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  • Suramin Inhibits Osteoarthritic Cartilage Degradation by Increasing Extracellular Levels of Chondroprotective Tissue Inhibitor of Metalloproteinases 3.

    12 December 2017

    Osteoarthritis is a common degenerative joint disease for which no disease-modifying drugs are currently available. Attempts to treat the disease with small molecule inhibitors of the metalloproteinases that degrade the cartilage matrix have been hampered by a lack of specificity. We aimed to inhibit cartilage degradation by augmenting levels of the endogenous metalloproteinase inhibitor, tissue inhibitor of metalloproteinases (TIMP)-3, through blocking its interaction with the endocytic scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1). We discovered that suramin (C51H40N6O23S6) bound to TIMP-3 with a KD value of 1.9 ± 0.2 nM and inhibited its endocytosis via LRP1, thus increasing extracellular levels of TIMP-3 and inhibiting cartilage degradation by the TIMP-3 target enzyme, adamalysin-like metalloproteinase with thrombospondin motifs 5. NF279 (8,8'-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt), a structural analog of suramin, has an increased affinity for TIMP-3 and increased ability to inhibit TIMP-3 endocytosis and protect cartilage. Suramin is thus a promising scaffold for the development of novel therapeutics to increase TIMP-3 levels and inhibit cartilage degradation in osteoarthritis.

  • Application of autofluorescence robotic histology for quantitative evaluation of the 3-dimensional morphology of murine articular cartilage.

    8 December 2017

    Murine models of osteoarthritis (OA) are increasingly important for understating pathogenesis and for testing new therapeutic approaches. Their translational potential is, however, limited by the reduced size of mouse limbs which requires a much higher resolution to evaluate their articular cartilage compared to clinical imaging tools. In experimental models, this tissue has been predominantly assessed by time-consuming histopathology using standardized semi-quantitative scoring systems. This study aimed to develop a novel imaging method for 3-dimensional (3D) histology of mouse articular cartilage, using a robotic system-termed here "3D histocutter"-which automatically sections tissue samples and serially acquires fluorescence microscopy images of each section. Tibiae dissected from C57Bl/6 mice, either naïve or OA-induced by surgical destabilization of the medial meniscus (DMM), were imaged using the 3D histocutter by exploiting tissue autofluorescence. Accuracy of 3D imaging was validated by ex vivo contrast-enhanced micro-CT and sensitivity to lesion detection compared with conventional histology. Reconstructions of tibiae obtained from 3D histocutter serial sections showed an excellent agreement with contrast-enhanced micro-CT reconstructions. Furthermore, osteoarthritic features, including articular cartilage loss and osteophytes, were also visualized. An in-house developed software allowed to automatically evaluate articular cartilage morphology, eliminating the subjectivity associated to semi-quantitative scoring and considerably increasing analysis throughput. The novelty of this methodology is, not only the increased throughput in imaging and evaluating mouse articular cartilage morphology starting from conventionally embedded samples, but also the ability to add the third dimension to conventional histomorphometry which might be useful to improve disease assessment in the model.

  • Understanding of regional variation in the use of surgery.

    12 December 2017

    The use of common surgical procedures varies widely across regions. Differences in illness burden, diagnostic practices, and patient attitudes about medical intervention explain only a small degree of regional variation in surgery rates. Evidence suggests that surgical variation results mainly from differences in physician beliefs about the indications for surgery, and the extent to which patient preferences are incorporated into treatment decisions. These two components of clinical decision making help to explain the so-called surgical signatures of specific procedures, and why some consistently vary more than others. Variation in clinical decision making is, in turn, affected by broad environmental factors, including technology diffusion, supply of specialists, local training frameworks, financial incentives, and regulatory factors, which vary across countries. Better scientific evidence about the comparative effectiveness of surgical and non-surgical interventions could help to mitigate regional variation, but broader dissemination of shared decision aids will be essential to reduce variation in preference-sensitive disorders.

  • Changing the mindset in life sciences toward translation: a consensus.

    5 December 2017

    Participants at the recent Translate! 2014 meeting in Berlin, Germany, reached a consensus on the rate-limiting factor for advancing translational medicine.

  • Designer hips.

    8 December 2017

  • Cell proliferation is a key determinant of the outcome of FOXO3a activation.

    12 December 2017

    The FOXO family of forkhead transcription factors have a pivotal role in determining cell fate in response to oxidative stress. FOXO activity can either promote cell survival or induce cell death. Increased FOXO-mediated cell death has been implicated in the pathogenesis of degenerative diseases affecting musculoskeletal tissues. The aim of this study was to determine the conditions under which one member of the FOXO family, FOXO3a, promotes cell survival as opposed to cell death. Treatment of primary human tenocytes with 1 pM hydrogen peroxide for 18 h resulted in increased protein levels of FOXO3a. In peroxide-treated cells cultured in low serum media, FOXO3a inhibited cell proliferation and protected against apoptosis. However in peroxide treated cells cultured in high serum media, cell proliferation was unchanged but level of apoptosis significantly increased. Similarly, in tenocytes transduced to over-express FOXO3a, cell proliferation was inhibited and level of apoptosis unchanged in cells cultured in low serum. However there was a robust increase in cell death in FOXO3a-expressing cells cultured in high serum. Inhibition of cell proliferation in either peroxide-treated or FOXO3a-expressing cells cultured in high serum protected against apoptosis induction. Conversely, addition of a Chk2 inhibitor to peroxide-treated or FOXO3a-expressing cells overrode the inhibitory effect of FOXO3a on cell proliferation and led to increased apoptosis in cells cultured in low serum. This study demonstrates that proliferating cells may be particularly susceptible to the apoptosis-inducing actions of FOXO3a. Inhibition of cell proliferation by FOXO3a may be a critical event in allowing the pro-survival rather than the pro-apoptotic activity of FOXO3a to prevail.

  • Orthopaedic trial networks.

    12 December 2017

    Randomized controlled trials (RCTs) are considered the most robust design for evaluating health care interventions. However, it is difficult to acquire funding for RCTs, and they are complex to set up. Threats to their successful conduct and impact on clinical practice, particularly in surgical trials, include problems with recruitment, notably in terms of clinical equipoise and patient acceptability. Historically, RCTs are less common in surgical specialties, and their contribution to the orthopaedic literature remains small. Orthopaedic networks, such as orthopaedic associations, specialist societies, travel fellowships, and clinical research networks, provide an opportunity to meet the challenges of promoting RCTs in orthopaedic clinical practice. This can include identifying important research questions to help prioritize funding; educating and training surgeons in the design and practice of RCTs; helping to promote and coordinate RCTs; and disseminating the findings of RCTs. Orthopaedic trial networks should be encouraged to promote a research culture in which RCTs are feasible and to ensure that scarce resources utilized to support their funding are used most efficiently and to best effect. In particular, the use of networks is encouraged to support the conduct of RCTs in achieving patient recruitment, which is crucial in providing the evidence base to inform orthopaedic practice. Furthermore, to improve generalizability, acceptance of study findings and communication between orthopaedic surgeons, as well as international collaboration in trials, should be part of the strategy for the future.