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Preventing osteoarthritis

OA pathogenesis. Proteases important in driving matrix breakdownAggrecanases (Adamts5, ?Adamts4)Collagenases (Mmp13 ? Others)What drives protease expression in vivo?? Inflammatory cytokines (e.g. IL1)Mechanical factorsOA is a balance between degradation and repair?Repair' infrequently leads t

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Preventing osteoarthritis

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    1. Dr Tonia Vincent Kennedy Institute of Rheumatology Oxford University Preventing osteoarthritis

    2. OA pathogenesis Proteases important in driving matrix breakdown Aggrecanases (Adamts5, ?Adamts4) Collagenases (Mmp13 ? Others) What drives protease expression in vivo? ? Inflammatory cytokines (e.g. IL1) Mechanical factors OA is a balance between degradation and repair Repair infrequently leads to mechanically sound hyaline cartilage

    3. Strategies for disease prevention

    5. Destabilisation of Medial Meniscus (DMM) model of OA

    7. This model was first characterised by applying it to naive C57BL/6 mice. These graphs demonstrate that the technique reliably, progressively and repeatably induces cartilage degradation in murine knees. Note that sham surgery has no effect, and the scores are actually similar to completely non-operated mice at similar ages. Also there appears to be a tendency for increasing damage in the contralateral knee at 12 weeks, which may be a function of altered weight-bearing, and I will return to this point again.This model was first characterised by applying it to naive C57BL/6 mice. These graphs demonstrate that the technique reliably, progressively and repeatably induces cartilage degradation in murine knees. Note that sham surgery has no effect, and the scores are actually similar to completely non-operated mice at similar ages. Also there appears to be a tendency for increasing damage in the contralateral knee at 12 weeks, which may be a function of altered weight-bearing, and I will return to this point again.

    8. QUESTIONS Can we detect pathogenic proteases in OA joints? How early are these genes regulated in OA? In which tissues of the joint are they regulated? How important is mechanical joint loading for gene expression?

    9. Investigating gene expression in the OA joint

    10. Genes expressed in the joint after DMM surgery (6h)

    12. Genes expressed in the joint after DMM surgery (6h)

    15. Sciatic neurectomy protects against OA

    17. Conclusions 1 Gene expression in destabilised joints is highly mechanosensitive. Pathogenic proteases are induced in the articular cartilage following joint destabilisation Dynamic joint flexion appears to induce pathogenic genes such as Adamts5 Walking without dynamic flexion protects a destabilised joint from developing OA.

    18. WHAT ARE THE MECHANISMS OF MECHANOTRANSDUCTION IN VIVO?

    19. Activation of chondrocytes upon injury

    21. Fibroblast growth factor 2 (Fgf2) in articular cartilage

    22. Novel model of cartilage injury

    24. Is Fgf2 a mechanotransducer in vivo?

    27. Conclusions II Fgf2 is an important mechanotransducer in vitro and in vivo Fgf2-dependent genes are driven by uniaxial joint compression ? Fgf2-dependent genes are good for the joint.

    28. Strategies for disease prevention

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