Osteoarthritis (OA) is a debilitating and painful disease of synovial joints that affects an estimated 21 million people in the United States and more than 10% of the population over 60 years old. Normal cartilage structure is maintained through chondrocyte-mediated synthesis and degradation of the cartilage extracellular matrix (ECM). The application of biomechanical signals through joint loading is known to be critical in preserving this tissue homeostasis. However, the mechanisms by which chondrocytes respond to mechanical loading of the cartilage, in both physiological and pathological settings, are not fully understood. Recently, the transient receptor potential vanilloid 4 (TRPV4) ion channel, a Ca++ preferred cation channel, has emerged as a central focus in chondrocyte osmotic and mechanical stimuli signal transduction. TRPV4 has been identified as a potent regulator of chondrocyte gene-expression and ECM production in vitro, and spontaneous joint degeneration has been described in vivo with global trpv4 gene deletion. Age-associated changes in this signaling pathway may explain the vulnerability of aging cartilage to progressive degeneration and OA. The goal of this study is to characterize the role of TRPV4 in cartilage maintenance during aging. We hypothesize that the initiation and progression of joint degeneration in aging is due to altered TRPV4-mediated Ca++ signaling in response osmotic and mechanical stimuli.
In Specific Aim 1, we will comprehensively characterize the chondrocyte TRPV4 channel during aging and OA, including trpv4 gene expression, TRPV4 protein levels and TRPV4 function, and relate this to quantitative analyses of the corresponding morphological and material changes.
In Specific Aim 2, we will generate cartilage-targeted, inducible trpv4 knockout mice to further study the specific role of TRPV4 signaling in adult cartilage and OA development, looking again at both macro and microscopic TRPV4-dependant changes of the cartilage. This study is intended to elucidate how cartilage metabolism is regulated by mechanical factors and how this cartilage homeostasis is disrupted during aging and disease. This fellowship will not only help equip me with the knowledge and tools to begin a productive career as a physician-scientist in orthopedic bioengineering and translational research, but the project proposed here will directly apply these talents towards the development of novel diagnostic, pharmaceutical, and biophysical interventions for better treatment of OA.
Aging is one of the primary risk factors for osteoarthritis (OA), although the mechanisms responsible for age-related joint degeneration are not well understood. The response of chondrocytes, the cells of cartilage, to mechanical loading is critical for articular cartilage resiliency and joint health. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel, a transducer of osmotic and mechanical stimuli, may be the physiological link between aging and OA joint degeneration. We aim to characterize chondrocyte TRPV4 function during aging and OA pathogenesis, utilizing a novel TRPV4-deficient mouse model to further explore this relationship.
|O'Conor, Christopher J; Ramalingam, Sendhilnathan; Zelenski, Nicole A et al. (2016) Cartilage-Specific Knockout of the Mechanosensory Ion Channel TRPV4 Decreases Age-Related Osteoarthritis. Sci Rep 6:29053|
|McNulty, Amy L; Leddy, Holly A; Liedtke, Wolfgang et al. (2015) TRPV4 as a therapeutic target for joint diseases. Naunyn Schmiedebergs Arch Pharmacol 388:437-50|
|Sanchez-Adams, Johannah; Leddy, Holly A; McNulty, Amy L et al. (2014) The mechanobiology of articular cartilage: bearing the burden of osteoarthritis. Curr Rheumatol Rep 16:451|
|O'Conor, Christopher J; Leddy, Holly A; Benefield, Halei C et al. (2014) TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. Proc Natl Acad Sci U S A 111:1316-21|
|O'Conor, Christopher J; Griffin, Timothy M; Liedtke, Wolfgang et al. (2013) Increased susceptibility of Trpv4-deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet. Ann Rheum Dis 72:300-4|
|O'Conor, Christopher J; Case, Natasha; Guilak, Farshid (2013) Mechanical regulation of chondrogenesis. Stem Cell Res Ther 4:61|