Recent data suggest that there are multiple regulatory pathways by which chondrocytes sense and respond to mechanical stimuli, including upstream signaling pathways and mechanisms that may lead to direct changes at the level of transcription, translation and post-translational modifications, and cell-mediated extracellular assembly and degradation of matrix. Correspondingly, there may be multiple pathways by which physical stimuli can alter not only the rate of matrix production, but the quality and functionality of newly synthesized proteoglycans, collagens, and other molecules. In this manner, specific mechanical loading regimes may either enhance or compromise the ultimate biomechanical function of cartilage. We propose to (1) Quantify the effects of static, dynamic, and injurious compression on the morphology of intracellular organelles within chondrocytes of cartilage explants; (2) Quantify the effects of static, dynamic, and injurious compression on changes in the intracellular localization and activity of chondroitin 6-0-sulfotransferase (C6ST) transfected into primary bovine chondrocytes that are seeded into alginate gel disks subjected to compression; (3) Determine the effects of graded levels of injurious strain and strain rate on cell viability; on mRNA levels for aggrecan, collagen types I, IIA, IIB, and selected matrix metalloproteinases; on changes in morphology of intracellular organelles; and on cell-level spatial profiles of matrix turnover, and (4) Quantify the biosynthetic response of human cartilages to static, dynamic and injurious compression, using tissue from the distal femur, tibial plateau, and talocrural joint surfaces, and identify biosynthetic and degradative responses at the tissue and cell levels as a function of tissue age, location, and position.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045779-03
Application #
6171193
Study Section
Special Emphasis Panel (ZAR1-TLB-B (O3))
Program Officer
Tyree, Bernadette
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$212,106
Indirect Cost
Name
Massachusetts Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
City
Cambridge
State
MA
Country
United States
Zip Code
02139
Wang, Yang; Li, Yang; Khabut, Areej et al. (2017) Quantitative proteomics analysis of cartilage response to mechanical injury and cytokine treatment. Matrix Biol 63:11-22
Varady, N H; Grodzinsky, A J (2016) Osteoarthritis year in review 2015: mechanics. Osteoarthritis Cartilage 24:27-35
Ã…hrman, Emma; Lorenzo, Pilar; Holmgren, Kristin et al. (2014) Novel cartilage oligomeric matrix protein (COMP) neoepitopes identified in synovial fluids from patients with joint diseases using affinity chromatography and mass spectrometry. J Biol Chem 289:20908-16
Li, Y; Frank, E H; Wang, Y et al. (2013) Moderate dynamic compression inhibits pro-catabolic response of cartilage to mechanical injury, tumor necrosis factor-? and interleukin-6, but accentuates degradation above a strain threshold. Osteoarthritis Cartilage 21:1933-41
Rolauffs, Bernd; Kurz, Bodo; Felka, Tino et al. (2013) Stress-vs-time signals allow the prediction of structurally catastrophic events during fracturing of immature cartilage and predetermine the biomechanical, biochemical, and structural impairment. J Struct Biol 183:501-511
Byun, Sangwon; Sinskey, Yunna L; Lu, Yihong C S et al. (2013) Transport of anti-IL-6 antigen binding fragments into cartilage and the effects of injury. Arch Biochem Biophys 532:15-22
Byun, Sangwon; Sinskey, Yunna L; Lu, Yihong C S et al. (2013) Transport and binding of tumor necrosis factor-? in articular cartilage depend on its quaternary structure. Arch Biochem Biophys 540:1-8
Kopesky, Paul W; Vanderploeg, Eric J; Kisiday, John D et al. (2011) Controlled delivery of transforming growth factor ?1 by self-assembling peptide hydrogels induces chondrogenesis of bone marrow stromal cells and modulates Smad2/3 signaling. Tissue Eng Part A 17:83-92
Lu, Yihong C S; Evans, Christopher H; Grodzinsky, Alan J (2011) Effects of short-term glucocorticoid treatment on changes in cartilage matrix degradation and chondrocyte gene expression induced by mechanical injury and inflammatory cytokines. Arthritis Res Ther 13:R142
Miller, Rachel E; Grodzinsky, Alan J; Cummings, Kiersten et al. (2010) Intraarticular injection of heparin-binding insulin-like growth factor 1 sustains delivery of insulin-like growth factor 1 to cartilage through binding to chondroitin sulfate. Arthritis Rheum 62:3686-94

Showing the most recent 10 out of 45 publications