Osteoarthritis and rheumatoid arthritis are diseases of complex etiopathology associated with progressive inflammation and cartilage destruction. Rehabilitative physical therapies such as continuous passive motion (CPM)/exercise yield beneficial effects on arthritic joints as well as on post-surgical arthritic joints by an as-yet-unknown mechanism, but one that is likely to involve mechanical activation of cells. Since inflammatory cytokines like IL-1B play a major role in cartilage destruction, it is the hypothesis that mechanical strain exerts anti- inflammatory effects on arthritic joints by blocking proinflammatory signals and subsequent gene induction induced by IL-1. This is based on the facts that, in vitro, chondrocytes respond to cyclic tensile strain (CTS) by suppression of IL-1-dependent proteins that are responsible for cartilage degradation. CTS simultaneously induces gene exression of proteins inhibited by IL- 1B, that are reparative in nature. These effects of CTS are mediated via inhibition of IL-1B-induced nuclear factor (NF)-kB translocation to the nucleus, as well as the synthesis of its subunit. CTS exerts these effects at concentrations of IL-1B similar to those present in inflamed synovial joints, suggesting the clinical relevance of actions of mechanical strain. In this proposal the PIs wish to confirm in vitro findings using an in vivo model system of antigen induced arthrits (AIA) and an apparatus that subjects arthritic joints to CPM. Long term goals are to understand the molecular mechanisms of stress-induced anti-inflammatory responses that limit the degeneration in joint diseases and constitute the basis for rehabilitative physical therapies like CPM. Specifically, the PIs will (i) determine if CPM therapy exerts its beneficial effects on the arthritic joints by regulating the synthesis of catabolic proteins or their inhibitors. (ii) determine if CPM therapy exerts its beneficial effects on arthritic joints via induction of matrix-associated proteins. (iii) determine if the intracellular mechanisms of CPM in vivo are mediated via inhibition of nuclear factor (NF)-kB subunits p65 and p50 synthesis in the tissues of knee joints from CPM treated and untreated rabbits with AIA. This understanding of the signalling pathways that mediate the beneficial effects of mechanical strain is necessary for defining the biological basis for the efficacy of CPM/exercise, for the development of defined parameters for safe application of physical therapies to accelerate cartilage repair as well as for the use of CPM in novel non-invasive rehabilitative therapies for not only cartilage repatr but also for other diseases.
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