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.
Farnsworth CW, Schott EM, Jensen SE, Zukoski J, Benvie AM, Refaai MA, Kates SL, Schwarz EM, Zuscik MJ, Gill SR, Mooney RA. "Adaptive Upregulation of Clumping Factor A (ClfA) by Staphylococcus aureus in the Obese, Type 2 Diabetic Host Mediates Increased Virulence." Infection and immunity.. 2017 Jun 0; 85(6)Epub 2017 May 23.
Dar QA, Schott EM, Catheline SE, Maynard RD, Liu Z, Kamal F, Farnsworth CW, Ketz JP, Mooney RA, Hilton MJ, Jonason JH, Prawitt J, Zuscik MJ. "Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis." PloS one. 2017 12(4):e0174705. Epub 2017 Apr 06.
Wexler O, Gough MS, Morgan MA, Mack CM, Apostolakos MJ, Doolin KP, Mooney RA, Arning E, Bottiglieri T, Pietropaoli AP. "Methionine Metabolites in Patients With Sepsis." Journal of intensive care medicine.. 2016 Sep 2; Epub 2016 Sep 02.
Hamada D, Maynard R, Schott E, Drinkwater CJ, Ketz JP, Kates SL, Jonason JH, Hilton MJ, Zuscik MJ, Mooney RA. "Suppressive Effects of Insulin on Tumor Necrosis Factor-Dependent Early Osteoarthritic Changes Associated With Obesity and Type 2 Diabetes Mellitus." Arthritis & rheumatology.. 2016 Jun 0; 68(6):1392-402.
Beier EE, Inzana JA, Sheu TJ, Shu L, Puzas JE, Mooney RA. "Effects of Combined Exposure to Lead and High-Fat Diet on Bone Quality in Juvenile Male Mice." Environmental health perspectives.. 2015 Oct 0; 123(10):935-43. Epub 2015 Apr 10
Farnsworth CW, Shehatou CT, Maynard R, Nishitani K, Kates SL, Zuscik MJ, Schwarz EM, Daiss JL, Mooney RA. "A humoral immune defect distinguishes the response to Staphylococcus aureus infections in mice with obesity and type 2 diabetes from that in mice with type 1 diabetes." Infection and immunity.. 2015 Jun 0; 83(6):2264-74. Epub 2015 Mar 23.
Barry CT, Hazard C, Hah Z, Cheng G, Partin A, Mooney RA, Chuang KH, Cao W, Rubens DJ, Parker KJ. "Shear wave dispersion in lean versus steatotic rat livers." Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.. 2015 Jun 0; 34(6):1123-9.