Osteoarthritis (OA) is a painful and debilitating disease of the synovial joints, affecting over 27 million people in the United States. The prevalence of obesity has risen dramatically in the past two decades, and we now know that obesity is likely to be the primary preventable risk factor for OA. The goal of this project is to examine the influence of dietary fatty acids in obesity-associated OA in mice, and to examine their interaction with altered biomechanical and pro-inflammatory factors using various in vivo and in vitro models. We propose that low-grade chronic systemic inflammation ? due to obesity or pro-inflammatory fatty acids in the diet ? acts in synergy with local inflammatory cytokines or altered mechanical loading following injury to promote a state of inflammation and matrix degradation in the articular cartilage.
In Aim 1, we will examine the role of a high-fat diet rich in omega-6 fatty acids in the development of OA, and we will examine the effects of endogenous conversion of omega-6 to omega-3 fatty acids to mitigate OA severity in the Fat-1 transgenic mouse.
In Aim 2, we will examine the effects of systemic or local gene therapy using the Fat-1 gene to mitigate obesity-induced OA.
In Aim 3, we will use controlled in vitro models of cartilage explant loading to examine the effects of mechanical stress in combination with pro- inflammatory cytokines and fatty acids on the anabolic and catabolic activities of the chondrocytes. Detailed studies of the interactions between specific dietary composition, pro-inflammatory mediators, and tissue metabolism in articular cartilage will improve our understanding of the pathology of the OA, particularly as it relates in vivo to biomechanical factors such as obesity or injury. The results of this study will provide new insights into key elements of the pathogenesis of obesity-induced, and ultimately could lead to new treatments that exploit dietary or gene therapies to prevent disease. ! !

Public Health Relevance

The goal of this project is to examine the influence of dietary fatty acids on obesity-associated osteoarthritis in mice, and to examine their interaction with altered biomechanical and pro-inflammatory cytokines using various in vivo and in vitro models. We will test the hypothesis the genetic conversion of pro-inflammatory omega-6 fatty acids to anti-inflammatory omega-3 fatty acids will mitigate the severity of obesity-induced osteoarthritis.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Structure and Regeneration Study Section (SBSR)
Program Officer
Williams, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Guilak, Farshid; Nims, Robert J; Dicks, Amanda et al. (2018) Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol 71-72:40-50
Rowland, Christopher R; Glass, Katherine A; Ettyreddy, Adarsh R et al. (2018) Regulation of decellularized tissue remodeling via scaffold-mediated lentiviral delivery in anatomically-shaped osteochondral constructs. Biomaterials 177:161-175
Furman, Bridgette D; Kent, Collin L; Huebner, Janet L et al. (2018) CXCL10 is upregulated in synovium and cartilage following articular fracture. J Orthop Res 36:1220-1227
Tang, Ruhang; Jing, Liufang; Willard, Vincent P et al. (2018) Differentiation of human induced pluripotent stem cells into nucleus pulposus-like cells. Stem Cell Res Ther 9:61
Erdemir, Ahmet; Hunter, Peter J; Holzapfel, Gerhard A et al. (2018) Perspectives on Sharing Models and Related Resources in Computational Biomechanics Research. J Biomech Eng 140:
Collins, Amber T; Kulvaranon, Micaela L; Cutcliffe, Hattie C et al. (2018) Obesity alters the in vivo mechanical response and biochemical properties of cartilage as measured by MRI. Arthritis Res Ther 20:232
Liu, Betty; Goode, Adam P; Carter, Teralyn E et al. (2017) Matrix metalloproteinase activity and prostaglandin E2 are elevated in the synovial fluid of meniscus tear patients. Connect Tissue Res 58:305-316
Wu, Chia-Lung; Kimmerling, Kelly A; Little, Dianne et al. (2017) Serum and synovial fluid lipidomic profiles predict obesity-associated osteoarthritis, synovitis, and wound repair. Sci Rep 7:44315
Brunger, Jonathan M; Zutshi, Ananya; Willard, Vincent P et al. (2017) CRISPR/Cas9 Editing of Murine Induced Pluripotent Stem Cells for Engineering Inflammation-Resistant Tissues. Arthritis Rheumatol 69:1111-1121
Wu, Chia-Lung; McNeill, Jenna; Goon, Kelsey et al. (2017) Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas-Induced Apoptosis-Transgenic Mice. Arthritis Rheumatol 69:1772-1783

Showing the most recent 10 out of 51 publications