Growth factor gene transfer to articular chondrocytes may be capable of augmenting cell-based approaches to articular cartilage repair. Currently available data is insufficient to enable translation into clinical use. The purpose of this proposal is to help close the gap between present mechanistic knowledge and therapeutic application. We will focus on three related specific aims.
Aim 1 : Define a potentially therapeutic set of growth factor genes for articular cartilage repair by determining how interactions among selected growth factors regulate articular chondrocyte function. Hypothesis 1: IGF-I, FGF-2, BMP-2, and BMP-7, when employed for articular chondrcyte gene transfer, interact to differentially regulate the expression of genes that influence chondrocyte reparative functions.
Aim 2 : Determine whether genetic and tissue engineering methods, when applied to articular chondrocytes, are interdependent. Hypothesis 2: Chemically distinct biomaterials, including alginate, collagen, and hyaluronic acid-based gels, differentially modulate the effects of growth factor gene transfer.
Aim 3 : Determine whether transfer of an optimized set of growth factor genes coupled with an optimized biomaterial can generate durable repair in a large animal model of cartilage loss. Hypothesis 3: Optimal repair of articular cartilage lesions requires a modulation of cell proliferation and matrix synthesis. Articular chondrocytes treated by gene transfer with selected combinations of growth factors and delivered in a selected hydrogel differentially promote repair of intrachondral articular cartilage defects in the equine knee. The demonstration that interactions between these genetic engineering and tissue engineering technologies promote repair by articular chondrocytes would lend insight into the mechanisms that regulate cell-based therapies and provide a key step in the translation of these therapies to human articular cartilage diseases.

Public Health Relevance

Articular cartilage damage is the cause of pain and disability from acute joint trauma and chronic joint arthritis, and remains an unsolved problem in modern orthopaedics. Current therapies can help the symptoms that result from cartilage loss, but treatments are lacking that can correct the cartilage loss itself. This is a translational research project that will combine gene therapy and tissue engineering methods in a pre-clinical model to test a potential new treatment approach to articular cartilage repair.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047702-11
Application #
8616717
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2001-04-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
11
Fiscal Year
2014
Total Cost
$472,077
Indirect Cost
$122,273
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
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
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
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 33:1571-9
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
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, 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
Shi, Shuiliang; Mercer, Scott; Eckert, George J et al. (2012) Regulation of articular chondrocyte aggrecan and collagen gene expression by multiple growth factor gene transfer. J Orthop Res 30:1026-31
Shi, Shuiliang; Mercer, Scott; Trippel, Stephen B (2010) Effect of transfection strategy on growth factor overexpression by articular chondrocytes. J Orthop Res 28:103-9

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