Role of JAK in experimentally induced periodontal disease progression in rats

Abstract

Many cytokines with biologically relevant functions in inflammatory diseases such as rheumatoid arthritis and periodontal disease exert their biological functions through the JAK-STAT signal transduction pathway. Activated JAKs phosphorylate the receptor's cytoplasmic domain, inducing the activation of its substrates, mainly proteins known as STATs, which in turn dimerize and translocate from the cytoplasm to the nucleus, regulating the transcription of several genes that participate in the inflammatory response. Activation of this pathway is essential for signaling cytokines and other stimuli that regulate inflammatory gene expression, and thus appears to play a critical role in the pathogenesis of inflammatory diseases. In view of the relevance of activating this signaling pathway for the progression of arthritis, systemic administration of a JAK inhibitor has been indicated for the treatment of patients refractory to other rheumatic disease-modifying drugs (DMARDs), and has been associated with a significant improvement in the signs and symptoms of the disease. Preclinical studies in models of rheumatic disease, colitis, Crohn's disease, and psoriasis also indicate inhibition of the inflammatory process, reduction in bone resorption levels, and improvement in disease signs. Considering that periodontal disease and rheumatoid arthritis have similar pathogenesis and expression profiles of inflammatory mediators, it is possible that JAK inhibition can modulate the destruction of mineralized and non-mineralized tissue, reducing bone loss and the inflammatory process during the progression of periodontal disease in vivo. However, information about the role of the pathway in the pathogenesis of the disease is still scarce and contradictory. In order to evaluate this hypothesis, this study aims to evaluate the effect of JAK inhibition on the progression of periodontal disease in rats. Animals with ligature-induced periodontal disease will receive systemically (orally) the JAK1-3 inhibitor, daily, for 7 days, to evaluate the following outcomes: analysis of alveolar bone loss (computerized microphotography), identification and quantification of leukocytes (CD45+ cells ) and osteoclasts (TRAP+ cells) in gingival tissues (through immunohistochemical reactions), and microscopic analysis of the inflammatory process (through stereometric analysis). Data obtained from this study may contribute to clarifying the role of the pathway in the pathogenesis of periodontal disease and provide information that could serve as a biological basis for future therapeutic interventions based on modulation of the immune response.(AU)