Proceedings of the Musculoskeletal Health in the 21st Century Workshop of in joint

prognostic biomarkers a systemic can joint tissues contribute to OA pathogenesis, direct effects of have been to cause cell damage and inflammation by various mechanisms in several tissues Whether and how glucose directly affects joint tissues and cells is just beginning to be unraveled. Indirect effects of high glucose can result from enhanced formation of advanced glycation end products (AGEs) which accumulate in OA cartilage in an age-dependent manner and play a proinflammatory and pro-catabolic role mediated by activation of their specific receptor, RAGE, on chondrocytes and synovial cells. Some direct effects of high glucose have also been demonstrated, namely induction of IGF-1 resistance [1] and inhibition of dehydroascorbate transport which can compromise collagen synthesis [2]. Our studies have been aimed at determining whether and how hyperglycemia affects chondrocyte functions and contributes to OA development and progression. The results obtained showed that high and low glucose concentrations regulate the availability of facilitative glucose transporter (GLUT) isoforms and the glucose transport capacity Our laboratory research uses a basic science mechanistic approach to investigate the influence of endogenous damage-associated molecular patterns (DAMPs) in driving chronic inflammation in joints. Molecules of interest include interaction of the DAMPs tenascin-C and fibronectin with oral pathogens. Femoral acetabular impingement (FAI) is thought to be a key underlying reason for the development of osteoarthritis of the hip. There are two main types of FAI, cam-type and pincer-type. The cam-type FAI gives rise to cartilage delamination initially thought to occur on the acetabular side of the joint. The purpose of the current study was to look at the effects of cam-type impingement on the generation of shear strains at the bone/ cartilage interface, using both experimental and finite element simulation methods. Sagittal slices (n=9) of femoral porcine cartilage-bone, 10 mm thick, were loaded using a five-axis custom test machine with a curved (radius 90 mm) steel indenter. The five-axis test machine allowed the samples to be subjected to compression and mixed compression/shear loading regimens. The specimen strains were measured using two dimensional digital image correlation (DIC). Each test was also simulated using finite element analysis, and the results compared with the DIC data. The specimens were then cyclically loaded either with or without damage to the cartilage layers; damage simulated clinically reported lesions. Maximal shear strain was found at the cartilage-bone interface, and was a function of compressive loading level. The finite element predictions matched the DIC measurements. The two parameters that were most important in terms of shear strain were the cartilage thickness and contact area radius. It was found that increased cartilage thickness and increased contact radius gave rise to higher shear strains. Cyclically loading the damaged specimens produced features of cartilage delamination consistent with clinical observations. The results of this study indicate high shear strain at the bone/cartilage interface is a possible mechanism leading to cartilage delamination, and may be the mechanism behind cartilage degradation in patients with cam-type FAI. Folate-based radiotracers have been used in patients with cancer and inflammatory diseases to visualize folate receptor expressing cells using PET or SPECT techniques. Activated macrophages express folate receptor beta (FR- b ) and this allows specific imaging of these cells in-vivo . From previous work using SPECT imaging to visualize folate receptor expressing macrophages in both animal models and in patients with OA we know that macrophages are present in OA affected joints. However, it remains unclear what role these macrophages play in the different stages of OA and whether their role can be influenced by specific targeting. In Wistar rats osteoarthritis was induced using a low dose of intra-articular papain injections in one knee joint combined with exposure to a moderate exercise protocol. After six weeks and twelve an in vivo folate SPECT/CT scan and micro-CT analyses were performed. Macrophages from human peripheral blood monocytes were cultured (7 days) in the presence of GM-CSF (M1 proinflammatory phenotype) or M-CSF (M2 anti-inflammatory phenotype). Subsequently the macrophages were treated with LPS, cytokines (IL-4, IL-10, IFN-y) or a corticoid steroid (triamcinolone acetonide, 1µg/ml). Folate receptor beta (FR b ) as well as other macrophage marker expressions were measured using FACS. Intra-articular injections with triamcinolone strongly enhanced FR b + macrophage activation and fully prevented osteophyte formation. There were no beneficial effects of the corticoid steroid against cartilage degradation or subchondral bone sclerosis. In in-vitro cultures triamcinolone strongly induced the monocyte-macrophages differentiation towards CD163 + and FR b + cells, specifically in GM-CSF stimulated (M1) cultures. Addition of triamcinolone to M-CSF stimulated (M2) monocytes showed enhanced IL10 expression on mRNA level. In conclusion enhanced FR b expression in monocytes that were induced to macrophage differentiation. The triamcinolone injections stimulate synovial macrophage activation and triggers the macrophages towards a more anti-inflammatory subtype. large notochordal cells in the nucleus pulposus of 13% of the cell in young dogs and in predominant cell type in the nonchondrodystrophoid dogs ages chondrodystrophoid dogs early degenerative changes in the disc and a concomitant reduction in proteoglycan content, increased collagen, and loss of water content making the discs likely to herniate Certain lifestyle factors may increase or decrease risk of IVDD and this is a 20 year cohort study comparing medical and psychosocial outcomes of military personnel both exposed and not exposed, to significant trauma. The Bio-Mil-OA study, a sub-study of the ADVANCE study, is an ideal opportunity to investigate the predictive value of biomarkers in joint pain and osteoarthritis. The ADVANCE study is a 20 year cohort study of 600 combat casualties and 600 matched non exposed participants investigating the predictive value of biomarkers and trauma on the long term development of pain and OA in the hip and knee. Validated serum biomarkers for OA, knee and hip radiographs and patient reported outcomes for pain and function will be taken at baseline and at 5 years. The predictive value of the biomarkers in predicting OA development and progression and joint pain in those exposed to different levels of trauma will be investigated using quantitative immunoassays for catabolic markers of cartilage matrix degradation. long-term Exercise and Osteoarthritis is on secondary prevention of progression of injury and/or overuse to OA. Biomechanical and neurophysiological mechanisms of abnormal movement and joint loading are investigated using 3D motion analysis and electromyographic techniques, and evidence is emerging that mechanistic-based exercises can correct abnormal movement. Movement screening tools in clinical/field environments are used increasingly to assess movement control and functional performance, primarily in sport, to predict injury and/or inform intervention. Robustness of screening tools is variable, in terms of reliability, validity and prediction of injury risk. Consensus is needed for terminology and establishing which screening tests are appropriate for specific cohorts and movement problems. High quality longitudinal trails are needed to ensure effective use of exercise for OA prevention. Activity needs to be maintained for long-lasting effects but adherence to changing lifestyle remains a major challenge. For exercises targeting movement problems, studies need to elucidate which elements, modes, doses, and frequency and duration of exercise are optimal for specific joints and body regions. It remains unknown whether exercise can influence disease parthenogenesis and progression. Evidence of cost-effectiveness of exercise as a clinical intervention for OA is also needed. Understanding and overcoming barriers to exercise and enabling access will be crucial for widespread uptake of exercise. Translation research is needed to determine how to change practice and influence GP referral to exercise programmes. stress, reduced cell proliferation and abnormal ECM assembly are important pathological consequences of mutant protein expression. Ongoing work aims to consolidate data from other models of skeletal disorders using a systems biology approach as part of the EU FP7 SYBIL (Systems biology for the functional validation of genetic determinants of skeletal diseases) project, in order to gain a mechanistic understanding of disease processes and to deliver new and validated therapeutic targets. Key to delivery of new targets and therapies is the identification of relevant disease biomarkers, which will allow the monitoring of responses to therapeutic interventions. This is particularly critical for skeletal diseases, for which biopsy material is not readily accessible. We have identified differences in the extractability of a number of ECM components from the cartilage of MED and PSACH mouse models, relative to controls. The differences in extractability of these proteins (which include FACIT collagens (types XII and XIV), tenascins (C and X), and fetuin A) may represent differences in the stability of these proteins within the cartilage ECM, which might potentially be exploited for use as biomarkers of disease progression. We are currently using biochemical and mass spectrometry analysis of easily obtained biological samples such as blood, urine and cell culture medium in order to identify and validate novel biomarkers for skeletal diseases. Development of biocompatible materials has great potential in biomedical engineering both