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    ABSTRACT: Osteoarthritis (OA) is a debilitating chronic condition widely prevalent in ageing populations. Because the pathology of the disease includes cartilage erosion and joint remodelling, OA patients experience a great deal of pain. Despite numerous studies, details of OA are frequently inseparable from other types of chronic pain, and its causes are unknown. In most circumstances in OA, the cartilage lacks afferent innervation, although other joint tissues contain nociceptive neurones. In addition to physical joint damage, there is a strong element of joint inflammation. Genetic studies have identified several associations between ion channels and OA pain, including NaV1.7, P2X7, and TRPV1, but several other channels have also been implicated. Many ion channels involved with OA pain are common to those seen in inflammatory pain. This review considers causes of OA pain and discusses three possible pain-reducing strategies involving ion channel modulation: chondroprotection, innate afferent nerve inhibition, and inhibition of inflammatory hyperalgesia. Future targets for OA pain analgesia could involve a number of ion channels.
    Current Pain and Headache Reports 12/2013; 17(12):378.
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    ABSTRACT: Tissue sensitisation and chronic pain have been described in chronic-active laminitis in the horse, making treatment of such cases difficult. Purinergic P2X receptors are linked to chronic pain and inflammation. The aim of this study was to examine the expression of purinergic P2X receptor subtypes 1, 2, 3 and 7 in the hoof, palmar digital vessels and nerve, dorsal root ganglia and spinal cord in horses with chronic-active laminitis (n=5) compared to non-laminitic horses (n=5). Immunohistochemical analysis was performed on tissue sections using antibodies against P2X receptor subtypes 1-3 and 7. In horses with laminitis, there was a reduction in the thickness of the tunica media layer of the palmar digital vein as a proportion of the whole vessel diameter (0.48±0.05) compared to the non-laminitic group (0.57±0.04; P=0.02). P2X receptor subtype 3 was expressed in the smooth muscle layer (tunica media) of the palmar digital artery of horses with laminitis, but was absent in horses without laminitis. There was strong expression of P2X receptor subtype 7 in the proliferating, partially keratinised, epidermal cells of the secondary epidermal lamellae in the hooves of horses with laminitis, but no immunopositivity in horses without laminitis.
    The Veterinary Journal 08/2013;
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    ABSTRACT: Osteochondral lesions are a major cause of pain and disability in several species including dogs, horses and human beings. The objective of this study was to assess three potential sources of canine cells for their osteochondral regenerative potential. Cartilage, synovium and adipose tissue cells were grown in pellet culture in chondrogenic or osteogenic media. Cartilage-derived pellets displayed the best chondrogenic differentiation as indicated by significantly higher COL2A1 and SOX9 mRNA expression, greater glycosaminoglycan content, and higher retention of Safranin-O stain compared to the synovium and adipose-derived cells. Following application of the osteogenic media, all three cell sources exhibited small areas of positive alizarin red staining. Poor intracellular alkaline phosphatase activity was found in all three cell types when stimulated although osteocalcin and RUNX2 expression were significantly increased. Cells isolated and cultured from canine articular cartilage retained their specific chondrocytic phenotype. Furthermore, canine adipocytes and synovial cells did not undergo chondrogenic differentiation and did not exhibit evidence of multipotency. Although osteogenic differentiation was initiated at a genomic level, phenotypic osteoblastic differentiation was not observed. The findings of this study suggest that cells isolated from canine adipose tissue and synovium are sub-optimal substitutes for chondrocytes when engineering articular cartilage in vitro.
    The Veterinary Journal 07/2013;
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    ABSTRACT: To identify the effect of alterations in physical parameters such as oxygen and pH on processes associated with cellular redox balance in osteoarthritic chondrocytes. Human osteoarthritic chondrocytes (HOAC) were isolated from total knee arthroplasty samples and cultured in 3D-alignate beads in four different oxygen tensions (<1%, 2%, 5% and 21% O2), at pH 7.2 and 6.2 and in the presence or absence of 10ng/ml, interleukin-1β (IL-1β). Cell viability, media glycosaminoglycan levels, media nitrate/nitrate levels, active MMP-13 and intracellular ATP were measured over a 96-hour time course. Intracellular reactive oxygen species, mitochondrial membrane potential, intracellular pH and reduced/oxidised glutathione (GSH/GSSG) were additionally measured after 48 hour incubation under these experimental conditions. Hypoxia (2% O2) and anoxia (<1% O2), acidosis (pH 6.2) and 10ng/ml IL-1β reduced HOAC cell viability and increased glycosaminoglycan media levels. Acidosis and IL-1β increased nitrite/nitrate release, but increases were moderate at 2% O2 and significantly reduced at <1% O2. Intracellular ATP was significantly reduced following hypoxia and anoxia and acidosis. At 48 hours cellular ROS levels were increased by acidosis and IL-1β but reduced in hypoxia and anoxia. Mitochondrial membrane potential was reduced in low oxygen, acidosis and IL-1β. Anoxia also resulted in intracellular acidosis. GSH/GSSG ratio was reduced in low oxygen conditions, acidosis and IL-1β. This study shows that oxygen and pH affect elements of the redox system in human osteoarthritic chondrocytes including cellular anti-oxidants, mitochondrial membrane potential and reactive oxygen species levels.
    Osteoarthritis and Cartilage 07/2013;
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    ABSTRACT: The predominant function of tendon is to position the limb during locomotion. Specific tendons also act as energy stores. Energy storing (ES) tendons are prone to injury, the incidence of which increases with age. This is likely related to their function; ES tendons are exposed to higher strains and require a greater ability to recoil than positional tendons. The specialised properties of ES tendons are thought to be achieved through structural and compositional differences. However, little is known about structure-function relationships in tendon. This study uses fascicles from the equine superficial digital flexor (SDFT) and common digital extensor (CDET) as examples of ES and positional tendons. We hypothesised that extension and recoil behaviour at the micro-level would differ between tendon types, and would alter with age in the injury prone SDFT. Supporting this, the results show that extension in the CDET is dominated by fibre sliding. By contrast, greater rotation was observed in the SDFT, suggesting a helical component to fascicles in this tendon. This was accompanied by greater recovery and less hysteresis loss in SDFT samples. In samples from aged SDFTs, the amount of rotation and the ability to recover decreased, while hysteresis loss increased. These findings indicate that fascicles in the ES SDFT may have a helical structure, enabling the more efficient recoil observed. Further, the helix structure appears to alter with ageing; this coincides with a reduction in the ability of SDFT fascicles to recoil. This may affect tendon fatigue resistance and predispose aged tendons to injury.
    Acta Biomaterialia 05/2013;
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    ABSTRACT: Footprints are the most direct source of evidence about locomotor biomechanics in extinct vertebrates. One of the principal suppositions underpinning biomechanical inferences is that footprint geometry correlates with dynamic foot pressure, which, in turn, is linked with overall limb motion of the trackmaker. In this study, we perform the first quantitative test of this long-standing assumption, using topological statistical analysis of plantar pressures and experimental and computer-simulated footprints. In computer-simulated footprints, the relative distribution of depth differed from the distribution of both peak and pressure impulse in all simulations. Analysis of footprint samples with common loading inputs and similar depths reveals that only shallow footprints lack significant topological differences between depth and pressure distributions. Topological comparison of plantar pressures and experimental beach footprints demonstrates that geometry is highly dependent on overall print depth; deeper footprints are characterized by greater relative forefoot, and particularly toe, depth than shallow footprints. The highlighted difference between 'shallow' and 'deep' footprints clearly emphasizes the need to understand variation in foot mechanics across different degrees of substrate compliance. Overall, our results indicate that extreme caution is required when applying the 'depth equals pressure' paradigm to hominin footprints, and by extension, those of other extant and extinct tetrapods.
    Journal of The Royal Society Interface 01/2013; 10(83):20130009.
  • Clinical Infectious Diseases 12/2012;
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    ABSTRACT: Few studies have examined the effect of dietary restriction in horses with equine metabolic syndrome (EMS). This study aimed to determine improvements in insulin sensitivity following dietary restriction for 6weeks, and to determine if the improvement would be greater in horses receiving short-chain fructo-oligosaccharides (sc-FOS). Dietary management involved feeding grass hay, restricted to 1.25% of body mass (BM) as daily dry matter intake and soaked in cold water prior to feeding, with the addition of a vitamin and mineral nutraceutical supplement with or without the addition of sc-FOS (10g/100kg). Soaking the hay resulted in a significant reduction in non-structural carbohydrates (38%, P=0.01), digestible energy (6.78%, P=0.01) and water soluble minerals. Following 6weeks of dietary restriction with soaked grass hay and nutraceutical supplement, horses lost an average of 6.8% BM and showed reductions in body condition score (BCS) and belly circumference. Sensitivity to insulin improved overall, as determined by the total insulin response during the combined glucose insulin test. The magnitude of improvement in insulin sensitivity was associated with the degree of insulin resistance recorded at outset, and the extent of overall losses in BM and BCS, but was independent of the addition of sc-FOS. The nutraceutical supplement was highly palatable and no adverse effects were noted. From the findings of this study a strict dietary program in combination with a specifically designed vitamin and mineral nutraceutical supplement can be recommended to obtain rapid improvements in BM, BCS and insulin sensitivity of animals presenting with EMS.
    The Veterinary Journal 11/2012;
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    ABSTRACT: Hypoxia and acidosis are recognized features of inflammatory arthroses. This study describes the effects of IGF-1 and TGF-β(1) on pH regulatory mechanisms in articular cartilage under hypoxic conditions. Acid efflux, reactive oxygen species (ROS), and mitochondrial membrane potential were measured in equine articular chondrocytes isolated in the presence of serum (10% fetal calf serum), IGF-1 (1, 10, 50, 100 ng/ml) or TGF-β(1) (0.1, 1, 10 ng/ml) and then exposed to a short-term (3 h) hypoxic insult (1% O(2) ). Serum and 100 ng/ml IGF-1 but not TGF-β(1) attenuated hypoxic regulation of pH homeostasis. IGF-1 appeared to act through mitochondrial membrane potential stabilization and maintenance of intracellular ROS levels in very low levels of oxygen. Using protein phosphorylation inhibitors PD98059 (25 µM) and wortmannin (200 nM) and Western blotting, ERK1/2 and PI-3 kinase pathways are important for the effect of IGF-1 downstream to ROS generation in normoxia but only PI-3 kinase is implicated in hypoxia. These results show that oxygen and growth factors interact to regulate pH recovery in articular chondrocytes by modulating intracellular oxygen metabolites. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.
    Journal of Orthopaedic Research 09/2012;
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    ABSTRACT: BACKGROUND & PURPOSE: Chondrocytes exist within cartilage and serve to maintain the extracellular matrix. It has been postulated that osteoarthritic (OA) chondrocytes lose the ability to regulate their volume, affecting extracellular matrix production. In previous studies we identified expression of epithelial sodium channels (ENaC) in human chondrocytes, but their function remained unknown. Although ENaC typically has Na(+) transport roles, it is also involved in the cell volume regulation of rat hepatocytes. ENaC is a member of the degenerin (Deg) family and ENaC/Deg-like channels have a low conductance and high sensitivity to benzamil. In this study we investigated whether canine chondrocytes express functional ENaC/Deg-like ion channels and, if so, what their function may be. EXPERIMENTAL APPROACH: Canine chondrocytes were harvested from dogs euthanatized for unassociated welfare reasons. We used immunohistochemistry and patch-clamp electrophysiology to investigate ENaC expression and video microscopy to analyse the effects of pharmacological inhibition of ENaC/Deg on cell volume regulation. KEY RESULTS: Immunofluorescence showed that canine chondrocytes expressed ENaC protein. Single-channel recordings demonstrated expression of a benzamil-sensitive Na(+) conductance (9pS) and whole-cell experiments show this to be approximately 1.5nS/cell with high selectivity for Na(+) . Benzamil hyperpolarised chondrocytes by approximately 8mV with a pD (2) 8.4. Chondrocyte regulatory volume decrease (RVI) was inhibited by benzamil (pD (2) 7.5), but persisted when extracellular Na(+) ions were replaced by Li(+) . CONCLUSION: Our data suggest that benzamil inhibits RVI by reducing the influx of Na(+) ions through ENaC/Deg-like ion channels and present ENaC/Deg as a possible target for pharmacological modulation of chondrocyte volume.
    British Journal of Pharmacology 08/2012;
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