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)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG007996-21
Application #
8663765
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
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
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Matsuzaki, Tokio; Alvarez-Garcia, Oscar; Mokuda, Sho et al. (2018) FoxO transcription factors modulate autophagy and proteoglycan 4 in cartilage homeostasis and osteoarthritis. Sci Transl Med 10:
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Jin, Yunyun; Cong, Qian; Gvozdenovic-Jeremic, Jelena et al. (2018) Enpp1 inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling. Development 145:
Grogan, Shawn P; Duffy, Stuart F; Pauli, Chantal et al. (2018) Gene expression profiles of the meniscus avascular phenotype: A guide for meniscus tissue engineering. J Orthop Res 36:1947-1958
Baek, Jihye; Sovani, Sujata; Choi, Wonchul et al. (2018) Meniscal Tissue Engineering Using Aligned Collagen Fibrous Scaffolds: Comparison of Different Human Cell Sources. Tissue Eng Part A 24:81-93

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