? Arthritis is a widespread debilitating disease in which the joint cartilage becomes disintegrated. Regenerating cartilage in vitro may be part of a plausible treatment for these conditions. The understanding how cartilage is degraded and how to produce new cartilage through bioengineering requires a thorough understanding of the signaling events that take place during cartilage formation. Our long-range goal is to unveil the mechanisms that govern cartilage formation in the embryo, which will provide the knowledge for treating arthritis and other skeletal diseases. The objective of this proposal is to investigate the regulation of Nkx3.2 expression and nuclear localization during chondrogenesis. Our central hypothesis is that the control of Nkx3.2 is a key mechanism to cartilage differentiation. We will test our hypothesis by pursuing the following Specific Aims: 1. Investigate the mechanisms of Nkx3.2 nuclear localization controlled by pro-chondrogenic signals Shh, BMP and Sox9. 2. Examine the effect of cartilage-inhibiting signals TNF-a and IL-1 (i on Nkx3.2 expression and nuclear localization. 3. Determine if Nkx3.2 promotes cartilage differentiation in human mesenchymal stem cells. Nkx3.2 is an important protein because it not only promotes cartilage formation, but also prevents chondrocyte hypertrophy. Thus, Nkx3.2 is a plausible candidate to be introduced into the progenitor cells in order to promote the formation of permanent cartilage. Understanding the regulation of this protein will help us in our future research of introducing Nkx3.2 in adult stem cells to direct and maintain differentiated chondrocyte phenotype in our endeavor of cartilage bioengineering, and on developing remedies for arthritis. ? ? ?

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Small Research Grants (R03)
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Special Emphasis Panel (ZAR1-EHB-M (O1))
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Tyree, Bernadette
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Tufts University
Anatomy/Cell Biology
Schools of Medicine
United States
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Uchimura, Tomoya; Hollander, Judith M; Nakamura, Daisy S et al. (2017) An essential role for IGF2 in cartilage development and glucose metabolism during postnatal long bone growth. Development 144:3533-3546
Nakamura, Daisy S; Hollander, Judith M; Uchimura, Tomoya et al. (2017) Pigment Epithelium-Derived Factor (PEDF) mediates cartilage matrix loss in an age-dependent manner under inflammatory conditions. BMC Musculoskelet Disord 18:39
Uchimura, Tomoya; Foote, Andrea T; Markel, David C et al. (2016) The Chondroprotective Role of Erythromycin in a Murine Joint Destruction Model. Cartilage 7:373-87
Uchimura, Tomoya; Foote, Andrea T; Smith, Eric L et al. (2015) Insulin-Like Growth Factor II (IGF-II) Inhibits IL-1?-Induced Cartilage Matrix Loss and Promotes Cartilage Integrity in Experimental Osteoarthritis. J Cell Biochem 116:2858-69
Cairns, Dana M; Liu, Renjing; Sen, Manpreet et al. (2012) Interplay of Nkx3.2, Sox9 and Pax3 regulates chondrogenic differentiation of muscle progenitor cells. PLoS One 7:e39642
Cairns, Dana M; Lee, Philip G; Uchimura, Tomoya et al. (2010) The role of muscle cells in regulating cartilage matrix production. J Orthop Res 28:529-36
Cairns, Dana M; Uchimura, Tomoya; Kwon, Heenam et al. (2010) Muscle cells enhance resistance to pro-inflammatory cytokine-induced cartilage destruction. Biochem Biophys Res Commun 392:22-8
Cairns, Dana M; Sato, Mie Elissa; Lee, Philip G et al. (2008) A gradient of Shh establishes mutually repressing somitic cell fates induced by Nkx3.2 and Pax3. Dev Biol 323:152-65