The overall goal of this project is to elucidate mechanobiological mechanisms and consequences of functional deterioration of articular cartilage, leading to partial-thickness erosions in the human knee in aging and osteoarthritis. Biomechanical abnormalities occur in the superficial zone of articular cartilage during normal aging, and this is associated with an increased incidence of osteoarthritis. The overall hypothesis is that the superficial zone of normal human knee articular cartilage undergoes aging-related mechanobiolgoical decompensation due to both cell and matrix dysfunction, with a resultant compromise in both cartilage lubrication and load-bearing properties. To address this hypothesis, we propose to test the following aims: 1) Analyze human and mouse knees for spatial signatures of biomechanical dysfunction or failure of the articular cartilage, and the relationship of such variation to putative determinants, matrix composition and structure and also cell organization and phenotype;2) Determine if in vitro dynamic loading of cartilage explants in compression and shear cause cell responses and matrix remodeling in the superficial zone that lead to aging-related compromise of cartilage lubrication and load-bearing functions.

Public Health Relevance

Completion of the proposed studies will help elucidate the mechanobiological cascade contributing to the age- and osteoarthritis-related deterioration of articular cartilage. Such an understanding may facilitate the development of new interventions to forestell the incidence of osteoarthritis.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01AG007996-21
Application #
8663765
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Wang, Yun; Viollet, Benoit; Terkeltaub, Robert et al. (2016) AMP-activated protein kinase suppresses urate crystal-induced inflammation and transduces colchicine effects in macrophages. Ann Rheum Dis 75:286-94
Nakamichi, Ryo; Ito, Yoshiaki; Inui, Masafumi et al. (2016) Mohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs. Nat Commun 7:12503
Alvarez-Garcia, O; Olmer, M; Akagi, R et al. (2016) Suppression of REDD1 in osteoarthritis cartilage, a novel mechanism for dysregulated mTOR signaling and defective autophagy. Osteoarthritis Cartilage 24:1639-47
Grogan, Shawn P; Pauli, Chantal; Lotz, Martin K et al. (2016) Relevance of meniscal cell regional phenotype to tissue engineering. Connect Tissue Res :
Temple-Wong, Michele M; Ren, Shuwen; Quach, Phu et al. (2016) Hyaluronan concentration and size distribution in human knee synovial fluid: variations with age and cartilage degeneration. Arthritis Res Ther 18:18
Yadav, Manisha C; Bottini, Massimo; Cory, Esther et al. (2016) Skeletal Mineralization Deficits and Impaired Biogenesis and Function of Chondrocyte-Derived Matrix Vesicles in Phospho1(-/-) and Phospho1/Pi t1 Double-Knockout Mice. J Bone Miner Res 31:1275-86
Shen, T; Alvarez-Garcia, O; Li, Y et al. (2016) Suppression of Sestrins in aging and osteoarthritic cartilage: dysfunction of an important stress defense mechanism. Osteoarthritis Cartilage :
Goodrich, Laurie R; Chen, Albert C; Werpy, Natasha M et al. (2016) Addition of Mesenchymal Stem Cells to Autologous Platelet-Enhanced Fibrin Scaffolds in Chondral Defects: Does It Enhance Repair? J Bone Joint Surg Am 98:23-34
Meinert, Christoph; Schrobback, Karsten; Levett, Peter A et al. (2016) Tailoring hydrogel surface properties to modulate cellular response to shear loading. Acta Biomater :
Alvarez-Garcia, Oscar; Fisch, Kathleen M; Wineinger, Nathan E et al. (2016) Increased DNA Methylation and Reduced Expression of Transcription Factors in Human Osteoarthritis Cartilage. Arthritis Rheumatol 68:1876-86

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