Andrew Dudley, Ph.D. – Principal Investigator
DRC II 6064
UNMC, Omaha, NE 68198-5965
Research Summary: Research in the laboratory seeks to uncover the mechanisms that regulate the development and homeostasis of musculoskeletal tissues using methods from embryology, molecular biology, cell biology, genetics, and tissue engineering, with the goal of generating novel therapies for regenerative medicine.
Our current work focuses on:
I. Cartilage Architecture. Cartilage and bone grow well in vitro, yet tissue engineering methods often do not produce tissue that displays growth and mechanical properties consistent with tissue in vivo. Our hypothesis is that the growth and mechanical properties derive from the specific arrangement of cells, which influences organization of the extracellular matrix, the key structural component of these tissues. We use the growth plate cartilage as a primary model system. In the growth plate cartilage, the transition of precursor, or resting, chondrocytes to a proliferative state is accompanied by an architectural change from spherical cells dispersed in the cartilage matrix to discoid cells stacked like coins. We have shown that this columnar arrangement occurs via a two-step process in which chondrocytes divide perpendicular to the column then the daughter cells rearrange and align with the column. Establishing the correct planes of cell division and rearrangement depends on noncanonical Wnt signaling, potentially through the planar cell polarity pathway, and the function of proteins attached to the cell surface via glycosylphosphatidylinositol (gpi) linkages. We are continuing to probe the mechanisms that regulate cartilage architecture through the development of novel in vitro and in vivo models with the long-term goal of developing systems that permit the fine-tuning of tissue architecture for repair and tissue regeneration.
II. Mechanism and regulation of chondrocyte hypertrophy. The terminal fate of growth plate chondrocytes is hypertrophy (growth in volume) and death. This process is important as it promotes elongation of bone and subsequently allows replacement of the cartilage matrix with bone matrix. However, in the articular cartilage, chondrocyte hypertrophy and matrix mineralization is associated only with pathological conditions such as osteoarthritis. We have shown that activation of calcium-calmodulin protein kinase II (CamkII) results in cell autonomous premature hypertrophy in growth plate chondrocytes. We are determining the mechanism of CamkII-induced hypertrophy and are identifying other regulators of the hypertrophic process. Our long-term objective is to develop pharmacological agents to regulate hypertrophy both as a means to control growth and to inhibit the progression of diseases such as osteoarthritis.
III. Secondary chondrogenesis and osteogenesis. Most cartilage and bone of the mature skeleton derives from condensates of mesenchyme that are patterned during embryogenesis. However, some cartilage and bone forms after birth in response to mechanical stress as a normal developmental process, eg. parts of the jaw, or as a pathological process, eg. in fibrodysplasia ossificans progressiva. Our studies are focused on identifying the relevant stem cell populations and stimuli that produce secondary skeletal tissue in the post natal period and in adults with the goal of developing new therapeutic approaches to regenerate skeletal tissue from endogenous cells.
- Tseng, Y.-H., Kokkotou, E., Schulz, T. J., Huang, T. L., Winnay, J. N., Taniguchi, C. M., Tran, T. T., Suzuki, R., Espinoza, D. O., Yamamoto, Y., Ahrens, M. J., Dudley, A. T., Norris, A. W., Kulkarni, R. N., Kahn, C. R. (2008) New role of bone morphogenetic protein 7 in brown adipogenesis and energy expenditure. Nature 454: 1000-1004. PMCID:PMC2745972
- Kim, J. H., Gurumurthy, C. B., Naramura, M., Zhang, Y., Dudley, A. T., Doglio, L., Band, H. and Band, V. (2009) The role of mammalian ecdysoneless in cell cycle regulation. JBC 284: 26402-26410. PMCID:PMC2785328
- Li, Y. and Dudley, A. T. (2009) Noncanonical Frizzled signaling regulates cell polarity in growth plate chondrocytes. Development 136:1083-1092. PMCID:PMC2685929
- Ahrens, M. J.*, Li, Y.* , Jiang, H. and Dudley, A. T. (2009) Convergent extension movements in growth plate chondrocytes require gpi-anchored cell surface proteins. Development, 136: 3463-3474. PMCID:PMC2752396
- Li, Y., Ahrens, M. J., Wu, A., Liu, J., and Dudley, A. T. (2010) Regulation of Ca2+/ calmodulin protein kinase II (CamkII) activity regulates the proliferative potential of growth plate chondrocytes. Development 138: 359-370. PMCID: PMC3005607
- Ahrens, M. J. and Dudley, A. T. (2011) Chemical pretreatment of growth plate cartilage increases immunofluorescence sensitivity. J. Histochem. Cytochem 59: 408-418. PMCID:PMC3201148
- Ahrens, M. J., Romereim, S. R. and Dudley, A. T. (2011) A re-evaluation of two key reagents for in vivo studies of Wnt signaling. Dev. Dyn. 240(9): 2060-2068. PMCID:PMC3192924
- Romereim, S. R. and Dudley, A. T.. (2011) Cell Polarity: the missing link in skeletogenesis? Organogenesis 7(3): 217-228 PMCID:PMC3243035
Andrew Dudley, PhD - Principal Investigator