The primary objective of this proposal (for competing continuation of R29/R01 AR43597) is to further elucidate the mechanisms through which the phospholipase C/inositol trisphosphate/calmodulin and adenylyl cyclase/cyclic AMP (cAMP) signaling pathways mediate transduction of compression-induced signals in chondrocytes, resulting in regulation of gene expression. Mechanical forces are key regulators of cell activity, morphology and function. The resident chondrocytes sense and respond to these stresses and strains by altering their metabolic and biosynthetic activities. Although the responses of articular cartilage or chondrocytes to mechanical modulation have been extensively studied, the mechanisms whereby the cells sense and transduce signals generated by the applied mechanical forces are much less understood. Work performed so far in R29/R01 AR43597 has shown that the compression-induced transient elevation of aggrecan gene expression in articular cartilage requires signaling through the adenylyl cyclase/cAMP and phospholipase C/phoshphoinositol (PI) signaling pathways. Further characterization of the signaling process revealed that 1) protein kinase C activity is not required, 2) transduction of the compression-induced signals is inositol 1,4,5-trisphosphate (IP3)-dependent, 3) changes in intracellular Ca 2+concentration are required, and 4) the activities of Ca2+/calmodulin (CAM), CaM-dependent protein kinase II and partially calcineurin are required. This competitive renewal application proposes to test the hypothesis that the CREB/CBP complex functions as a common transcriptional mediator of the compression-induced signals transduced through the cAMP and CaM-dependent signaling pathways, leading to regulation of aggrecan gene expression. The roles of downstream effector molecules of the cAMP and CaM-dependent pathways in compression-induced modulation of CREB-mediated regulation of aggrecan gene expression will be investigated. Data obtained from these studies will enhance our understanding of mechanisms, operating downstream of cytoplasmic second messengers, whereby compression and other physical forces modulate chondrocyte biosynthetic activities and function.
| Mauck, R L; Soltz, M A; Wang, C C et al. (2000) Functional tissue engineering of articular cartilage through dynamic loading of chondrocyte-seeded agarose gels. J Biomech Eng 122:252-60 |
