Figure 2. The concept of the process of cartilage breakdown in the TMJ. A decreased adaptive capacity of the articulating structures and/or excessive physical stress to the TMJ that exceeds the normal adaptive capacity can induce dysfunctional remodeling. Functional overloading and increased joint friction may act together as etiological events for TMJ degenerative changes. Functional overloading can facilitate hypoxia in the TMJ and mediate the destructive processes associated with osteoarthrosis as an autocrine factor. Vascular endothelial growth factor (VEGF) induction in osteoarthritic cartilage by functional overloading is linked to activation of the hypoxia-induced transcription factor-1, leading to hypoxia in the joint tissue. Furthermore, VEGF regulates the production of matrix metalloproteinases and tissue-inhibitors of matrix metalloproteinases, which are among the effectors of extracellular matrix remodeling. Overloading also causes collapse of joint lubrication as the result of the hyaluronic acid degradation by free radicals. The regulation of hyaluronic acid production is controlled by various pro-inflammatory cytokines. Of these cytokines, tumor necrosis factor- and interleukin-1 and -6 play crucial roles in the pathogenesis of osteoarthrosis with respect to the acceleration and progression of cartilage degradation, because they promote bone resorption through the differentiation and activation of osteoclasts.