscale topographical cues are now under development. We aimed to systematically evaluate the effect of topographic architecture on the cellular phenotype of fibroblasts from healthy and diseased tendons. Electrospun polydioxanone scaffolds with fiber diameters ranging from 300 to 4000 nm, in either a highly aligned or random configuration, were produced. Healthy tendon fibroblasts cultured for 7 days on scaffolds with highly aligned fibers demonstrated a distinctive elongated morphology, whilst those cultured on randomly configured fibers demonstrated a flattened and spread morphology. The effect of scaffold micro-architecture on the transcriptome of both healthy and diseased tendon fibroblasts was assessed with bulk RNA-seq. Both healthy (n = 3) and diseased tendon cells (n = 3) demonstrated a similar transcriptional response to architectural variants. Gene set enrichment analysis revealed that large diameter (≥2000 nm) aligned scaffolds induced an upregulation of genes involved in cellular replication and a downregulation of genes defining inflammatory responses and cell adhesion. Similarly, PDPN and CD248, markers of inflammatory or "activated" fibroblasts, were downregulated during culture of both healthy and diseased fibroblasts on aligned scaffolds with large (≥2000 nm) fiber diameters. In conclusion scaffold architectures resembling that of disordered type III collagen, typically present during the earlier phases of wound healing, resulted in tendon fibroblast activation. Conversely, scaffolds mimicking aligned diameter collagen I fibrils, present during tissue remodelling, did not activate tendon derived fibroblasts. This has implications for the design of scaffolds used during rotator cuff repair augmentation.

Rotator cuff repair with biological graft augmentation causes adverse tissue outcomes.

Background and purpose - Biological patches can be used to augment rotator cuff tendon repair in an attempt to improve healing and reduce rates of re-rupture. However, little is known about the in vivo tissue response to these patches. We assessed native rotator cuff tissue response after surgical repair and augmentation with 2 commercially available extracellular matrix (ECM) patches. Patients and methods - Patients underwent a rotator cuff repair augmented with either GraftJacket (Wright Medical), Permacol (Zimmer Biomet), or no patch (Control), applied using an onlay technique. A sample of supraspinatus tendon was collected intraoperatively and 4 weeks post-surgery, using ultrasound-guided biopsy. Histology and immunohistochemistry were performed on all samples. Results - The Permacol group (n = 3) and GraftJacket group (n = 4) demonstrated some changes in native tendon ECM compared with the control group (n = 3). Significant disruption of the extracellular matrix of the repaired native supraspinatus, underlying both patches, was observed. The patches did not generally increase cellularity, foreign body giant cell count, or vascularity compared to the control group. 1 patient in the Permacol group had an adverse tissue immune response characterized by extensive infiltration of IRF5+, CD68+, and CD206+ cells, suggesting involvement of macrophages with a pro-inflammatory phenotype. No significant differences in protein expression of CD4, CD45, CD68, CD206, BMP7, IRF5, TGFß, and PDPN were observed among the groups. Interpretation - Histological and immunohistochemical analysis of native tendon tissue after patch augmentation in rotator cuff repair raises some concerns about a lack of benefit and potential for harm from these materials.

Histological evaluation of cellular response to a multifilament electrospun suture for tendon repair.

BACKGROUND: Rotator cuff tendon repair in humans is a commonly performed procedure aimed at restoring the tendon-bone interface. Despite significant innovation of surgical techniques and suture anchor implants, only 60% of repairs heal successfully. One strategy to enhance repair is the use of bioactive sutures that provide the native tendon with biophysical cues for healing. We investigated the tissue response to a multifilament electrospun polydioxanone (PDO) suture in a sheep tendon injury model characterised by a natural history of failure of healing. METHODOLOGY AND RESULTS: Eight skeletally mature English Mule sheep underwent repair with electrospun sutures. Monofilament sutures were used as a control. Three months after surgery, all tendon repairs healed, without systemic features of inflammation, signs of tumour or infection at necropsy. A mild local inflammatory reaction was seen. On histology the electrospun sutures were densely infiltrated with predominantly tendon fibroblast-like cells. In comparison, no cellular infiltration was observed in the control suture. Neovascularisation was observed within the electrospun suture, whilst none was seen in the control. Foreign body giant cells were rarely seen with either sutures. CONCLUSION: This study demonstrates that a tissue response can be induced in tendon with a multifilament electrospun suture with no safety concerns.

Histopathological and immunohistochemical evaluation of cellular response to a woven and electrospun polydioxanone (PDO) and polycaprolactone (PCL) patch for tendon repair.

We investigated endogenous tissue response to a woven and electrospun polydioxanone (PDO) and polycaprolactone (PCL) patch intended for tendon repair. A sheep tendon injury model characterised by a natural history of consistent failure of healing was chosen to assess the biological potential of woven and aligned electrospun fibres to induce a reparative response. Patches were implanted into 8 female adult English Mule sheep. Significant infiltration of tendon fibroblasts was observed within the electrospun component of the patch but not within the woven component. The cellular infiltrate into the electrospun fibres was accompanied by an extensive network of new blood vessel formation. Tendon fibroblasts were the most abundant scaffold-populating cell type. CD45+, CD4+ and CD14+ cells were also present, with few foreign body giant cells. There were no local or systemic signs of excessive inflammation with normal hematology and serology for inflammatory markers three months after scaffold implantation. In conclusion, we demonstrate that an endogenous healing response can be safely induced in tendon by means of biophysical cues using a woven and electrospun patch.

Author Correction: Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions.

Endometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.

ERK1/2 drives IL-1ß-induced expression of TGF-ß1 and BMP-2 in torn tendons.

Diseased and injured tendons develop fibrosis, driven by factors including TGF-ß, BMPs and CTGF. IL-1ß and its signal transducer Erk1/2 are known to regulate TGF-ß expression in animal tendons. We utilised tissues and cells isolated from patients with shoulder tendon tears and tendons of healthy volunteers to advance understanding of how inflammation induces fibrosis in diseased human tendons. ERK1/2 expression was reduced in torn (diseased) compared to healthy patient tendon tissues. We next investigated the fibrotic responses of tendon-derived cells isolated from healthy and diseased human tendon tissues in an inflammatory milieu. IL-1ß treatment induced profound ERK1/2 signalling, TGFB1 and BMP2 mRNA expression in diseased compared to healthy tendon-derived cells. In the diseased cells, the ERK1/2 inhibitor (PD98059) completely blocked the IL-1ß-induced TGFB1 and partially reduced BMP2 mRNA expression. Conversely, the same treatment of healthy cells did not modulate IL-1ß-induced TGFB1 or BMP2 mRNA expression. ERK1/2 inhibition did not attenuate IL-1ß-induced CTGF mRNA expression in healthy or diseased tendon cells. These findings highlight differences between ERK1/2 signalling pathway activation and expression of TGF-ß1 and BMP-2 between healthy and diseased tendon tissues and cells, advancing understanding of inflammation induced fibrosis during the development of human tendon disease and subsequent repair.

Proresolving Mediators LXB4 and RvE1 Regulate Inflammation in Stromal Cells from Patients with Shoulder Tendon Tears.

Tendon stromal cells isolated from patients with chronic shoulder rotator cuff tendon tears have dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation; therefore, new therapeutic approaches that target tendon stromal cells are required. We examined whether two specialized proresolving mediators (SPMs), lipoxin B4 (LXB4) and resolvin E1 (RvE1), modulate the bioactive lipid mediator profiles of IL-1ß-stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also examined whether LXB4 or RvE1 treatments moderated the proinflammatory phenotype of tendon tear stromal cells. Incubation of IL-1ß-treated patient-derived tendon cells in LXB4 or RvE1 up-regulated concentrations of SPMs. RvE1 treatment of diseased tendon stromal cells increased 15-epi-LXB4 and regulated postaglandin F2α. LXB4 or RvE1 also induced expression of the SPM biosynthetic enzymes 12-lipoxygenase and 15-lipoxygenase. RvE1 treatment up-regulated the proresolving receptor human resolvin E1 compared with vehicle-treated cells. Incubation in LXB4 or RvE1 moderated the proinflammatory phenotype of patient-derived tendon tear cells, regulating markers of tendon inflammation, including podoplanin, CD90, phosphorylated signal transducer and activator of transcription 1, and IL-6. LXB4 and RvE1 counterregulate inflammatory processes in tendon stromal cells, supporting the role of these molecules as potential therapeutics to resolve tendon inflammation.