The mechanical environment of the chondrocytes is one of several important environmental factors which regulate the normal balance between the synthesis and degradation of the articular cartilage extracellular matrix. Chondrocytes are surrounded by a pericellular matrix, which together with the chondrocyte and a surrounding capsule have been termed the """"""""chondron"""""""". The functional role of this complex structural unit of cartilage is not known. The central hypothesis of this study is that the pericellular matrix plays a significant biomechanical role in regulating the mechanical stress environment of the chondrocyte. This hypothesis will be tested by combining detailed measurements of the mechanical properties of the pericellular matrix of isolated chondrons, with a finite element model of the chondron within articular cartilage. In this manner, the applicants propose to show, theoretically, that the mechanical properties of the pericellular matrix significantly affect the stress-strain and fluid flow environments of the chondrocyte; they propose to show, experimentally, that the presence of the in vivo pericellular matrix alters the chondrocytes' metabolic response to mechanical stress. Further, it is proposed that the mechanical properties of the pericellular matrix are changed with osteoarthritis, resulting in an alteration in the mechanical environment of the chondrocyte. It is expected that these alterations in the mechanical environment will affect the chondrocytes' ability to regulate proteoglycan synthesis rates in response to mechanical stress. These experiments will be performed using an isolated chondron model from adult human cartilage. The following Specific Aims will be completed: 1) to combine novel micromechanical experiments (micropipette aspiration and atomic force microscopy), with theoretical modeling, to determine the biphasic mechanical properties of the pericellular matrix in isolated chondrons. These measured properties will be utilized in a finite element model of the chondron in the extracellular matrix to quantify the mechanical stress environment of the chondrocyte. The theoretical predictions of chondron deformation will be validated, in situ, using three-dimensional confocal microscopy; 2) to use these methods to quantify the changes that occur in the biphasic properties of the pericellular matrix with osteoarthritis; 3) to determine the effects of enzymatic degradation on the mechanical properties of the pericellular matrix; and 4) to quantify the role of the pericellular matrix in regulating the rate of proteoglycan metabolism in response to stress, using isolated chondrocytes and chondrons compressed in an alginate matrix. The long-term goal of these studies is to better understand the mechanisms through which mechanical factors influence cartilage maintenance in both health and disease. Identification of these mechanisms will hopefully lead to new treatments which exploit optimal mechanical and biochemical modalities for the prevention of osteoarthritis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
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Orthopedics and Musculoskeletal Study Section (ORTH)
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Duke University
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Rowland, Christopher R; Glass, Katherine A; Ettyreddy, Adarsh R et al. (2018) Regulation of decellularized tissue remodeling via scaffold-mediated lentiviral delivery in anatomically-shaped osteochondral constructs. Biomaterials 177:161-175
Furman, Bridgette D; Kent, Collin L; Huebner, Janet L et al. (2018) CXCL10 is upregulated in synovium and cartilage following articular fracture. J Orthop Res 36:1220-1227
Tang, Ruhang; Jing, Liufang; Willard, Vincent P et al. (2018) Differentiation of human induced pluripotent stem cells into nucleus pulposus-like cells. Stem Cell Res Ther 9:61
Erdemir, Ahmet; Hunter, Peter J; Holzapfel, Gerhard A et al. (2018) Perspectives on Sharing Models and Related Resources in Computational Biomechanics Research. J Biomech Eng 140:
Guilak, Farshid; Nims, Robert J; Dicks, Amanda et al. (2018) Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol 71-72:40-50
Adkar, Shaunak S; Brunger, Jonathan M; Willard, Vincent P et al. (2017) Genome Engineering for Personalized Arthritis Therapeutics. Trends Mol Med 23:917-931
Liu, Betty; Goode, Adam P; Carter, Teralyn E et al. (2017) Matrix metalloproteinase activity and prostaglandin E2 are elevated in the synovial fluid of meniscus tear patients. Connect Tissue Res 58:305-316
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
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
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

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