Degeneration of the fibrocartilaginous menisci has long been associated with chondral degeneration in advanced osteoarthritis (OA) of the knee, but the relationship between meniscal degeneration in the onset and progression of knee OA remains unclear. Meniscal tears have long been recognized as a contributing factor to knee OA, primarily due to changes in joint biomechanics that result in local increases or decreases in the mechanical stresses on the cartilage. However, a variety of recent findings suggest that degenerative meniscal changes, regardless of whether or not tears are present, may be an early event in the development of idiopathic knee OA. Despite the growing indications of the importance of asymptomatic meniscal degeneration, relatively little is currently known regarding the mechanisms contributing to meniscal degeneration or the reasons why meniscal lesions appear to precede cartilage degeneration. The proposed studies will investigate the effects of biochemical and biomechanical induction of meniscal degradation.
Aim 1 will examine the progression of meniscal degradation induced by exogenous Interleukin-l (IL-1) to test the hypothesis that the accelerated meniscal response to IL-1 involves proteolytic processes active in cartilage degradation and is dispersed throughout both inner (compression) and outer (tension) zones.
Aim 2 will examine the progression of meniscal degradation induced by compressive overload to test the hypothesis that moderate compressive overload of meniscal explants will induce cell-mediated matrix degradation involving the same catabolic processes induced by IL-1 stimulation.
Aim 3 will examine the ability of aggrecanase inhibition to protect the meniscal matrix from degradation to test the hypothesis that prevention of aggrecan depletion will protect the collagen from proteolytic degradation. These studies will provide important new insights into the progression of meniscal degeneration and could lead to novel diagnostic or therapeutic targets to prevent or delay the progression of OA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR052861-05
Application #
7500134
Study Section
Special Emphasis Panel (ZRG1-MOSS-A (04))
Program Officer
Panagis, James S
Project Start
2005-08-05
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
5
Fiscal Year
2009
Total Cost
$291,473
Indirect Cost
Name
Stanford University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Son, Min-Sun; Levenston, Marc E (2017) Quantitative tracking of passage and 3D culture effects on chondrocyte and fibrochondrocyte gene expression. J Tissue Eng Regen Med 11:1185-1194
Nishimuta, James F; Bendernagel, Monica F; Levenston, Marc E (2017) Co-culture with infrapatellar fat pad differentially stimulates proteoglycan synthesis and accumulation in cartilage and meniscus tissues. Connect Tissue Res 58:447-455
Nishimuta, J F; Levenston, M E (2015) Meniscus is more susceptible than cartilage to catabolic and anti-anabolic effects of adipokines. Osteoarthritis Cartilage 23:1551-62
Son, M; Goodman, S B; Chen, W et al. (2013) Regional variation in T1? and T2 times in osteoarthritic human menisci: correlation with mechanical properties and matrix composition. Osteoarthritis Cartilage 21:796-805
Vanderploeg, Eric J; Wilson, Christopher G; Imler, Stacy M et al. (2012) Regional variations in the distribution and colocalization of extracellular matrix proteins in the juvenile bovine meniscus. J Anat 221:174-86
Nishimuta, J F; Levenston, M E (2012) Response of cartilage and meniscus tissue explants to in vitro compressive overload. Osteoarthritis Cartilage 20:422-9
Nguyen, An M; Levenston, Marc E (2012) Comparison of osmotic swelling influences on meniscal fibrocartilage and articular cartilage tissue mechanics in compression and shear. J Orthop Res 30:95-102
Son, M; Levenston, M E (2012) Discrimination of meniscal cell phenotypes using gene expression profiles. Eur Cell Mater 23:195-208
Petsche, Steven J; Chernyak, Dimitri; Martiz, Jaime et al. (2012) Depth-dependent transverse shear properties of the human corneal stroma. Invest Ophthalmol Vis Sci 53:873-80
Lai, J H; Levenston, M E (2010) Meniscus and cartilage exhibit distinct intra-tissue strain distributions under unconfined compression. Osteoarthritis Cartilage 18:1291-9

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