Osteoarthritis and rheumatoid arthritis are diseases of complex etiopathology associated with progressive inflammation and cartilage destruction. Physical therapies, such as continuous passive motion, yield beneficial effects on arthritic joints by an as-yet unknown mechanism, but one that is likely to involve mechanical activation of chondrocytes. Since inflammatory cytokines like IL-1beta play a major role in cartilage destruction, it is hypothesized that mechanical strain exerts it anti-inflammatory effects on IL-1beta actions via regulating activation of transcription factors, which in turn positively or negatively affect IL-1-induced transcriptional regulation. This is based upon the facts that, in vitro, cyclic tension strain (CTS) suppresses IL-1-dependent mRNA transcription of multiple proteins that induce catabolic responses, while it induces mRNA synthesis for proteins inhibited by IL-1beta which are reparative in nature. These observations suggest that CTS acts upstream of mRNA induction via regulation of signal transduction cascade of IL-1beta. Furthermore, CTS exerts its effects at concentrations of IL-1beta similar to those present in inflamed synovial joints, suggesting that these findings are of clinical relevance. The signal transduction mechanisms of mechanical stress are largely unknown. Il-1-activated chondrocytes are the first cells that provide defined CTS responses, which can be evaluated at the transcriptional level and related to gene activation. These cells are thus ideally suited for systematic examination of mechanisms of CTS-mediated signal transduction, specifically those which are involved in the anti-inflammatory actions of IL-1beta. Utilizing this system, the applicants specifically propose to: (1) examine the effects of CTS on receptor activation, by assessing activation of IL-1R-associated kinase; (2) identify CTS-mediated signals that inhibit IL-1beta-induced activation of NF-kB, by assessing the activation of kinases upstream of IkB (inhibitor of NF-kB), including IkB kinases, IKKalpha and IKKbeta; and (3) identify CTS-mediated signals that inhibit the IL-1beta-induced gene activation of AP-1, by assessing activation of 3 subfamilies of MAP kinases, ERK, MAPK p38 and SAPK, and their upstream MAPK, as well as characterize subunits of AP-1 (Jun/Fos) complexes that are activated by these kinases. It is suggested by the applicant that the understanding of signaling pathways induced by CTS, which facilitate tissue repair, will unveil an entirely new area for the development of therapeutics to limit the degenerative changes in synovial joints.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
7R01AT000646-05
Application #
6928726
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Khalsa, Partap Singh
Project Start
2000-09-29
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2008-07-31
Support Year
5
Fiscal Year
2004
Total Cost
$222,750
Indirect Cost
Name
Ohio State University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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