Robert A. Mooney, Ph.D.
Johns Hopkins University School of Medicine
Department of Pathology and Laboratory Medicine
Center for Musculoskeletal Research
The Mooney Laboratory has been involved in the study of diabetes and obesity for many years. Projects have included studies of insulin action, insulin receptor inhibition and obesity-dependent insulin resistance. During a recent sabbatical in the Center for Musculoskeletal Research at the University of Rochester, Dr. Mooney began to apply this expertise to the study of bone diseases, particularly osteoporosis and osteoarthritis.
Osteoarthritis (OA) affects nearly 27 million Americans. With joint trauma, obesity and diabetes being strong risk factors for OA, the proportion of individuals with more than one of these risk factors is substantial. Despite these risk factors, little is known about the pathologic mechanisms that mediate the increased OA risk after traumatic joint injury in the setting of obesity and diabetes.
The demonstration that obesity is a chronic inflammatory state implicates increased circulating proinflammatory cytokines and adipokines as potential pathologic mediators. The Mooney Laboratory has developed a mouse model of posttraumatic knee OA in the setting of obesity-associated type 2 diabetes. Results demonstrate accelerated OA progression and increased osteophyte formation in this metabolic setting with the novel observation of hyperplastic synovial membrane with increased expression of tumor necrosis factor-alpha (TNF-alpha)(ref 6). This work was recently featured in Research Highlights, February 2012, Nature Reviews/ Rheumatology.
We are exploring the hypothesis that obesity-associated diabetes accelerates progression of osteoarthritis following traumatic injury in part through a pathway that is independent of biomechanical factors and is mediated by TNF-alpha and BMP-2. The results from these investigations are designed to definitively establish the metabolic dysfunction of obesity-associated diabetes as a risk factor for accelerated OA and define TNF-alpha and BMP-2 as a critical mediators of and therapeutic targets for trauma-associated OA in the obese, diabetic population.
During his sabbatical, Dr. Mooney also observed that mice placed on a high-fat diet while skeletally immature had 50% less trabecular bone volume in the femur and tibia than mice on a lean diet. Mice placed on the high-fat diet after skeletal maturity had no decrease in trabecular bone volume relative to controls. The lab is now investigating the hypothesis that a high-fat diet, and possibly its associated obesity and type 2 diabetes during childhood and adolescence, can lead to osteoporosis in the immature skeleton that may predispose the individual to future fractures. A recently funded project is also investigating the co-morbidities of lead exposure and diabetes on bone quality. The results of these studies will be a basis for future mechanistic studies to define the cellular and molecular pathways impacted by high fat diet on the skeleton.
Galloway, C., Ashton, J., Sparks, J., Mooney, R., and Smith, H. (2010) Metabolic Regulation of APOBEC-1 Complementation Factor Trafficking in Mouse Models of Obesity and its Positive Correlation with the Expression of ApoB Protein in Hepatocytes. BBA-Molecular Basis of Disease 1802, 976-85.
Gaudy, A.M., Clementi, A.H., Campbell, J.S., Smrcka, A.V., and Mooney, R.A. (2010) Suppressor of Cytokine Signaling-3 is a Glucagon-Inducible Inhibitor of PKA Activity and Gluconeogenic Gene Expression in Hepatocytes. J. Biol. Chem. 285, 41356-41365.
Gough, M.S., Morgan, M.A., Mack, C.M., Darling, D.C., Frasier, L.M., Doolin, K.P., Apostolakos, M.J., Stewart, J.C., Graves, B.T., Arning, E., Bottiglieri, T., Mooney, R.A., Frampton, M.W., and Pietropaoli, A.P. (2011) Low Arginine Bioavailability in Severe Sepsis Predicts Outcomes. Critical Care Medicine. 39, 1351-1358.
4) Clementi, A.C., Gaudy, A.M., Zimmers, T.A., Koniaris, L.G., and Mooney, R.A. (2011) Deletion of IL-6 improves pyruvate tolerance without altering hepatic insulin signaling in the Lepdb mouse. Metabolism. 60, 1610-1619.
Sampson, E.R., Hilton, M.J., Tian, Y., Chen, D., Schwarz, E.M., Mooney, R.A., Bukata, S.V., O’Keefe, R.J., Awad, H., Puzas, J.E., Rosier, R.N., and Zuscik, M.J. (2011) Teriparatide as a Chondro-Regenerative Therapy for Injury-Induced Knee Osteoarthritis. Science Translational Medicine. 21 September 2011 3:101ra93. DOI:10.1126/scitranslmed.3002214
Mooney, R.A., Sampson, E.R., Lerea, J., Rosier, R.N., and Zuscik, M.J. (2011) High Fat Diet Accelerates Progression of Osteoarthritis Following Meniscal/Ligamentous Injury. Arthritis Research and Therapy. 13, R198.
Barry, C.T., Mills, B., Hah, Z., Mooney, R.A., Ryan, C.K., Rubens, D.J., And Parker, K.J. (2012) Shear wave dispersion measures liver steatosis. Ultrasound in medicine and biology. 38, 175-182.