The mechanical environment of the chondrocytes is an important factor that affects the health and function of the diarthrodial joint. The biomechanical and physicochemical signals to which chondrocytes are exposed depend on the interactions between the cell, pericellular matrix, and extracellular matrix of articular cartilage. The goals of this study are to measure the intrinsic biomechanical, physicochemical, and diffusion properties of the chondrocyte pericellular matrix, and to test the hypothesis that these properties are altered in osteoarthritic cartilage. Furthermore, we propose that type VI collagen, which is abundantly present in the pericellular matrix, influences the physical properties of this region. We will use several novel micromechanical experimental techniques in combination with theoretical modeling to quantify the triphasic mechanical properties of the pericellular matrix in the isolated chondron model and in transgenic mice.
The aims of this project are to measure the triphasic mechanical properties of the pericellular matrix from normal and osteoarthritic cartilage using atomic force microscopy, incorporate these findings in a theoretical triphasic model of cell-matrix interactions in cartilage, and validate these predictions using confocal microscopy. We will also use new fluorescence-based methods to measure the diffusion properties of the pericellular matrix of normal and OA cartilage. Finally, we will determine the role of type VI collagen on the triphasic mechanical properties of the pericellular matrix and subsequently, the mechanical environment of the chondrocyte. The long-term goals of this study are to improve our understanding of the role of mechanical factors in the regulation of cartilage metabolism in normal and diseased conditions. A better understanding of these pathways will hopefully lead to the development of new pharmaceutical or biophysical interventions for the treatment of osteoarthritis.

Public Health Relevance

The goals of this study are to measure the intrinsic biomechanical, physicochemical, and diffusion properties of the chondrocyte pericellular matrix, and to test the hypothesis that these properties are altered in osteoarthritic cartilage. Furthermore, we propose that type VI collagen, which is abundantly present in the pericellular matrix, influences the physical properties of this region. We will use several novel micromechanical experimental techniques, coupled with theoretical modeling to quantify the triphasic mechanical properties of the pericellular matrix and to determine the influence of this region on the physicochemical environment of the chondrocyte in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG015768-17
Application #
8658344
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Williams, John
Project Start
1998-01-01
Project End
2017-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
17
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
Brunger, Jonathan M; Zutshi, Ananya; Willard, Vincent P et al. (2017) Genome Engineering of Stem Cells for Autonomously Regulated, Closed-Loop Delivery of Biologic Drugs. Stem Cell Reports 8:1202-1213
Bridgen, Devin T; Fearing, Bailey V; Jing, Liufang et al. (2017) Regulation of human nucleus pulposus cells by peptide-coupled substrates. Acta Biomater 55:100-108
Brunger, Jonathan M; Zutshi, Ananya; Willard, Vincent P et al. (2017) CRISPR/Cas9 Editing of Murine Induced Pluripotent Stem Cells for Engineering Inflammation-Resistant Tissues. Arthritis Rheumatol 69:1111-1121
Adkar, Shaunak S; Brunger, Jonathan M; Willard, Vincent P et al. (2017) Genome Engineering for Personalized Arthritis Therapeutics. Trends Mol Med 23:917-931
Wu, Chia-Lung; Kimmerling, Kelly A; Little, Dianne et al. (2017) Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair. Sci Rep 7:44315
Furman, Bridgette D; Kent, Collin L; Huebner, Janet L et al. (2017) CXCL10 is upregulated in synovium and cartilage following articular fracture. J Orthop Res :
Wu, Chia-Lung; McNeill, Jenna; Goon, Kelsey et al. (2017) Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas-Induced Apoptosis-Transgenic Mice. Arthritis Rheumatol 69:1772-1783
Hatcher, Courtney C; Collins, Amber T; Kim, Sophia Y et al. (2017) Relationship between T1rho magnetic resonance imaging, synovial fluid biomarkers, and the biochemical and biomechanical properties of cartilage. J Biomech 55:18-26
Rowland, Christopher R; Colucci, Lina A; Guilak, Farshid (2016) Fabrication of anatomically-shaped cartilage constructs using decellularized cartilage-derived matrix scaffolds. Biomaterials 91:57-72
Cucchiarini, M; McNulty, A L; Mauck, R L et al. (2016) Advances in combining gene therapy with cell and tissue engineering-based approaches to enhance healing of the meniscus. Osteoarthritis Cartilage 24:1330-9

Showing the most recent 10 out of 225 publications