Bioengineering Joint Lubricants from Cultured Synoviocytes This proposed revision seeks to augment the parent grant, NIH R01 AR051565 Mechanisms of Articular Cartilage Lubrication, by Building an Interdisciplinary Research Team (BIRT) establishing collaboration in the fields of Tissue Engineering and Immunology. The synovial fluid of human joints normally functions biomechanically by lubricating articular cartilage, facilitating load-bearing and relative motion of apposing tissue surfaces with low friction and wear. In vivo, a deficiency in the lubricant function of synovial fluid may contribute to the cartilage erosion that occurs in post-injury degeneration, rheumatoid arthritis, and osteoarthritis. In vitro, a fluid with lubricant qualities like that of normal synovial fluid may be useful for engineering tissues in the form of cartilaginous or osteocartilaginous constructs including whole joints, when they are conditioned mechanically in a bioreactor by articulating motion. One component of synovial fluid that functions as a lubricant is hyaluronan (HA). The HA in synovial fluid is contributed primarily by the fibroblast-like synoviocytes of the synovial lining. In synovial fluids of injured and diseased joints, the decreased concentration and molecular weight of HA appear related to the elevated concentrations of certain cytokines. While HA secretion by fibroblast-like synoviocytes is regulated by IL-12 and TGF-21, the mechanisms of such regulation remain to be established. Knowledge of the immune regulation of HA secretion in vitro may facilitate the bioengineering of bioreactors to produce solutions that mimic the lubricant function and HA composition of native synovial fluid. The hypothesis of this study is that immune regulation, via IL-12 and TGF-21, of human synoviocyte HA secretion is through signaling pathways that modulate specific HA synthase enzymes, resulting in altered levels and molecular weight distributions of secreted HA, and, consequently, lubricant function. The associated aims are to assess (1) mechanisms of IL-12 and TGF-21 regulation of HA secretion in human synoviocytes by assessing HA synthase (HAS) mRNA, HAS protein, and HAS intracellular trafficking, after stimulation with cytokines, individually and in combination, and with inhibitors of selected signaling pathways, and (2) consequences of cytokine-regulated HA secretion in human synoviocytes by determining the molecular weight distribution and lubricating function of secreted HA in a """"""""bioengineered synovial fluid."""""""" ? ? ?
Testing the above hypotheses would contribute to the understanding of immune regulation of lubrication of synovial joints in health and disease. It would also facilitate mechanobiological approaches to the engineering of tissues for the restoration of articular cartilage by demonstrating how immune regulation can be harnessed to generate a liquid lubricant.
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