(Taken from the application) It is known that mechanical signals regulate cartilage growth and regeneration. For example, during distraction osteogenesis, mechanical load-induced matrix deformation activates the chondrocyte proliferation and differentiation process. This process is also activated in osteoarthritic cartilage where cell-matrix interaction is altered. However, the pathways by which a mechanical signal is transduced from extracellular matrix to the nucleus to stimulate chondrocyte proliferation and differentiation remain unknown. The long term goal of this study is to analyze the molecular mechanisms underlying matrix deformation-regulated cartilage growth. Our central hypothesis is that mechanical signals regulate cartilage growth by a two-step process. First, mechanical signals are transduced from the matrix to the cell by pericellular matrix molecules, and from the cytoplasm to the nucleus by intracellular kinases. Second, in response to these signals, chondrocytes accelerate proliferation, differentiation, and synthesis of matrix molecules. This response can be further modulated by hormonal molecules in the chondrocyte microenvironment. To test this hypothesis systematically, this proposal contains four specific aims: 1) examine whether cyclic matrix deformation stimulates chondrocyte proliferation and/or differentiation. A novel three dimensional chondrocyte culture system will be used to analyze the cellular responses to mechanical stimuli. 2) analyze whether mechanical signals are transduced to the cell by a pericellular """"""""bridging"""""""" molecule cartilage matrix protein (CMP). The responses to mechanical stimulation will be analyzed from cells transfected with a dominant negative CMP mini-gene. 3) determine whether signals are transmitted to the nucleus by MAP kinases. MAP kinases activities will be blocked by specific inhibitors during mechanical stimulation. 4) reveal whether parathyroid hormone (PTH) has a synergetic effect on the stimulation of chondrocyte activities by mechanical signals. The rates of proliferation and differentiation will be quantified from the cells which are mechanically stimulated in the presence of 0.1uM human PTH (1-34).
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