Dennis McGonagle

University of Leeds, Leeds, England, United Kingdom

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Publications (253)1523.16 Total impact

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    ABSTRACT: Fracture healing is a complex process regulated by a variety of cells and signalling molecules which act both locally and systemically. The aim of this study was to investigate potential changes in patients' mesenchymal stem cells (MSCs) in the iliac crest (IC) bone marrow (BM) and in peripheral blood (PB) in relation to the severity of trauma and to correlate them with systemic changes reflective of inflammatory and platelet responses following fracture. ICBM samples were aspirated from two trauma groups: isolated trauma and polytrauma (n = 8 and 18, respectively) at two time-points post-fracture and from non-trauma controls (n = 7). Matched PB was collected every other day for a minimum of 14 days. BM MSCs were enumerated using colony forming-fibroblast (CFU-F) assay and flow cytometry for the CD45-CD271+ phenotype. Regardless of the severity of trauma, no significant increase or decrease in BM MSCs was observed following fracture and MSCs were not mobilised into PB. However, direct positive correlations were observed between changes in the numbers of aspirated BM MSCs and time-matched changes in their serum PDGF-AA and -BB. In vitro, patients' serum induced MSC proliferation in a manner reflecting changes in PDGFs. PDGF receptors CD140a and CD140b were expressed on native CD45-CD271+ BM MSCs (average 12% and 64%, respectively) and changed over time in direct relationship with platelets/PDGFs. Platelet lysates and other platelet-derived products are used to expand MSCs ex vivo. This study demonstrates that endogenous PDGFs can influence MSC responses in vivo. This indicates a highly dynamic, rather than static, MSC nature in humans.
    BMC Medicine 12/2015; 13(1):6. · 7.28 Impact Factor
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    Jennifer Ng, Ai Lyn Tan, Dennis McGonagle
    Annals of the rheumatic diseases. 01/2015;
  • Rheumatology (Oxford, England) 11/2014; · 4.44 Impact Factor
  • Peggy Jacques, Dennis McGonagle
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    ABSTRACT: Given that entheses are sites of high mechanical stress that concentrate the forces of large contracting muscles down onto a small footprint of bone contact, it was recognized nearly 60 decades ago that stress and injury at such sites may play a role in the pathogenesis of mechanically related enthesopathy. In recent years, the role of mechanical stress and its related consequences on inflammatory enthesitis have also been recognized. Clinical imaging studies and experimental animal models of spondyloarthropathy including tumor necrosis factor (TNF) transgenic models and interleukin (IL)-23 overexpression systems are associated with a primary enthesitis with disease subsequently spreading to adjacent joint structures including the synovium and bone. Joint mechanical stress, without discernible microdamage or injury, leads to spondyloarthritis (SpA) in a TNF transgenic model. Normal-aged human entheses often demonstrate microdamage, but it is unclear whether an abnormal response to mechanical stress alone or the need for stress-induced microdamage is involved in human disease initiation. Clinically, the contribution of mechanical stress to SpA including psoriatic arthritis (PsA) helps conceptualize the disease in a new way and provides obvious mechanistic links to skin and nail Koebner responses. It also offers novel epidemiological explanations for why PsA develops in subjects with high body mass indices most typically in the fourth and fifth decades. Molecularly, the monogenic forms of SpA including caspase recruitment domain-containing protein 14 (CARD14) and IL36RN mutations have site-specific expression of mutated proteins in the skin, thus offering a direct molecular link between local inflammation-related pathway dysregulation and local stress or injury in disease causation. Given that many of the pathways that govern both immunity and mechanical stress including extracellular-signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) are shared, it may be difficult to develop strategies that selectively target mechanical stress-related pathways. However, occupational- and obesity-related factors may be potentially modifiable in susceptible individuals to prevent or ameliorate disease. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Bailli&egrave re s Best Practice and Research in Clinical Rheumatology 10/2014; 28(5):703-710. · 3.06 Impact Factor
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    ABSTRACT: Dactylitis is a hallmark of psoriatic arthritis (PsA) where flexor tenosynovitis is common. This study explored the microanatomical basis of dactylitis using high-resolution MRI (hrMRI) to visualise the small entheses around the digits.
    Annals of the Rheumatic Diseases 09/2014; · 9.27 Impact Factor
  • Dennis McGonagle, Kay-Geert A Hermann, Ai Lyn Tan
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    ABSTRACT: Rheumatologists have long considered OA and PsA as two completely distinct arthropathies. This review highlights how some forms of generalized OA and PsA may afflict the same entheseal-associated anatomical territories. While degeneration or inflammation may be clearly discernible at the two extremes, there may be a group of patients where differentiation is impossible. Misdiagnosis of a primary degeneration-related pathology as being part of the PsA spectrum could lead to apparent failure of disease-modifying agents, including apparent anti-TNF and apparent IL23/17 axis therapy failure. This is not a reflection of poor clinical acumen, but rather a failure to appreciate that the pathological process overlaps in the two diseases. Whether the category of OA-PsA overlap disease exists or whether it represents the co-occurrence of two common arthropathies that afflict the same anatomical territories has implications for the optimal diagnosis and management of both OA and PsA.
    Rheumatology (Oxford, England) 09/2014; · 4.44 Impact Factor
  • Dennis McGonagle, Kay-Geert A Hermann, Ai Lyn Tan
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    ABSTRACT: Rheumatologists have long considered OA and PsA as two completely distinct arthropathies. This review highlights how some forms of generalized OA and PsA may afflict the same entheseal-associated anatomical territories. While degeneration or inflammation may be clearly discernible at the two extremes, there may be a group of patients where differentiation is impossible. Misdiagnosis of a primary degeneration-related pathology as being part of the PsA spectrum could lead to apparent failure of disease-modifying agents, including apparent anti-TNF and apparent IL23/17 axis therapy failure. This is not a reflection of poor clinical acumen, but rather a failure to appreciate that the pathological process overlaps in the two diseases. Whether the category of OA-PsA overlap disease exists or whether it represents the co-occurrence of two common arthropathies that afflict the same anatomical territories has implications for the optimal diagnosis and management of both OA and PsA.
    Rheumatology (Oxford, England) 09/2014; · 4.44 Impact Factor
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    ABSTRACT: Objective This study explored posterior cruciate ligament (PCL) synovio-entheseal complex (SEC) microanatomy to determine whether it may participate in the early osteoarthritis (OA) disease process. Methods SEC microanatomy and OA features were evaluated in 14 non-arthritic cadaveric knees (mean age=69.9) using magnetic resonance imaging (MRI) and histology. MRI images of 49 subjects selected from the progression cohort of the Osteoarthritis Initiative were evaluated by a musculoskeletal radiologist using an original semi-quantitative method for features associated with OA at the PCL tibial enthesis. Statistical analysis was performed using chi-square and Wilcoxon signed-rank tests to evaluate associations between SEC configuration and OA features. Results The PCL formed a SEC-like structure encompassing bone- and ligament-lining intra-articular cartilages to which the posterior root of the medial meniscus contributed. Degenerative features at the PCL-SEC included: neovascularisation (44%), enthesis chondrocyte clustering (44%), collagen matrix fissuring at the enthesis (56%) and in the PCL itself (67%), tidemark duplication (44%), bone remodelling (44%) and microscopic inflammatory changes (33%). In the OAI cohort, SEC-related pathology included BMLs (69%) and osteophytosis (94%) at locations that corresponded to SEC-related cartilages. Posterior joint recess effusion (49%) was linked to MRI abnormalities at PCL-SEC cartilages (χ2 =7.27, p = 0.007). Conclusions The PCL has a prominent SEC configuration that is associated with microscopic OA changes in aged clinically non-diseased joints. MRI determined knee OA commonly exhibited pathological features at this site which was associated with adjacent joint effusion. Thus, the PCL-SEC could play a hitherto unappreciated role in the early OA disease process.
    Osteoarthritis and Cartilage 09/2014; 22(9). · 4.26 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • Miriam Wittmann, Dennis McGonagle, Thomas Werfel
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    ABSTRACT: This review focuses on treatment targets for the most common inflammatory skin diseases, eczema and psoriasis with an emphasis on cytokines expressed in the uppermost layer of the skin which is easily accessible for diagnostic and therapeutic approaches. Recently, a significant body of research has highlighted the influence of the skin barrier and the patients’ microbiome on skin inflammatory responses and we will comment on their impact on mediator regulation. Itch is a prominent dermatology symptom which is influenced by cytokines and can via itch–scratch cycle impact on the skin barrier and mediator expression associated with damage. Taking the contribution of pruritus and superficial skin damage into account, we address cytokines as targets for stratified treatment approaches in subgroups of eczema and psoriasis.
    Cytokine & Growth Factor Reviews 08/2014; · 6.54 Impact Factor
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    ABSTRACT: IntroductionGelatinous Heberden’s nodes (HNs), also termed synovial cysts, are a common form of generalized osteoarthritis (OA). We sought to determine whether HN cases at clinical presentation contained multipotential stromal cells (MSCs) and to explore whether such cells were more closely related to bone marrow (BM) or synovial fluid (SF) MSCs by transcriptional analysis.MethodsAt clinical presentation, gelatinous material was extracted/extruded from the distal phalangeal joint of OA patients with HNs. From this, plastic adherent cells were culture-expanded for phenotypic and functional characterization and comparison with BM- and SF-MSCs. Mesenchymal related gene expression was studied by using a custom-designed TaqMan Low Density Array to determine transcriptional similarities between different MSC groups and skin fibroblasts.ResultsIn all cases, HN material produced MSC-like colonies. Adherent cultures displayed an MSC phenotype (CD29+, CD44+, CD73+, CD81+, and CD90+ and CD14- CD19-, CD31-, CD34-, CD45-, and HLADR-) and exhibited osteogenic, chondrogenic lineage differentiation but weak adipogenesis. Gene cluster analysis showed that HN-MSCs were more closely related to SF- than normal or OA BM-MSCs with significantly higher expression of synovium-related gene markers such as bone morphogenic protein 4 (BMP4), bone morphogenetic protein receptor type 1A (BMPR1A), protein/leucine-rich end leucine-rich repeat protein (PRELP), secreted frizzled-related protein 4 (SFRP4), and tumor necrosis factor alpha-induced protein 6 (TNFAIP6) (P <0.05).ConclusionsGelatinous HNs derived from hand OA at clinical presentation contain a population of MSCs that share transcriptional similarities with SF-derived MSCs. Their aberrant entrapment within the synovial cysts may impact on their normal role in joint homeostasis.
    Arthritis Research & Therapy 06/2014; 16(3):R119. · 4.12 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: The aims of this study were to investigate the extent of MRI-determined joint disease (erosion and synovitis) in SLE and to link this to autoantibody profiles known to be relevant to SLE, including ACPA, RF and anti-RA33 antibodies.
    Rheumatology (Oxford, England) 05/2014; · 4.44 Impact Factor
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    ABSTRACT: To monitor progression to inflammatory arthritis (IA) in individuals with non-specific musculoskeletal (MSK) symptoms and positive anticyclic citrullinated peptide (anti-CCP) antibodies. To develop a pragmatic model to predict development of IA in this patient group. In this prospective observational cohort, patients with new non-specific MSK symptoms and positive anti-CCP were recruited from regional primary care and secondary care referrals. Clinical, imaging and serological parameters were assessed at baseline. Cox regression analysis was performed to identify predictors of progression to IA and develop a risk score to stratify patients at presentation. 100 consecutive patients (73 women, mean age 51 years) were followed up for median 19.8 months (range 0.1-69.0); 50 developed IA after a median 7.9 months (range 0.1-52.4), 34 within 12 months. The majority (43/50) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis. A model for progression to IA was devised using four variables: tenderness of hand or foot joints, early morning stiffness ≥30 min, high-positive autoantibodies, and positive ultrasonographic power Doppler signal. None of the five individuals at low risk (score 0) progressed to IA, compared with 31% of 29 at moderate risk (1-2) and 62% of 66 at high risk (≥3). Adding shared epitope increased the number at low risk (score 0-1; 0/11 progressed). In patients presenting with non-specific MSK symptoms and anti-CCP, the risk of progression to IA could be quantified using data available in clinical practice. The proposed risk score may be used to stratify patients for early therapeutic intervention. NCT02012764 at ClinicalTrials.gov.
    Annals of the rheumatic diseases 04/2014; · 9.27 Impact Factor
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    ABSTRACT: Aim: To enumerate and characterize multipotential stromal cells (MSCs) in a cellular bone allograft and compare with fresh age-matched iliac crest bone and bone marrow (BM) aspirate. Materials & methods: MSC characterization used functional assays, confocal/scanning electron microscopy and whole-genome microarrays. Resident MSCs were enumerated by flow cytometry following enzymatic extraction. Results: Allograft material contained live osteocytes and proliferative bone-lining cells defined as MSCs by phenotypic and functional capacities. Without cultivation/expansion, the allograft displayed an 'osteoinductive' molecular signature and the presence of CD45(-)CD271(+)CD73(+)CD90(+)CD105(+) MSCs; with a purity over 100-fold that of iliac crest bone. In comparison with BM, MSC numbers enzymatically released from one gram of cellular allograft were equivalent to approximately 45 ml of BM aspirate. Conclusion: Cellular allograft bone represents a unique nonimmune material rich in MSCs and osteocytes. This osteoinductive graft represents an attractive alternative to autograft bone or composite/synthetic grafts in orthopedics and broader regenerative medicine settings.
    Regenerative Medicine 03/2014; · 3.87 Impact Factor
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    ABSTRACT: The vast majority of literature pertaining to mesenchymal stem cells (MSC) immunomodulation has focussed on bone marrow derived MSC that are systemically infused to alleviate inflammatory conditions. Rheumatoid arthritis (RA) is the commonest autoimmune joint disease that has witnessed significant therapeutic advances in the past decade, but remains stubbornly difficult to treat in a subset of cases. Preclinical research has demonstrated that bone marrow, adipose, synovial and umbilical cord derived MSC all suppress the functions of different immune cells thus raising the possibility of new therapies for autoimmune diseases including RA. Indeed, preliminary evidence for MSC efficacy has been reported in some cases of RA and Systemic Lupus Erythromatosis (SLE). The potential use of BM-MSC for RA therapy is emerging but the use of synovial MSC (S-MSC) to suppress the exaggerated immune response within the inflamed joints remains rudimentary. Synovial fibroblasts that are likely derived from S-MSCs, also give rise to a cell cultured progeny termed fibroblast like synoviocytes (FLS), which are key players in the perpetuation of joint inflammation and destruction. A better understanding of the link between these cells and their biology could be a key to developing novel MSC based strategies for therapy. The review briefly focuses on BM-MSC and gives particular attention to joint niche synovial MSC and FLS with respect to immunoregulatory potential therapy roles.
    QJM: monthly journal of the Association of Physicians 02/2014; 107(7). · 2.46 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A114-A114. · 9.27 Impact Factor
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    ABSTRACT: Hypervascularization in finger clubbing is recognized, but its microanatomical basis remains unclear. This pilot descriptive study used magnetic resonance imaging (MRI) to explore this further. High-resolution MRI acquired with contrast agent was carried out in 4 patients with finger clubbing and 4 healthy volunteers. The anatomy of the nail bed, capsular structures, and bony changes were described. Marked nail bed thickening and contrast enhancement was noted in all clubbed fingers, with bone edema in 3 of the 4 patients. None of the healthy subjects had similar abnormalities. This confirms that hypervascularization of the nail bed observed in the microanatomy on high-resolution MRI is associated with clubbed appearances of the nails.
    The Journal of Rheumatology 01/2014; 41(3). · 3.17 Impact Factor
  • Annals of the rheumatic diseases 01/2014; · 9.27 Impact Factor
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    ABSTRACT: Adult stem cells are characterised by longer telomeres compared to mature cells from the same tissue. In this study, candidate CD146 (+) umbilical cord (UC) mesenchymal stem cells (MSCs) were purified by cell sorting from UC tissue digests and their telomere lengths were measured in comparison to donor-matched CD146-negative fraction. UC tissue fragments were enzymatically treated with collagenase and the cells were used for cell sorting, colony-forming fibroblast (CFU-F) assay or for long-term MSC cultivation. Telomere lengths were measured by qPCR in both culture-expanded MSCs and candidate native UC MSCs. Immunohistochemistry was undertaken to study the topography of CD146 (+) cells. Culture-expanded UC MSCs had a stable expression of CD73, CD90 and CD105, whereas CD146 declined in later passages which correlated with the shortening of telomeres in the same cultures. In three out of four donors, telomeres in candidate native UC MSCs (CD45 (-)CD235α (-)CD31 (-)CD146 (+)) were longer compared to donor-matched CD146 (-) population (CD45 (-)CD235α (-)CD31 (-)CD146 (-)). The frequency of CD45 (-)CD235α (-)CD31 (-)CD146 (+) cells measured by flow cytometry was ~1000-fold above that of donor-matched CFU-Fs (means 10.4% and 0.01%, respectively). CD146 (+) cells were also abundant in situ having a broad topography including high levels of positivity in muscle areas in addition to vessels.
    F1000Research. 01/2014; 3:126.
  • Laura J. Savage, Dennis G. McGonagle
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    ABSTRACT: The therapy of psoriatic arthritis (PsA) has blossomed in the past decade. Inhibition of tumor necrosis factor (TNF) has been at the fore of this approach and has paved the way for the investigation of many other potential pro-inflammatory and signaling pathways. Most of the initial studies of TNF inhibitors in PsA have been conducted in specific populations, largely focusing on those with established, peripheral joint disease. That said, in excess of 10 years’ worth of real world clinical experience has led to increased confidence in the wider use of these agents. We are now faced with an exciting time of discovery of many new molecules; these not only include new, large protein biological agents, but also smaller synthetic chemical molecules, many of which can be administered orally. Those currently under development are discussed within this article. Whilst there is scarce data about their real world efficacy and safety profile, it is evident that the therapeutic armamentarium for treating PsA will greatly increase in the foreseeable future and this is anticipated to improve patient outcomes.
    Biologics in Therapy. 12/2013; 3(2).
    This article is viewable in ResearchGate's enriched format
  • Dennis McGonagle, Rebecca C Thomas, Georg Schett
    Annals of the rheumatic diseases 11/2013; · 9.27 Impact Factor

Publication Stats

8k Citations
1,523.16 Total Impact Points

Institutions

  • 1997–2015
    • University of Leeds
      • • Leeds Institute of Rheumatic and Musculoskeletal Medicine
      • • Section of Clinical Musculoskeletal Disease
      • • NIHR Leeds Musculoskeletal Biomedical Research Unit
      • • Leeds Institute of Molecular Medicine (LIMM)
      Leeds, England, United Kingdom
  • 2004–2014
    • Leeds Teaching Hospitals NHS Trust
      • • Department of Trauma and Orthopaedics
      • • Department of Radiology
      Leeds, England, United Kingdom
  • 2011–2013
    • Istanbul Medical University
      İstanbul, Istanbul, Turkey
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
  • 2012
    • University of Verona
      Verona, Veneto, Italy
  • 2010–2012
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
  • 2009
    • National University of Ireland, Galway
      Gaillimh, Connaught, Ireland
    • National Institute for Health Research
      Londinium, England, United Kingdom
    • Imperial College London
      Londinium, England, United Kingdom
  • 2004–2009
    • Cardiff University
      • School of Biosciences
      Cardiff, WLS, United Kingdom
  • 2007–2008
    • St. James University
      Сент-Джеймс, New York, United States