Articular cartilage damage remains an unsolved problem in orthopaedics. The purpose of the proposed studies is to elucidate the potential role of autocrine/paracrine mechanisms in growth factor-mediated articular cartilage repair. The studies will employ in vitro recombinant adeno-associated virus (rAAV) mediated gene transfer methods to test the following hypotheses: (1) local growth factor production can be achieved by rAAV vector-mediated gene transfer to bovine articular chondrocytes and will augment cartilage repair in acute cartilage trauma; (2) local growth factor production can be achieved by rAAV vector-mediated gene transfer of human articular chondrocytes and will augment repair of osteoarthritic cartilage; (3) local production of more than one growth factor can be achieved by rAAV vector-mediated gene transfer and expressed growth factors will interact in the regulation of repair in traumatic and osteoarthritic cartilage damage; and (4) local growth factor production, coupled with expression of growth factor receptors can be achieved by rAAV-mediated gene transfer to chondrocytes and will augment repair in traumatic and OA cartilage damage. These hypotheses will be tested using insulin-like growth factor I (IGF-I) and fibroblast growth factor-2, (FGF-2) and, in Aim 4, the type I IGF receptor (IGF-IR). Repair will be assessed using biosynthetic, histological, biochemical and biomechanical parameters. The demonstration by these studies that growth factor-mediated cartilage repair can be achieved through autocrine/paracrine mechanisms would not only lend insight into the role of these factors in cartilage regulation, but may serve to facilitate the development of future potential gene transfer-based therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047702-06
Application #
7103416
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Wang, Fei
Project Start
2002-09-09
Project End
2010-02-28
Budget Start
2007-09-01
Budget End
2010-02-28
Support Year
6
Fiscal Year
2007
Total Cost
$286,327
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Orthopedics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Shi, Shuiliang; Kelly, Brian J; Wang, Congrong et al. (2017) Human IGF-I propeptide A promotes articular chondrocyte biosynthesis and employs glycosylation-dependent heparin binding. Biochim Biophys Acta 1862:567-575
Bonitsky, Craig M; McGann, Megan E; Selep, Michael J et al. (2017) Genipin crosslinking decreases the mechanical wear and biochemical degradation of impacted cartilage in vitro. J Orthop Res 35:558-565
Chan, Deva D; Cai, Luyao; Butz, Kent D et al. (2016) In vivo articular cartilage deformation: noninvasive quantification of intratissue strain during joint contact in the human knee. Sci Rep 6:19220
McGann, Megan E; Bonitsky, Craig M; Jackson, Mariah L et al. (2015) Genipin crosslinking of cartilage enhances resistance to biochemical degradation and mechanical wear. J Orthop Res 33:1571-1579
Shi, Shuiliang; Wang, Congrong; Acton, Anthony J et al. (2015) Role of sox9 in growth factor regulation of articular chondrocytes. J Cell Biochem 116:1391-400
Shi, Shuiliang; Chan, Albert G; Mercer, Scott et al. (2014) Endogenous versus exogenous growth factor regulation of articular chondrocytes. J Orthop Res 32:54-60
Griebel, Adam J; Trippel, Stephen B; Emery, Nancy C et al. (2014) Noninvasive assessment of osteoarthritis severity in human explants by multicontrast MRI. Magn Reson Med 71:807-14
Griebel, A J; Trippel, S B; Neu, C P (2013) Noninvasive dualMRI-based strains vary by depth and region in human osteoarthritic articular cartilage. Osteoarthritis Cartilage 21:394-400
Shi, Shuiliang; Mercer, Scott; Eckert, George J et al. (2013) Growth factor transgenes interactively regulate articular chondrocytes. J Cell Biochem 114:908-19
Shi, Shuiliang; Mercer, Scott; Eckert, George J et al. (2013) Growth factor regulation of growth factor production by multiple gene transfer to chondrocytes. Growth Factors 31:32-8

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