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• Developing and testing non-pharmacologic therapies (especially braces and shoewear) for the management of knee osteoarthritis.
  
  
• Natural history studies evaluating biomechanics, pain, and using MRI and biomarker measurements to improve understanding of predictors and progression of OA
  
  
• Tissue and molecular engineering studies to regenerate tissues in adults and to recapitulate key events in embryonic tissue formation and growth.  These techniques have been used for a number of years for focal cartilage defects in persons without OA. The application of autologous chondrocyte transplantation and meniscal allograft surgery has been attempted in persons with OA with little success to date primarily because of lack of consideration of the altered mechanical environment and the continued activity of cytokines and chemokines. Careful thought and a staged approach to this activity could result in true biologic joint replacement.
  
  
• Translational approaches to improve our understanding of musculoskeletal disease etiopathogenesis through analysis of routinely discarded tissue from joint replacement surgeries.  These analyses explore the histopathology and cell biology of diseased tissues in osteoarthritis, use gene expression to identify common transcripts that are differentially expressed in disease tissues versus uninvolved tissue, and identify new molecules that show a unique distribution to disease tissue and that have potential as molecular markers of this process using proteomics.
  
  
• Development of disease (structure) modifying therapies for osteoarthritis. OA is a clinical condition manifest by structural changes in many tissues. If structural modification is the intent of treatment this should only be done mindful of attaining symptomatic improvement and not divorced from it. This is particularly important as there is a current predilection of focusing treatment targets on hyaline articular cartilage. Articular cartilage is both aneural and avascular. As such, cartilage is incapable of directly generating pain, inflammation, stiffness, or any of the symptoms that patients with OA typically describe. Given its relative unimportance to OA's symptomatic presentation, it is ironic that articular cartilage has received so much attention while other common symptom sources in the joint are ignored. Interventions that focus exclusively on nourishing, replenishing, or replacing articular cartilage have little chance of providing long-term symptomatic relief unless they also simultaneously relieve strain on other innervated structures. This is true whether the intervention is dietary, pharmacologic or surgical. A more logical approach is to assess the function of the entire joint organ and to target intervention to the reduction of pain and physical limitation on all moving parts. An important element in delineating the structural endpoints of choice for clinical trials is that they are associated with symptom change, or are at least, a surrogate for a clinically meaningful endpoint, as treatments which affect these structures are likely to alleviate pain. We are focusing on both endpoint (14) and clinical trial development with this perspective in mind.