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Chapman K.,University of Oxford | Chapman K.,Institute of Musculoskeletal science | Ferreira T.,University of Oxford | Morris A.,University of Oxford | And 2 more authors.
Genetic Epidemiology | Year: 2011

Large-scale meta-analyses of genome-wide association scans (GWAS) have been successful in discovering common risk variants with modest and small effects. The detection of lower frequency signals will undoubtedly require concerted efforts of at least similar scale. We investigate the sample size-dictated power limits of GWAS meta-analyses, in the presence and absence of modest levels of heterogeneity and across a range of different allelic architectures. We find that data combination through large-scale collaboration is vital in the quest for complex trait susceptibility loci, but that effect size heterogeneity across meta-analyzed studies drawn from similar populations does not appear to have a profound effect on sample size requirements. © 2011 Wiley Periodicals, Inc.


Bala Y.,University of Melbourne | Chapurlat R.,French Institute of Health and Medical Research | Felsenberg D.,Charité - Medical University of Berlin | Laroche M.,Toulouse University Hospital Center | And 9 more authors.
Journal of Bone and Mineral Research | Year: 2014

During early menopause, steady-state bone remodeling is perturbed; the number of basic multicellular units (BMUs) excavating cavities upon the endosteal surface exceeds the number (generated before menopause) concurrently refilling. Later in menopause, steady-state is restored; the many BMUs generated in early menopause refill as similarly large numbers of BMUs concurrently excavate new cavities. We hypothesized that risedronate reduces the number of cavities excavated. However, in younger postmenopausal women, the fewer cavities excavated will still exceed the fewer BMUs now refilling, so net porosity increases, but less than in controls. In older postmenopausal women, the fewer cavities excavated during treatment will be less than the many (generated during early menopause) now refilling, so net porosity decreases and trabecular volumetric bone mineral density (vBMD) increases. We recruited 324 postmenopausal women in two similarly designed double-blind placebo-controlled studies that included 161 younger (Group 1, ≤ 55 years) and 163 older (Group 2, ≥ 55 years) women randomized 2:1 to risedronate 35 mg/week or placebo. High-resolution peripheral computed tomography was used to image the distal radius and tibia. Cortical porosity was quantified using the StrAx1.0 software. Risedronate reduced serum carboxyterminal cross-linking telopeptide of type 1 bone collagen (CTX-1) and serum amino-terminal propeptide of type 1 procollagen (P1NP) by ∼50%. In the younger group, distal radius compact-appearing cortex porosity increased by 4.2% ± 1.6% (p = 0.01) in controls. This was prevented by risedronate. Trabecular vBMD decreased by 3.6% ± 1.4% (p = 0.02) in controls and decreased by 1.6% ± 0.6% (p = 0.005) in the risedronate-treated group. In the older group, changes did not achieve significance apart from a reduction in compact-appearing cortex porosity in the risedronate-treated group (0.9% ± 0.4%, p = 0.047). No between-group differences reached significance. Results were comparable at the distal tibia. Between-group differences were significant for compact-appearing cortex porosity (p = 0.005). Risedronate slows microstructural deterioration in younger and partly reverses it in older postmenopausal women, features likely to contribute to antifracture efficacy. © 2014 American Society for Bone and Mineral Research. © 2014 American Society for Bone and Mineral Research.


Dean B.J.F.,Institute of Musculoskeletal science | Franklin S.L.,Institute of Musculoskeletal science | Carr A.J.,Institute of Musculoskeletal science
Clinical Orthopaedics and Related Research | Year: 2013

Background: The pathogenesis of tendinopathy is complex and incompletely understood. Although significant advances have been made in terms of understanding the pathological changes in both the extracellular matrix and the cells involved, relatively little is known about the role of neuronal regulation in tendinopathy. The frequent mismatch between tendon pathology and pain may be explained, in part, by differences in the peripheral neuronal phenotype of patients. Questions/purposes: The primary purpose of this review was to determine whether evidence exists of changes in the peripheral neuronal phenotype in painful human tendinopathy and, if so, to identify the associated histological and molecular changes. The secondary purpose was to determine if any changes in the peripheral neuronal phenotype reported correlate with pain symptoms. Methods: We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines. The Medline and Embase databases were searched using specific search criteria. Only studies analyzing the peripheral tissue of patients with the clinical diagnosis of tendinopathy were included. Inclusion was agreed on by two independent researchers on review of abstracts or full text. Results: Overall in the 27 included studies, there was clear evidence of changes in the peripheral neuronal phenotype in painful human tendinopathy. The excitatory glutaminergic system was significantly upregulated in seven studies, there was a significant increase in sensory neuropeptide expression in four studies, and there were significant changes in the molecular morphology of tenocytes, blood vessels, and nerves. In rotator cuff tendinopathy, substance P has been shown to correlate with pain and the neural density in the subacromial bursa has been shown to correlate with rest pain. Conclusions: The peripheral neuronal phenotype is an important factor in the pathogenesis of painful human tendinopathy. Further research in this area specifically correlating tissue changes to clinical scores has great potential in further developing our understanding of the disease process. © 2013 The Association of Bone and Joint Surgeons®.


Ackermann P.W.,Karolinska University Hospital | Franklin S.L.,Institute of Musculoskeletal science | Dean B.J.F.,Institute of Musculoskeletal science | Carr A.J.,Institute of Musculoskeletal science | And 2 more authors.
Frontiers in Bioscience - Landmark | Year: 2014

The regulatory mechanisms involved in tendon homeostasis and repair are not fully understood. Accumulating data, however, demonstrate that the nervous system, in addition to afferent (sensory) functions, through efferent pathways plays an active role in regulating pain, inflammation, and tissue repair. In normal-, healing- and tendinopathic tendons three neurosignalling pathways consisting of autonomic, sensory and glutamatergic neuromediators have been established. In healthy tendons, neuromediators are found in the paratenon, whereas the proper tendon is practically devoid of nerves, reflecting that normal tendon homeostasis is regulated by pro- and antiinflammatory mediators from the tendon surroundings. During tendon repair, however, there is extensive nerve ingrowth into the tendon proper and subsequent timedependent appearance of sensory, autonomic and glutamatergic mediators, which amplify and fine-tune inflammation and tendon regeneration. In tendinopathy, excessive and protracted sensory and glutamatergic signalling may be involved in inflammatory, painful and hypertrophic tissue reactions. As our understanding of these processes improves, neuronal mediators may prove to be useful in the development of targeted pharmacotherapy and tissue engineering approaches to painful, degenerative and traumatic tendon disorders.


Reeve J.,Institute of Musculoskeletal Science | Loveridge N.,Addenbrookes Hospital | Loveridge N.,MRC Human Nutrition Research
Bone | Year: 2014

Every hip fracture begins with a microscopic crack, which enlarges explosively over microseconds. Most hip fractures in the elderly occur on falling from standing height, usually sideways or backwards. The typically moderate level of trauma very rarely causes fracture in younger people. Here, this paradox is traced to the decline of multiple protective mechanisms at many length scales from nanometres to that of the whole femur. With normal ageing, the femoral neck asymmetrically and progressively loses bone tissue precisely where the cortex is already thinnest and is also compressed in a sideways fall. At the microscopic scale of the basic remodelling unit (BMU) that renews bone tissue, increased numbers of actively remodelling BMUs associated with the reduced mechanical loading in a typically inactive old age augments the numbers of mechanical flaws in the structure potentially capable of initiating cracking. Menopause and over-deep osteoclastic resorption are associated with incomplete BMU refilling leading to excessive porosity, cortical thinning and disconnection of trabeculae. In the femoral cortex, replacement of damaged bone or bone containing dead osteocytes is inefficient, impeding the homeostatic mechanisms that match strength to habitual mechanical usage. In consequence the participation of healthy osteocytes in crack-impeding mechanisms is impaired. Observational studies demonstrate that protective crack deflection in the elderly is reduced. At the most microscopic levels attention now centres on the role of tissue ageing, which may alter the relationship between mineral and matrix that optimises the inhibition of crack progression and on the role of osteocyte ageing and death that impedes tissue maintenance and repair. This review examines recent developments in the understanding of why the elderly hip becomes fragile. This growing understanding is suggesting novel testable approaches for reducing risk of hip fracture that might translate into control of the growing worldwide impact of hip fractures on our ageing populations. © 2014 The Authors.


Tilley J.M.R.,University of Oxford | Chaudhury S.,Institute of Musculoskeletal science | Hakimi O.,Institute of Musculoskeletal science | Carr A.J.,Institute of Musculoskeletal science | Czernuszka J.T.,University of Oxford
Journal of Materials Science: Materials in Medicine | Year: 2012

Tissue engineering scaffolds encourage cell proliferation whilst degrading to facilitate tissue regeneration. Their mechanical properties therefore change, decreasing due to scaffold degradation and increasing due to extracellular matrix deposition. This work compares the changing properties of collagen scaffolds incubated in culture medium, with and without human tenocytes, in order to investigate the relationship between degradation and tenocyte proliferation. The material properties of scaffolds are compared over 26 days using mechanical testing, differential scanning calorimetry, infra-red spectroscopy, and histology and biochemical assays. For medium- only scaffolds, the mechanical properties decrease rapidly, while culture medium sulfhydryl content increases significantly, with no significant changes in the denaturation temperature of scaffold collagen content. Conversely, the mechanical properties and collagen content of tenocyteseeded scaffolds increase significantly while culture medium sulfhydryl content decreases and denaturation temperature remains the same. These results indicate that tenocytes proliferation both reduces the degradation of collagen scaffolds incubated in culture medium and produces scaffolds with improved properties. © 2012 Springer Science+Business Media, LLC.


Dean B.J.F.,Institute of Musculoskeletal science | Franklin S.L.,Institute of Musculoskeletal science | Murphy R.J.,Institute of Musculoskeletal science | Javaid M.K.,Institute of Musculoskeletal science | Carr A.J.,Institute of Musculoskeletal science
British Journal of Sports Medicine | Year: 2014

Background Glucocorticoid injection (GCI) and surgical rotator cuff repair are two widely used treatments for rotator cuff tendinopathy. Little is known about the way in which medical and surgical treatments affect the human rotator cuff tendon in vivo. We assessed the histological and immunohistochemical effects of these common treatments on the rotator cuff tendon. Study design Controlled laboratory study. Methods Supraspinatus tendon biopsies were taken before and after treatment from 12 patients undergoing GCI and 8 patients undergoing surgical rotator cuff repair. All patients were symptomatic and none of the patients undergoing local GCI had full thickness tears of the rotator cuff. The tendon tissue was then analysed using histological techniques and immunohistochemistry. Results There was a significant increase in nuclei count and vascularity after rotator cuff repair and not after GCI (both p=0.008). Hypoxia inducible factor 1α (HIF-1α) and cell proliferation were only increased after rotator cuff repair (both p=0.03) and not GCI. The ionotropicN-methyl-D-aspartate receptor 1 (NMDAR1) glutamate receptor was only increased after GCI and not rotator cuff repair (p=0.016). An increase in glutamate was seen in both groups following treatment (both p=0.04), while an increase in the receptor metabotropic glutamate receptor 7 (mGluR7) was only seen after rotator cuff repair (p=0.016). Conclusions The increases in cell proliferation, vascularity and HIF-1α after surgical rotator cuff repair appear consistent with a proliferative healing response,and these features are not seen after GCI. The increase in the glutamate receptor NMDAR1 after GCI raises concerns about the potential excitotoxic tendon damage that may result from this common treatment.


Dean B.J.F.,Institute of Musculoskeletal science | Gwilym S.E.,Institute of Musculoskeletal science | Carr A.J.,Institute of Musculoskeletal science
British Journal of Sports Medicine | Year: 2013

If a patient asks 'why does my shoulder hurt?' the conversation will quickly turn to scientific theory and sometimes unsubstantiated conjecture. Frequently, the clinician becomes aware of the limits of the scientific basis of their explanation, demonstrating the incompleteness of our understanding of the nature of shoulder pain. This review takes a systematic approach to help answer fundamental questions relating to shoulder pain, with a view to providing insights into future research and novel methods for treating shoulder pain. We shall explore the roles of (1) the peripheral receptors, (2) peripheral pain processing or 'nociception', (3) the spinal cord, (4) the brain, (5) the location of receptors in the shoulder and (6) the neural anatomy of the shoulder. We also consider how these factors might contribute to the variability in the clinical presentation, the diagnosis and the treatment of shoulder pain. In this way we aim to provide an overview of the component parts of the peripheral pain detection system and central pain processing mechanisms in shoulder pain that interact to produce clinical pain.


Dean B.J.F.,Institute of Musculoskeletal science | Lostis E.,Institute of Musculoskeletal science | Oakley T.,Institute of Musculoskeletal science | Rombach I.,Institute of Musculoskeletal science | And 2 more authors.
Seminars in Arthritis and Rheumatism | Year: 2014

Objective: Our primary objective was to summarise the known effects of locally administered glucocorticoid on tendon tissue and tendon cells. Methods: We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. The search yielded 50 articles, which consisted of 13 human studies, 36 animal studies and one combined human/animal study. Results: Histologically, there was a loss of collagen organisation (6 studies) and an increase in collagen necrosis (3 studies). The proliferation (8 studies) and viability (9 studies) of fibroblasts was reduced. Collagen synthesis was decreased in 17 studies. An increased inflammatory cell infiltrate was shown in 4 studies. Increased cellular toxicity was demonstrated by 3 studies.The mechanical properties of tendon were investigated by 18 studies. Descriptively, 6 of these studies showed a decrease in mechanical properties, 3 showed an increase, while the remaining 9 showed no significant change. A meta-analysis of the mechanical data revealed a significant deterioration in mechanical properties, with an overall effect size of -0.67 (95% CI = 0.01 to -1.33) (data from 9 studies). Conclusions: Overall it is clear that the local administration of glucocorticoid has significant negative effects on tendon cells in vitro, including reduced cell viability, cell proliferation and collagen synthesis. There is increased collagen disorganisation and necrosis as shown by in vivo studies. The mechanical properties of tendon are also significantly reduced. This review supports the emerging clinical evidence that shows significant long-term harms to tendon tissue and cells associated with glucocorticoid injections. © 2014 Elsevier Inc.


Brown C.P.,Institute of Musculoskeletal science
Nature Reviews Rheumatology | Year: 2013

Nanoscience has arrived. Biological applications of nanoscience are particularly prominent and can be useful in a range of disciplines. Advances in nanoscience are underpinning breakthroughs in biomedical research and are beginning to be adopted by the rheumatology and musculoskeletal science communities. Within these fields, nanoscience can be applied to imaging, drug delivery, implant development, regenerative medicine, and the characterization of nanoscale features of cells, matrices and biomaterials. Nanoscience and nanotechnology also provide means by which the interaction of cells with their environment can be studied, thereby increasing the understanding of disease and regenerative processes. Although its potential is clear, nanoscience research tends to be highly technical, generally targeting an audience of physicists, chemists, materials scientists and engineers, and is difficult for a general audience to follow. This Review aims to step back from the most technical aspects of nanoscience and provide a widely accessible view of how it can be applied to advance the field of rheumatology, with an emphasis on technologies that can have an immediate impact on rheumatology and musculoskeletal research. © 2013 Macmillan Publishers Limited.

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