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1.
BMC Public Health ; 24(1): 769, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38475746

RESUMO

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.


Assuntos
Dor Crônica , Dor Musculoesquelética , Refugiados , Migrantes , Feminino , Humanos , África do Norte , Europa (Continente) , Oriente Médio , Prevalência , Estudos Prospectivos , Estudos Retrospectivos , Masculino
2.
Knee Surg Sports Traumatol Arthrosc ; 31(3): 986-997, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36063186

RESUMO

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.


Assuntos
Artroplastia do Joelho , Prótese do Joelho , Osteoartrite do Joelho , Humanos , Pessoa de Meia-Idade , Artroplastia do Joelho/métodos , Reoperação , Osteoartrite do Joelho/cirurgia , Resultado do Tratamento , Articulação do Joelho/cirurgia
3.
Am J Pathol ; 189(11): 2258-2268, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31437425

RESUMO

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.


Assuntos
Ácido Eicosapentaenoico/análogos & derivados , Lipoxinas/farmacologia , Lesões do Ombro/patologia , Células Estromais/efeitos dos fármacos , Traumatismos dos Tendões/patologia , Tendões/efeitos dos fármacos , Idoso , Anti-Inflamatórios/farmacologia , Células Cultivadas , Ácido Eicosapentaenoico/farmacologia , Feminino , Humanos , Inflamação/metabolismo , Inflamação/patologia , Inflamação/prevenção & controle , Mediadores da Inflamação/metabolismo , Lacerações/metabolismo , Lacerações/patologia , Masculino , Pessoa de Meia-Idade , Ombro/patologia , Lesões do Ombro/metabolismo , Articulação do Ombro/efeitos dos fármacos , Articulação do Ombro/metabolismo , Articulação do Ombro/patologia , Células Estromais/metabolismo , Células Estromais/patologia , Traumatismos dos Tendões/metabolismo , Tendões/metabolismo , Tendões/patologia
4.
FASEB J ; 33(7): 8043-8054, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30916999

RESUMO

Resolution of inflammation is poorly understood in Achilles tendon disorders. Herein, we investigated the bioactive lipid mediator profiles of tendon-derived stromal cells isolated from patients with Achilles tendinopathy (AT) or Achilles rupture (AR) under baseline and IL-1ß-stimulated conditions. We also determined whether incubating these cells with 2 of the mediators produced by tendon-derived stromal cells, 15-epi-Lipoxin A4 (15-epi-LXA4) or maresin (MaR)-1, moderated their proinflammatory phenotype. Under baseline conditions, AT cells showed concurrent increased levels of proinflammatory eicosanoids and proresolving mediators compared with AR cells. IL-1ß treatment induced profound prostaglandin E2 release in AR compared with AT cells. Incubation of IL-1ß treated AT and AR tendon-derived stromal cells in 15-epi-LXA4 or MaR1 reduced proinflammatory eicosanoids and potentiated the release of proresolving mediators. These mediators also induced specialized proresolving mediator (SPM) biosynthetic enzymes arachidonate lipoxygenase (ALOX) 12 and ALOX15 and up-regulated the proresolving receptor ALX compared with vehicle-treated cells. Incubation in 15-epi-LXA4 or MaR1 also moderated the proinflammatory phenotype of AT and AR cells, regulating podoplanin, CD90, signal transducer and activator of transcription (STAT)-1, IL-6, IFN regulatory factor (IRF) 5, and TLR4 and suppressed c-Jun N-terminal kinase 1/2/3, Lyn, STAT-3, and STAT-6 phosphokinase signaling. In summary, we identify proresolving mediators that are active in AT and AR and propose SPMs, including 15-epi-LXA4 or MaR1, as a potential strategy to counterregulate inflammatory processes in these cells.-Dakin, S. G., Colas, R. A., Newton, J., Gwilym, S., Jones, N., Reid, H. A. B., Wood, S., Appleton, L., Wheway, K., Watkins, B., Dalli, J., Carr, A. J. 15-Epi-LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture.


Assuntos
Tendão do Calcâneo/lesões , Ácidos Docosa-Hexaenoicos/farmacologia , Mediadores da Inflamação/farmacologia , Lipoxinas/farmacologia , Ruptura/patologia , Células Estromais/efeitos dos fármacos , Tendinopatia/patologia , Tendão do Calcâneo/patologia , Adulto , Idoso , Araquidonato 12-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/metabolismo , Biópsia , Células Cultivadas , Eicosanoides/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Interleucina-1beta/farmacologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia
5.
Acta Orthop ; 91(6): 782-788, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32691656

RESUMO

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.


Assuntos
Artroplastia , Colágeno , Biópsia Guiada por Imagem/métodos , Inflamação , Teste de Materiais/métodos , Lesões do Manguito Rotador/cirurgia , Manguito Rotador , Artroplastia/efeitos adversos , Artroplastia/instrumentação , Artroplastia/métodos , Materiais Biocompatíveis/efeitos adversos , Materiais Biocompatíveis/uso terapêutico , Colágeno/efeitos adversos , Colágeno/uso terapêutico , Feminino , Reação a Corpo Estranho/etiologia , Reação a Corpo Estranho/imunologia , Reação a Corpo Estranho/patologia , Humanos , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Manguito Rotador/irrigação sanguínea , Manguito Rotador/imunologia , Ultrassonografia/métodos , Reino Unido , Cicatrização/imunologia
6.
Surgeon ; 15(6): 349-354, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28619548

RESUMO

Tendinopathy is a common clinical problem and has a significant disease burden attached, not only in terms of health care costs, but also for patients directly in terms of time off work and impact upon quality of life. Controversy surrounds the pathogenesis of tendinopathy, however the recent systematic analysis of the evidence has demonstrated that many of the claims of an absence of inflammation in tendinopathy were more based around belief than robust scientific data. This review is a summary of the emerging research in this topical area, with a particular focus on the role of neuronal regulation and inflammation in tendinopathy.


Assuntos
Inflamação/complicações , Neurogênese/fisiologia , Tendinopatia/etiologia , Humanos , Inflamação/fisiopatologia , Tendinopatia/fisiopatologia , Tendões/inervação
7.
J Shoulder Elbow Surg ; 26(11): 2038-2046, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28865966

RESUMO

BACKGROUND: Retearing after rotator cuff surgery is a major clinical problem. Numerous scaffolds are being used to try to reduce retear rates. However, few have demonstrated clinical efficacy. We hypothesize that this lack of efficacy is due to insufficient mechanical properties. Therefore, we compared the macro and nano/micro mechanical properties of 7 commercially available scaffolds to those of the human supraspinatus tendons, whose function they seek to restore. METHODS: The clinically approved scaffolds tested were X-Repair, LARS ligament, Poly-Tape, BioFiber, GraftJacket, Permacol, and Conexa. Fresh frozen cadaveric human supraspinatus tendon samples were used. Macro mechanical properties were determined through tensile testing and rheometry. Scanning probe microscopy and scanning electron microscopy were performed to assess properties of materials at the nano/microscale (morphology, Young modulus, loss tangent). RESULTS: None of the scaffolds tested adequately approximated both the macro and micro mechanical properties of human supraspinatus tendon. Macroscale mechanical properties were insufficient to restore load-bearing function. The best-performing scaffolds on the macroscale (X-Repair, LARS ligament) had poor nano/microscale properties. Scaffolds approximating tendon properties on the nano/microscale (BioFiber, biologic scaffolds) had poor macroscale properties. CONCLUSION: Existing scaffolds failed to adequately approximate the mechanical properties of human supraspinatus tendons. Combining the macroscopic mechanical properties of a synthetic scaffold with the micro mechanical properties of biologic scaffold could better achieve this goal. Future work should focus on advancing techniques to create new scaffolds with more desirable mechanical properties. This may help improve outcomes for rotator cuff surgery patients.


Assuntos
Materiais Biocompatíveis , Teste de Materiais , Lesões do Manguito Rotador/cirurgia , Alicerces Teciduais , Idoso , Idoso de 80 Anos ou mais , Fenômenos Biomecânicos , Cadáver , Humanos , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Tendões/transplante , Resistência à Tração
8.
Acta Orthop ; 88(6): 606-611, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28880113

RESUMO

Background and purpose - There is a need to understand the reasons why a high proportion of rotator cuff repairs fail to heal. Using data from a large randomized clinical trial, we evaluated age and tear size as risk factors for failure of rotator cuff repair. Patients and methods - Between 2007 and 2014, 65 surgeons from 47 hospitals in the National Health Service (NHS) recruited 447 patients with atraumatic rotator cuff tendon tears to the United Kingdom Rotator Cuff Trial (UKUFF) and 256 underwent rotator cuff repair. Cuff integrity was assessed by imaging in 217 patients, at 12 months post-operation. Logistic regression analysis was used to determine the influence of age and intra-operative tear size on healing. Hand dominance, sex, and previous steroid injections were controlled for. Results - The overall healing rate was 122/217 (56%) at 12 months. Healing rate decreased with increasing tear size (small tears 66%, medium tears 68%, large tears 47%, and massive tears 27% healed). The mean age of patients with a healed repair was 61 years compared with 64 years for those with a non-healed repair. Mean age increased with larger tear sizes (small tears 59 years, medium tears 62 years, large tears 64 years, and massive tears 66 years). Increasing age was an independent factor that negatively influenced healing, even after controlling for tear size. Only massive tears were an independent predictor of non-healing, after controlling for age. Interpretation - Although increasing age and larger tear size are both risks for failure of rotator cuff repair healing, age is the dominant risk factor.


Assuntos
Artroscopia/efeitos adversos , Lesões do Manguito Rotador/diagnóstico , Manguito Rotador/cirurgia , Cicatrização , Fatores Etários , Feminino , Seguimentos , Humanos , Masculino , Período Pós-Operatório , Estudos Retrospectivos , Fatores de Risco , Lesões do Manguito Rotador/epidemiologia , Lesões do Manguito Rotador/cirurgia , Fatores de Tempo , Falha de Tratamento
9.
J Cell Physiol ; 231(1): 36-49, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26058815

RESUMO

Globally health care spending is increasing unsustainably. This is especially true of the treatment of musculoskeletal (MSK) disease where in the United States the MSK disease burden has doubled over the last 15 years. With an aging and increasingly obese population, the surge in MSK related spending is only set to worsen. Despite increased funding, research and attention to this pressing health need, little progress has been made toward novel therapies. Tissue engineering and regenerative medicine (TERM) strategies could provide the solutions required to mitigate this mounting burden. Biomaterial-based treatments in particular present a promising field of potentially cost-effective therapies. However, the translation of a scientific development to a successful treatment is fraught with difficulties. These barriers have so far limited translation of TERM science into clinical treatments. It is crucial for primary researchers to be aware of the barriers currently restricting the progression of science to treatments. Researchers need to act prospectively to ensure the clinical, financial, and regulatory hurdles which seem so far removed from laboratory science do not stall or prevent the subsequent translation of their idea into a treatment. The aim of this review is to explore the development and translation of new treatments. Increasing the understanding of these complexities and barriers among primary researchers could enhance the efficiency of biomaterial translation.


Assuntos
Materiais Biocompatíveis , Terapia Baseada em Transplante de Células e Tecidos , Medicina Regenerativa/tendências , Pesquisa/tendências , Engenharia Tecidual , Envelhecimento/fisiologia , Animais , Humanos
10.
Cell Stem Cell ; 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38917807

RESUMO

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.

11.
Nat Commun ; 15(1): 1394, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38374174

RESUMO

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.


Assuntos
Bursite , Humanos , c-Mer Tirosina Quinase/metabolismo , Inflamação/metabolismo , Membrana Sinovial/metabolismo , Fibrose
12.
Mol Ther ; 25(10): 2243-2244, 2017 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-28939087

Assuntos
MicroRNAs , Tendões
13.
Arthritis Res Ther ; 25(1): 27, 2023 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-36800974

RESUMO

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.


Assuntos
Cartilagem Articular , Osteoartrite , Humanos , Osteoartrite/tratamento farmacológico , Osteoartrite/genética , Osteoartrite/complicações , Osso e Ossos , Membrana Sinovial , Gerenciamento Clínico
14.
Rheumatol Adv Pract ; 7(2): rkad034, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38606003

RESUMO

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.

15.
Lancet Rheumatol ; 5(9): e553-e563, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38251499

RESUMO

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.


Assuntos
Artrite Reumatoide , Doenças Musculoesqueléticas , Osteoartrite , Animais , Humanos , Reações Cruzadas , Modelos Animais de Doenças
16.
Arthritis Res Ther ; 25(1): 154, 2023 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-37612718

RESUMO

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.


Assuntos
Artroplastia do Joelho , Osteoartrite , Humanos , Articulação do Joelho , Fibroblastos , Antígenos CD34
17.
Transl Sports Med ; 2022: 2799665, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-38655164

RESUMO

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.

19.
Front Bioeng Biotechnol ; 9: 795830, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35004653

RESUMO

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.

20.
Front Immunol ; 12: 676173, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34054865

RESUMO

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.


Assuntos
Condrócitos/imunologia , Interleucina-17/fisiologia , Osteoartrite do Joelho/etiologia , Membrana Sinovial/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Células Cultivadas , Condrócitos/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Humanos , Interleucina-17/farmacologia , NF-kappa B/fisiologia , Osteoartrite do Joelho/imunologia , Receptores de Interleucina-17/análise , Transdução de Sinais/efeitos dos fármacos , Membrana Sinovial/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/fisiologia
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