Biophysical signals play important roles in regulating cartilage growth and regeneration. During skeletal development and fracture healing, mechanical load-induced matrix deformation induces the process of chondrocyte proliferation and differentiation. This process is also activated in osteoarthritic cartilage where altered cell-matrix interaction results in an abnormal mechanical microenvironment. Therefore, the pathways by which a mechanical signal is transduced from extracellular matrix to the nucleus to stimulate chondrocyte proliferation and differentiation need to be better understood. The long-term goal of this study is to analyze the molecular mechanisms underlying matrix deformation-regulated cartilage growth. Data generated from current funding period suggest a hypothesis in which mechanical signals regulate cartilage growth by a two- step process. First, transduction of mechanical signals from matrix to the cell involves both matrilin-1 and -3, which form an extracellular regulatory circuit of a mechanostat, with matrilin-1 forming pericellular filaments transducing mechanical signals and matrilin-3 antagonistic to filament formation. Second, in response to mechanical signals, chondrocytes induce the production of BMP and activate its downstream transcriptional factors, which in turn regulate gene expression and chondrocyte differentiation. This hypothesis will be tested systematically and in depth using both in vitro and in vivo models in the next funding period. We will analyze how mechanical signal transduction to the cell is regulated by pericellular matrilin filaments (SA 1), identify the transcriptional factors required for mechanical stimulation of chondrocyte differentiation (SA 2), and determine the role of BMP signaling in mechanical activation of a gene promoter in cartilage (SA 3). These knowledge will be important for understanding the fundamental signaling mechanisms underlying mechanical activation of chondrocyte proliferation, differentiation, and gene expression, which occur during skeletal development, fracture healing, and osteoarthritis pathogenesis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Williams, John
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Rhode Island Hospital
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