Temporomandibular joint disorders (TMDs) affect a significant portion of the population of the USA, with the majority of those seeking treatment being women of childbearing age. Owing to this striking sexual dimorphism it has been postulated that sex hormones play a role in the maintenance of normal temporomandibular joint (TMJ) function. Proteoglycan 4 (PRG4) is a secreted lubricating molecule essential for maintaining low frictional levels within articular joints; however, its role in the TMJ is not well characterized. We identified conserved estrogen response elements within the 5' flanking region of the PRG4 gene of human and baboon, and found that treatment of baboon TMJ disc cells with estrogen attenuated PRG4 promoter activity and expression of PRG4 mRNA in vitro. This discovery of negative regulation of PRG4 by estrogen is the basis for the hypothesis that a causative event in the development of TMD is estrogen-mediated down regulation of PRG4 transcription. Insufficient quantity of PRG4 in the TMJ is expected to lead to increased friction and over time, degradation of TMJ components affecting the articulation of the mandibular condyle with the glenoid fossa of the temporal bone and disc placement, which largely describes the human TMD phenotype. In this study we propose three specific aims; 1) to determine the extent that estrogen decreases PRG4 expression in female and male baboon TMJ cells and TMJ organotypic cultures. Immunoblots and qPCR will be used to quantify estrogen effects on PRG4 expression in synovial and cartilage cells and tissues that will be compared to PRG4 expression in TMJ disc cells and tissue. 2) To characterize by ChIP analysis estrogen alpha and beta receptors and estrogen response element binding in PRG4 gene regulation in femal and baboon TMJ cells. 3) To provide a highly mentored environment and rigorous biomedical research training opportunities for the development of underrepresented students in the life sciences.
Proteoglycan-4 (PRG4) is known to be crucial for the healthy lubrication of articular joints and failure of the temporomandibular joint (TMJ) lubrication mechanism has been proposed to lead to TMJ disorders (TMD), which are reported predominantly by young females. The proposed study follows through on the finding that estrogen inhibits PRG4 gene expression in cells of the TMJ, possibly explaining the gender disparity seen in TMD patients. Characterizing estrogen-mediated inhibition of PRG4 expression is expected to lead to innovative therapeutic treatments beneficial for TMD patients.
