The proposed project focuses on osteoarthritis (OA), the most common joint disease in the United States. Characterized by cartilage degradation, OA is a debilitating condition that has no cure, causing chronic pain and long-term disability. Curren treatments focus on managing pain, which does not address the underlying problem of cartilage damage. A major hurdle in understanding OA is that it is a heterogeneous disease with different factors associated with it, such as joint injury, obesity and age. Despite the different initiating factors, the end result, cartilage destruction, remains the same and the mechanisms of cartilage degradation and protection is still not well understood. This proposal aims at examining the effect of ghrelin in joint cartilage maintenance and protection during OA. While originally identified as a 28 amino acid long peptide from the stomach, ghrelin was found to act in other tissues and was seen to be reduced in the serum of aged and obese individuals. Our preliminary studies indicated that ghrelin level was reduced in OA chondrocytes. Additionally, ghrelin administration in human articular chondrocytes promoted cartilage matrix production and reduced IL-1-induced NFkB signaling as well as inhibited matrix reduction in vitro. Furthermore, ghrelin's effect was abolished in chondrocytes from the ghrelin receptor (GHS-R) knockout mouse, suggesting its activities may be mediated by this receptor. Therefore, based on these results, this project is formed around the central hypothesis that ghrelin signaling inhibits inflammation and cartilage destruction of the joint, and thus has a protective effect on articular cartilage during OA development and progression in vivo. This hypothesis will be addressed with the following aims: 1) Determine whether ghrelin is sufficient in maintaining articular cartilage integrity during OA development in vivo in OA mice. 2) Determine whether ghrelin receptor signaling is critical for maintaining joint integrity in vivo. This study will contribute to the understanding of fundamental mechanisms that regulate inflammation and matrix destruction during OA onset and progression, which is significant from a basic science point as well as clinical perspective. Through this research, I will acquire a diverse set of skils and the critical training essential for my career development. Additionally, this project will be coupled with opportunities at Tufts to develop communication, mentoring, and leadership skills that will serve to prepare me for a future as an independent scientist and mentor.

Public Health Relevance

Osteoarthritis is the most common joint condition manifesting as cartilage degeneration, bone morphological changes, inflammation, and symptoms of pain. The mechanisms contributing to the early stages of this condition are still unknown, hindering development of treatments for osteoarthritis prior to irreversible cartilage degradation. This project focuses on the novel role of ghrelin on inflammation and cartilage protection in OA.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Lester, Gayle E
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Tufts University
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United States
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Hui Mingalone, Carrie K; Liu, Zhiyi; Hollander, Judith M et al. (2018) Bioluminescence and second harmonic generation imaging reveal dynamic changes in the inflammatory and collagen landscape in early osteoarthritis. Lab Invest 98:656-669
Gibson, Averi L; Hui Mingalone, Carrie K; Foote, Andrea T et al. (2017) Wnt7a Inhibits IL-1? Induced Catabolic Gene Expression and Prevents Articular Cartilage Damage in Experimental Osteoarthritis. Sci Rep 7:41823
Liu, Zhiyi; Pouli, Dimitra; Sood, Disha et al. (2017) Automated quantification of three-dimensional organization of fiber-like structures in biological tissues. Biomaterials 116:34-47