Arthritis Research Center for Sport

Nottingham, United Kingdom

Arthritis Research Center for Sport

Nottingham, United Kingdom
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Sanchez C.,University of Liège | Bay-Jensen A.-C.,Biomarkers and Research | Pap T.,University of Munster | Dvir-Ginzberg M.,Hebrew University of Jerusalem | And 6 more authors.
Osteoarthritis and Cartilage | Year: 2017

The extracellular matrix (ECM) of articular cartilage is comprised of complex networks of proteins and glycoproteins, all of which are expressed by its resident cell, the chondrocyte. Cartilage is a unique tissue given its complexity and ability to resist repeated load and deformation. The mechanisms by which articular cartilage maintains its integrity throughout our lifetime is not fully understood, however there are numerous regulatory pathways known to govern ECM turnover in response to mechanical stimuli. To further our understanding of this field, we envision that proteomic analysis of the secretome will provide information on how the chondrocyte remodels the surrounding ECM in response to load, in addition to providing information on the metabolic state of the cell. In this review, we attempt to summarize the recent mass spectrometry-based proteomic discoveries in healthy and diseased cartilage and chondrocytes, to facilitate the discovery of novel biomarkers linked to degenerative pathologies, such as osteoarthritis (OA). © 2017 Osteoarthritis Research Society International.


Tran G.,University of Leeds | Hensor E.M.A.,University of Leeds | Ray A.,University of Leeds | Kingsbury S.R.,University of Leeds | And 3 more authors.
Arthritis Research and Therapy | Year: 2017

Background: Ultrasound is increasingly used to evaluate shoulder pain, but the benefits of this are unclear. In this study, we examined whether ultrasound-defined pathologies have implications for clinical outcomes. Methods: We extracted reported pathologies from 3000 ultrasound scans of people with shoulder pain referred from primary care. In latent class analysis (LCA), we identified whether individual pathologies clustered in groups. Optimal group number was determined by the minimum Bayesian information criterion. A questionnaire was sent to all patients scanned over a 12-month period (n = 2322). Data collected included demographics, treatments received, current pain and function. The relationship between pathology-defined groups and clinical outcomes was examined. Results: LCA revealed four groups: (1) bursitis with limited inflammation elsewhere (n = 1280), (2) bursitis with extensive inflammation (n = 595), (3) rotator cuff tears (n = 558) and (4) limited pathology (n = 567). A total of 777 subjects (33%) completed questionnaires. The median (IQR) duration post-ultrasound scan was 25 (22-29) months. Subsequent injections were most common in groups 1 and 2 (groups 1-4 76%, 67%, 48% and 61%, respectively); surgery was most common in group 3 (groups 1-4 23%, 21%, 28% and 16%, respectively). Shoulder Pain and Disability Index scores were highest in group 3 (median 48 and 30, respectively) and lowest in group 4 (median 32 and 9, respectively). Patients in group 4 who had surgery reported poor outcomes. Conclusions: In a community-based population, we identified clusters of pathologies on the basis of ultrasound. Our retrospective data suggest that these groups have different treatment pathways and outcomes. This requires replication in a prospective study to determine the value of a pathology-based classification in people with shoulder pain. © 2017 The Author(s).


Elayyan J.,Hebrew University of Jerusalem | Lee E.-J.,University of Ulsan | Gabay O.,U.S. Food and Drug Administration | Smith C.A.,University of Manchester | And 7 more authors.
FASEB Journal | Year: 2017

Reduced SIRT1 activity and levels during osteoarthritis (OA) promote gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase in matrix metalloproteinase (MMP) 13, partially because of enhanced LEF1 transcriptional activity. In this study,we assessed the role of SIRT1 in LEF1-mediatedMMP13gene expression in human OA chondrocytes. Results showed that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1β, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression; however, overexpression of SIRT1 during IL-1β challenge impeded LEF1 levels and MMP13 gene expression. Previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, but we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mouse articular cartilage from Sirt1-/- presented increased LEF1 and MMP13 protein levels, similar to humanOA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in humanOAchondrocytes,which appears to bemediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression. © The Author(s).


Matta C.,Debrecen University | Mobasheri A.,Arthritis Research Center for Sport | Mobasheri A.,University of Bradford | Mobasheri A.,King Abdulaziz University | Mobasheri A.,University of Nottingham
Cellular Signalling | Year: 2014

During chondrogenesis, complex intracellular signalling pathways regulate an intricate series of events including condensation of chondroprogenitor cells and nodule formation followed by chondrogenic differentiation. Reversible phosphorylation of key target proteins is of particular importance during this process. Among protein kinases known to be involved in these pathways, protein kinase C (PKC) subtypes play pivotal roles. However, the precise function of PKC isoenzymes during chondrogenesis and in mature articular chondrocytes is still largely unclear. In this review, we provide a historical overview of how the concept of PKC-mediated chondrogenesis has evolved, starting from the first discoveries of PKC isoform expression and activity. Signalling components upstream and downstream of PKC, leading to the stimulation of chondrogenic differentiation, are also discussed. Although it is evident that we are only at the beginning to understand what roles are assigned to PKC subtypes during chondrogenesis and how they are regulated, there are many yet unexplored aspects in this area. There is evidence that calcium signalling is a central regulator in differentiating chondroprogenitors; still, clear links between intracellular calcium signalling and prototypical calcium-dependent PKC subtypes such as PKCalpha have not been established. Exploiting putative connections and shedding more light on how exactly PKC signalling pathways influence cartilage formation should open new perspectives for a better understanding of healthy as well as pathological differentiation processes of chondrocytes, and may also lead to the development of novel therapeutic approaches. © 2014.


Hdud I.M.,University of Nottingham | Mobasheri A.,University of Nottingham | Mobasheri A.,Medical Research Council Arthritis Research Center for Musculoskeletal Ageing Research | Mobasheri A.,Arthritis Research Center for Sport | And 3 more authors.
American Journal of Physiology - Cell Physiology | Year: 2014

The metabolic activity of articular chondrocytes is influenced by osmotic alterations that occur in articular cartilage secondary to mechanical load. The mechanisms that sense and transduce mechanical signals from cell swelling and initiate volume regulation are poorly understood. The purpose of this study was to investigate how the expression of two putative osmolyte channels [transient receptor potential vanilloid 4 (TRPV4) and large-conductance Ca2+-activated K+ (BKCa)] in chondrocytes is modulated in different osmotic conditions and to examine a potential role for MAPKs in this process. Isolated equine articular chondrocytes were subjected to anisosmotic conditions, and TRPV4 and BKCa channel expression and ERK1/2 and p38 MAPK protein phosphorylation were investigated using Western blotting. Results indicate that the TRPV4 channel contributes to the early stages of hypo-osmotic stress, while the BKCa channel is involved in responding to elevated intracellular Ca2+ and mediating regulatory volume decrease. ERK1/2 is phosphorylated by hypo-osmotic stress (P < 0.001), and p38 MAPK is phosphorylated by hyperosmotic stress (P < 0.001). In addition, this study demonstrates the importance of endogenous ERK1/2 phosphorylation in TRPV4 channel expression, where blocking ERK1/2 by a specific inhibitor (PD98059) prevented increased levels of the TRPV4 channel in cells exposed to hypo-osmotic stress and decreased TRPV4 channel expression to below control levels in iso-osmotic conditions (P < 0.001). © 2014 the American Physiological Society.


Jackson K.A.,University of Oxford | Glyn-Jones S.,University of Oxford | Batt M.E.,Arthritis Research Center for Sport | Arden N.K.,University of Oxford | Newton J.L.,University of Oxford
BMJ Open | Year: 2015

Objective: Hip pain and injury as a result of activity can lead to the development of early hip osteoarthritis (OA) in susceptible individuals. Our understanding of the factors that increase susceptibility continues to evolve. The ability to clearly identify individuals (and cohorts) with activity-related hip pain who are at risk of early hip OA is currently lacking. The purpose of this study was to gain expert consensus on which key clinical measures might help predict the risk of early hip OA in individuals presenting with activity-related hip pain. The agreed measures would constitute a standardised approach to initial clinical assessment to help identify these individuals. Methods: This Dephi study used online surveys to gain concordance of expert opinion in a structured process of 'rounds'. In this study, we asked 'What outcome measures are useful in predicting hip OA in activityrelated hip pain?' The Delphi panel consisted of experts from sport and exercise medicine, orthopaedics, rheumatology, physiotherapy and OA research. Results: The study identified key clinical measures in the history, examination and investigations (plain anteroposterior radiograph and femoroacetabular impingement views) that the panel agreed would be useful in predicting future risk of hip OA when assessing activity-related hip pain. The panel also agreed that certain investigations and tests (eg, MR angiography) did not currently have a role in routine assessment. There was a lack of consensus regarding the role of MRI, patient-reported outcome measures (PROMs) and certain biomechanical and functional assessments. Conclusions: We provide a standardised approach to the clinical assessment of patients with activity-related hip pain. Assessment measures rejected by the Delphi panel were newer, more expensive investigations that currently lack evidence. Assessment measures that did not reach consensus include MRI and PROMs. Their role remains ambiguous and would benefit from further research.


Wilson C.,University of Bath | Perkin O.J.,University of Bath | Perkin O.J.,Arthritis Research Center for Sport | McGuigan M.P.,University of Bath | And 2 more authors.
PLoS ONE | Year: 2016

The aim of this study was to determine the effect of aging on power generation and joint coordination during a leg press, in order to increase understanding of how functional movements are affected during the aging process. 44 older and 24 younger adults performed eight sub±maximal power repetitions on a seated leg press dynamometer. Peak power and velocity (at 40% maximum resistance) were measured along with the coordination (coupling angle) of the lower limb joints using the vector coding technique. The younger adults produced significantly greater peak power than the older adults (mean ± SD; 762W± 245 vs 361W± 162, p < 0.01) and at higher peak velocities (mean ± SD; 1.37 m/s ± 0.05 vs 1.00 m/s ± 0.06, p < 0.01). The older adults produced less consistent values of peak power than younger adults, evidenced by a higher coefficient of variation (mean ± SD; 7.6% ± 5.2 vs 5.0% ± 3.0, p < 0.01), however, there was significantly less variability in the coupling angles displayed by the older adults compared to the younger adults (mean ± SD; 2.0° ± 1.1 vs 3.5° ± 2.7, p < 0.01 (ankle±knee); 1.7° ± 0.6 vs 4.1° ± 3.0, p < 0.01 (knee±hip)). The results of this study demonstrate that older adults display higher outcome variability but lower variability in technique (coordination). The more rigid movement strategies displayed by the older adults potentially reflects an increased risk of overuse injury due to repetitive demands on the same structures, or the reduced ability to respond to unexpected situations due to a lack of flexibility in joint control. © 2016 Wilson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Dvir-Ginzberg M.,Hebrew University of Jerusalem | Mobasheri A.,University of Surrey | Mobasheri A.,Arthritis Research Center for Sport | Kumar A.,Hebrew University of Jerusalem
Current Rheumatology Reports | Year: 2016

The past decade has witnessed many advances in the understanding of sirtuin biology and related regulatory circuits supporting the capacity of these proteins to serve as energy-sensing molecules that contribute to healthspan in various tissues, including articular cartilage. Hence, there has been a significant increase in new investigations that aim to elucidate the mechanisms of sirtuin function and their roles in cartilage biology, skeletal development, and pathologies such as osteoarthritis (OA), rheumatoid arthritis (RA), and intervertebral disc degeneration (IVD). The majority of the work carried out to date has focused on SIRT1, although SIRT6 has more recently become a focus of some investigations. In vivo work with transgenic mice has shown that Sirt1 and Sirt6 are essential for maintaining cartilage homeostasis and that the use of sirtuin-activating molecules such as resveratrol may have beneficial effects on cartilage anabolism. Current thinking is that SIRT1 exerts positive effects on cartilage by encouraging chondrocyte survival, especially under stress conditions, which may provide a mechanism supporting the use of sirtuin small-molecule activators (STACS) for future therapeutic interventions in OA and other degenerative pathologies of joints, especially those that involve articular cartilage. © 2016, Springer Science+Business Media New York.


PubMed | Arthritis Research Center for Sport and University of Oxford
Type: Consensus Development Conference | Journal: BMJ open | Year: 2015

Hip pain and injury as a result of activity can lead to the development of early hip osteoarthritis (OA) in susceptible individuals. Our understanding of the factors that increase susceptibility continues to evolve. The ability to clearly identify individuals (and cohorts) with activity-related hip pain who are at risk of early hip OA is currently lacking. The purpose of this study was to gain expert consensus on which key clinical measures might help predict the risk of early hip OA in individuals presenting with activity-related hip pain. The agreed measures would constitute a standardised approach to initial clinical assessment to help identify these individuals.This Dephi study used online surveys to gain concordance of expert opinion in a structured process of rounds. In this study, we asked What outcome measures are useful in predicting hip OA in activity-related hip pain? The Delphi panel consisted of experts from sport and exercise medicine, orthopaedics, rheumatology, physiotherapy and OA research.The study identified key clinical measures in the history, examination and investigations (plain anteroposterior radiograph and femoroacetabular impingement views) that the panel agreed would be useful in predicting future risk of hip OA when assessing activity-related hip pain. The panel also agreed that certain investigations and tests (eg, MR angiography) did not currently have a role in routine assessment. There was a lack of consensus regarding the role of MRI, patient-reported outcome measures (PROMs) and certain biomechanical and functional assessments.We provide a standardised approach to the clinical assessment of patients with activity-related hip pain. Assessment measures rejected by the Delphi panel were newer, more expensive investigations that currently lack evidence. Assessment measures that did not reach consensus include MRI and PROMs. Their role remains ambiguous and would benefit from further research.


PubMed | Arthritis Research Center for Sport and King Abdulaziz University
Type: Journal Article | Journal: Annals of physical and rehabilitation medicine | Year: 2016

Osteoarthritis (OA) is one of the most common forms of arthritis. There is accumulating evidence to suggest that OA is an inflammatory disease of the entire synovial joint and has multiple phenotypes. This presents the OA research community with new challenges and opportunities. The main challenge is to understand the root cause of the disease and identify differences and similarities between OA phenotypes. The key opportunity is the possibility of developing personalized and individualized prevention and treatment strategies for OA patients with different phenotypes of the disease. Indeed, it has been suggested that this is the era of personalized prevention for OA. The aim of this mini-review paper is to focus on the pathophysiological aspects of OA development and progression, review the current concepts and discuss the future of personalized medicine for OA.The PubMed/MEDLINE bibliographic database was searched using the keywords pathophysiology and osteoarthritis.The PubMed/MEDLINE search yielded more than 12,000 relevant papers. A selection of these papers is reviewed here.There has been slow but steady progress in our understanding of the pathophysiology of OA over the last two decades. However, large gaps remain in our knowledge of OA pathogenesis and this impacts negatively on patients and drug development pipeline. In the absence of new pharmaceutical agents and disease modifying osteoarthritis drugs (DMOADs) it is clear that lifestyle modification and physical activity are important and may delay the need for surgical intervention.

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