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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017021-10
Application #
7796562
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Williams, John
Project Start
1998-09-30
Project End
2014-02-28
Budget Start
2010-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2010
Total Cost
$260,717
Indirect Cost
Name
Rhode Island Hospital
Department
Type
DUNS #
075710996
City
Providence
State
RI
Country
United States
Zip Code
02903
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Foradori, Matthew J; Chen, Qian; Fernandez, Cecilia A et al. (2014) Matrilin-1 is an inhibitor of neovascularization. J Biol Chem 289:14301-9
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Guan, Yingjie; Chen, Qian; Yang, Xu et al. (2012) Subcellular relocation of histone deacetylase 4 regulates growth plate chondrocyte differentiation through Ca2+/calmodulin-dependent kinase IV. Am J Physiol Cell Physiol 303:C33-40
Weng, Tujun; Yi, Lingxian; Huang, Junlan et al. (2012) Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice. Arthritis Rheum 64:3982-92
Guan, Ying-Jie; Yang, Xu; Wei, Lei et al. (2011) MiR-365: a mechanosensitive microRNA stimulates chondrocyte differentiation through targeting histone deacetylase 4. FASEB J 25:4457-66
Wei, Lei; Fleming, Braden C; Sun, Xiaojuan et al. (2010) Comparison of differential biomarkers of osteoarthritis with and without posttraumatic injury in the Hartley guinea pig model. J Orthop Res 28:900-6

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