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Determining the role of interleukin-1β in the Hartley guinea pig model of primary osteoarthritis

Santangelo, Kelly Susan
http://rave.ohiolink.edu/etdc/view?acc_num=osu1299649441

Abstract Details

2011, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Osteoarthritis (OA) is a debilitating disease associated with pain and dysfunction that remains an unresolved and widespread source of symptomatic health problems for many individuals, particularly those 40 years and older. Interleukin-1β (IL-1β) has been cited as a major cytokine involved in OA-related joint degeneration. Recognized as one of the most important mediators of inflammation and host response to infection, increased production of this cytokine has been linked to a wide variety of autoimmune conditions and autoinflammatory disorders. Characterization of its role in primary OA, however, remains elusive and potentially contradictory. Thus, the molecular interactions to explain the relationship between IL-1β and maintenance of healthy articular cartilage have been proposed but are not yet definitively established, and characterization of the function of IL-1β in a spontaneous, in vivo model remains elusive. As such, a primary aim of this study was to provide a comprehensive analysis of the temporal expression and tissue distribution of IL-1β using immunohistochemistry (IHC) throughout initiation and progression of OA in a naturally-occurring animal model. We subsequently elucidated that OA-prone Hartley guinea pig did not demonstrate reduced IL-1β in weight-bearing articular cartilage, synovium, meniscus, or subchondral bone during achievement of adult maturity as in the control guinea pig strain, and that this aberrant expression may correlate to early incidence of OA. As this temporal study provided evidence that IL-1β is a biomarker relevant to the development and progression of OA, and we then performed in vitro and in vivo studies to block and/or reduce the dysregulation of this cytokine’s expression such that we could provide evidence of its contribution to premature onset of spontaneous OA. Successful reduction of the IL-1β transcript was achieved via RNA interference (RNAi) techniques in vitro using a novel adeno-associated viral vector serotype 5 (AAV5) vector containing a targeting knockdown sequence validated in our laboratory. Importantly, in vitro decreases in IL-1β influenced the transcript levels of several critical mediators involved in OA pathogenesis in the direction of beneficial disease modification. We then proceeded with in vivo investigations to characterize gene expression changes influenced by either our AAV5 targeting knockdown vector or administration of an adenovirus (Ad) vector encoding the human interleukin-1 receptor antagonist protein (hIRAP). This work demonstrated that a reduction in IL-1β signaling by RNAi or hIRAP via AAV5 and Ad vectors, respectively, was achieved in the Hartley guinea pig model of naturally-occurring OA. Importantly, this manipulation was demonstrated over a 120-day period with no loss of reporter gene expression from either viral vector. Reducing IL-1β significantly decreased expression of three inflammatory mediators and one catabolic agent, while it simultaneously increased the number of a specific anabolic molecule, providing biological evidence that IL-1β serves an important role in primary OA. These changes may be anticipated to provide long-term beneficial disease modification, particularly under conditions of secondary joint stress due to injury, exercise, or obesity. Collectively, these findings can be interpreted as strong evidence that IL-1β does serve an important role in primary OA and that treatments aimed at decreasing its effective concentration and/or signaling pathway in vivo hold merit.
Alicia Bertone, DVM PhD (Advisor)
Jeffrey Bartlett, PhD (Committee Member)
Gerard Nuovo, MD (Committee Member)
Steven Weisbrode, VMD PhD (Committee Member)
Molecular Biology
osteoarthritis; interleukin-1; guinea pig; RNA interference; adeno-associated viral vector; adenoviral vector

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Citations

  • Santangelo, K. S. (2011). Determining the role of interleukin-1β in the Hartley guinea pig model of primary osteoarthritis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299649441

    APA Style (7th edition)

  • Santangelo, Kelly. Determining the role of interleukin-1β in the Hartley guinea pig model of primary osteoarthritis. 2011. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1299649441.

    MLA Style (8th edition)

  • Santangelo, Kelly. "Determining the role of interleukin-1β in the Hartley guinea pig model of primary osteoarthritis." Doctoral dissertation, Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1299649441

    Chicago Manual of Style (17th edition)

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© 2011, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.