Arthritis is a leading cause of disability in the United States. Despite its prevalence in our ever-aging society, effective treatment options for arthritis are still limited. Arthritis is caused by the destruction of joint cartilage, which is accompanied by inflammation and pain. Cartilage tissue engineering offers a promising solution to regenerate cartilage and restore tissue function. However, the presence of pro-inflammatory cytokines at the host site inevitably leads to matrix degradation, causing the engineered cartilage to be unstable. Therefore, for this technology to be applied clinically there is a critical need to engineer stable cartilage that is resistant to pro-inflammatory cytokine-induced degradation. Our long-term goal is to gain critical knowledge of cartilage regulation and enhance the technology of cartilage tissue engineering for clinical applications. We are developing a novel strategy that integrates concepts and approaches from developmental biology with those of tissue engineering. During embryogenesis, muscle is one of the tissues that develop alongside the presumptive cartilage tissue. Our extensive preliminary studies indicate a role of muscle cells in regulating cartilage homeostasis and inflammatory stimuli. Our central hypothesis is that muscle cells and optimal scaffold selection can be used to enhance the stability of engineered cartilage by enhancing cartilage matrix production and the resistance to pro-inflammatory cytokines. We plan to test this hypothesis by using primary human articular chondrocytes and mesenchymal stem cells seeded in 3D silk scaffolds. We plan to: 1) investigate the role of muscle cells in regulating cartilage matrix production, 2) investigate the role of muscle cells in regulating the response to pro-inflammatory cytokines, and 3) investigate the effect of scaffold material on muscle cell regulation of cartilage matrix production and the response to pro-inflammatory cytokines. Our research team consists of experts in the fields of developmental biology, tissue engineering, immunology and orthopaedics. We believe that our synergistic efforts and interdisciplinary approach will result in deeper understanding of the regulation of cartilage homeostasis and the response to pro- inflammatory stimuli, providing the fundamental knowledge for modeling and treating arthritis. Thus, our study aspires to meet the critical need of improving tissue engineering technology, and may lead to the development of a novel strategy to engineer stable cartilage for clinical applications.

Public Health Relevance

Arthritis, characterized by inflammation and joint destruction, is a leading cause of disability in our ever-aging society. However, effective treatment options for this prevailing disease still remain limited. We propose a novel strategy to engineer stable cartilage tissue that is resistant to inflammation by utilizing muscle cells. Thus, our research aspires to meet the critical need for improving cartilage regeneration and joint repair technology, which may ultimately be developed as an effective treatment method for arthritis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR059106-03
Application #
8298608
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Wang, Fei
Project Start
2010-09-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$367,417
Indirect Cost
$144,740
Name
Tufts University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
039318308
City
Boston
State
MA
Country
United States
Zip Code
02111
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Kwon, Heenam; Rainbow, Roshni S; Sun, Lin et al. (2015) Scaffold structure and fabrication method affect proinflammatory milieu in three-dimensional-cultured chondrocytes. J Biomed Mater Res A 103:534-44
Cairns, Dana M; Pignolo, Robert J; Uchimura, Tomoya et al. (2013) Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. J Clin Invest 123:3624-33
Rainbow, R S; Kwon, H; Foote, A T et al. (2013) Muscle cell-derived factors inhibit inflammatory stimuli-induced damage in hMSC-derived chondrocytes. Osteoarthritis Cartilage 21:990-8
Kwon, Heenam; Sun, Lin; Cairns, Dana M et al. (2013) The influence of scaffold material on chondrocytes under inflammatory conditions. Acta Biomater 9:6563-75
Brand, Joshua A; McAlindon, Timothy E; Zeng, Li (2012) A 3D system for culturing human articular chondrocytes in synovial fluid. J Vis Exp :e3587