Articular cartilage functions as a load-bearing tissue that is regulated by its mechanical environment. Although the effects of mechanical forces on articular cartilage are well-described, the molecular mechanisms responsible for these effects are not clear. The goal of these studies is to elucidate intracellular signal transduction pathways that mediate the biological effects of loading on cartilage. These studies will focus on the following four related specific aims. 1. Test the hypothesis that static and dynamic compressive loads influence distinct signal transduction pathways in articular chondrocytes. 2. Test the hypothesis that integrin-initiated and growth factor receptor-initiated pathways contribute to the response of articular chondrocytes to compressive loads. 3. Identify the specific signal transduction elements that are regulated by mechanical compression in articular chondrocytes. 4. Test the hypothesis that some aged cartilage possesses a defect in signal transduction that is manifested in its response to mechanical compression. These studies will conducted using bovine and human articular cartilage explant and gel suspension culture systems, focusing on proximal (membrane and cytoplasmic) events that mediate cell responses to extracellular signals. The demonstration by these studies that mechanical factors activate specific signal transduction pathways would not only lend insight into the molecular mechanisms that govern normal articular cartilage homeostasis, but would serve as a basis for investigating pathways whose disruption may contribute to cartilage disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR045749-01
Application #
2792572
Study Section
Special Emphasis Panel (ZAR1-TLB-B (O3))
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
1998-09-30
Budget End
1999-08-31
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Cucchiarini, Magali; Madry, Henning; Ma, Chunyan et al. (2005) Improved tissue repair in articular cartilage defects in vivo by rAAV-mediated overexpression of human fibroblast growth factor 2. Mol Ther 12:229-38
Madry, H; Kaul, G; Cucchiarini, M et al. (2005) Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I). Gene Ther 12:1171-9
Madry, Henning; Emkey, Greg; Zurakowski, David et al. (2004) Overexpression of human fibroblast growth factor 2 stimulates cell proliferation in an ex vivo model of articular chondrocyte transplantation. J Gene Med 6:238-45
Madry, Henning; Cucchiarini, Magali; Kaul, Gunter et al. (2004) Menisci are efficiently transduced by recombinant adeno-associated virus vectors in vitro and in vivo. Am J Sports Med 32:1860-5
Madry, Henning; Cucchiarini, Magali; Stein, Ute et al. (2003) Sustained transgene expression in cartilage defects in vivo after transplantation of articular chondrocytes modified by lipid-mediated gene transfer in a gel suspension delivery system. J Gene Med 5:502-9
Fanning, Paul J; Emkey, Gregory; Smith, Robert J et al. (2003) Mechanical regulation of mitogen-activated protein kinase signaling in articular cartilage. J Biol Chem 278:50940-8
Madry, Henning; Cucchiarini, Magali; Terwilliger, Ernest F et al. (2003) Recombinant adeno-associated virus vectors efficiently and persistently transduce chondrocytes in normal and osteoarthritic human articular cartilage. Hum Gene Ther 14:393-402
Jin, Moonsoo; Emkey, Greg R; Siparsky, Patrick et al. (2003) Combined effects of dynamic tissue shear deformation and insulin-like growth factor I on chondrocyte biosynthesis in cartilage explants. Arch Biochem Biophys 414:223-31
Madry, Henning; Padera, Robert; Seidel, Joachim et al. (2002) Gene transfer of a human insulin-like growth factor I cDNA enhances tissue engineering of cartilage. Hum Gene Ther 13:1621-30
Madry, H; Zurakowski, D; Trippel, S B (2001) Overexpression of human insulin-like growth factor-I promotes new tissue formation in an ex vivo model of articular chondrocyte transplantation. Gene Ther 8:1443-9

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