Disorders of the temporomandibular joint represent a common cause of facial pain. Although the precise etiology of TMD is yet to be fully elucidated, histological and arthroscopic studies suggest that especially at the late stages of joint degeneration, inflammation is evident and similar to that seen in osteoarthritis of other synovial joints. Chronic mechanical trauma to the TMJ triggers generation of reactive oxidant species; one consequence of which is the rapid formation of Advanced Glycation Endproducts (AGEs). Engagement of AGEs by their signal transduction receptor for AGE (RAGE) activates a range of cells linked to the inflammatory response, thereby triggering mononuclear phagocyte migration and cytokine generation at sites of immune/inflammatory foci. RAGE also interacts with S100/calgranulins; borne by inflammatory cells, these molecules, once released into the extracellular milieu upon their activation, ligate RAGE, thereby propagating proinflammatory mechanisms. Preliminary data reveal that RAGE is upregulated in samples retrieved from human subjects with TMD; in a murine model induced by bovine type II collagen in DBA/1 mice, expression of RAGE is enhanced in multiple cell types in inflamed joints. Blockade of RAGE in that model suppressed joint swelling; in parallel, joint tissue levels of cytokines TNF-alpha and IL-6 were diminished, along with antigen/activity of matrix metalloproteinase-9 (MMP). In a murine model demonstrating involvement of the TMJ, transgenic mice constitutively overexpressing human TNF-alpha, expression of RAGE was enhanced. These considerations lead us to hypothesize that generation of AGEs in the perturbed TMJ leads to upregulation and activation of their signalling receptor, RAGE, thereby activating key cell types linked to proinflammatory mechanisms in the joint. Once initiated, ligand-RAGE interaction sustains proinflammatory mechanisms, leading to chronic generation of cytokines and MMPs. To test these concepts, we propose to characterize the sites/times of RAGE/ligand expression in the TMJ of transgenic mice overexpressing TNF-alpha; to test the role of RAGE in joint/bone inflammation and destruction, we will assess the impact of pharmacologic blockade of RAGE, as well as genetic manipulation of the receptor in homozygous RAGE null mice. If successful, these studies will identify new markers for disease activity in TMD, as well as new targets for therapeutic intervention.
| Landesberg, Regina; Woo, Victoria; Huang, Linda et al. (2008) The expression of the receptor for glycation endproducts (RAGE) in oral squamous cell carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 105:617-24 |
