DESCRIPTION: The mechanisms underlying degenerative temporomandibular joint (TMJ) disease are poorly understood. This is due to a lack of suitable animal models and the histological study of pathological specimens, post-mortem tissues or radiological studies. This proposal was guided by preliminary observations from biochemical studies of fluids and tissues obtained from patients with dysfunction TMJs. These preliminary studies provided indirect evidence that oxidative stress may be an important mechanism of joint disease. The application tests a model of TMJ injury by oxidative stress that could have an impact on diagnostic and therapeutic approaches to TMJ disorders. The model suggests that biomechanical stresses generated within the TMJ with functional or parafunctional movements create short-lived, extremely reactive molecular species known as free radicals. Free radicals may initiate, either directly or indirectly, pro inflammatory cytokine synthesis, arachidonic acid catabolism and matrix degrading enzyme production or activation. Each of these processes has been implicated in pathogenesis of degenerative joint disease. The studies proposed in this application are designed to provide evidence that oxidative stress can evoke a cascading series of molecular events that could ultimately lead to TMJ disease. Specific Aim 1 will determine if hemoglobin, a primary source of redox active iron recovered from symptomatic TMJs, is sufficient to catalyze the free radical-mediated degradation of fibronectin. Fibronectin is a major component of extracellular matrices (ECM) and synovial fluid of the TMJ. Since fibronectin interacts with other ECM proteins, this grant will investigate its relative susceptibility to free radical-mediated degradation while bound to other ECM proteins in Specific Aim 2. Specific Aims 3 and 4 will determine if free radical generated fibronectin fragments can elicit ECM degradation by either direct (i.e. generation of proteolytic fibronectin fragments) or indirect i.e., stimulation of matrix metalloproteinase synthesis) mechanisms.