MEMBERS OF THE LABORATORY:
Colleen Carey Davis, PhD., Postdoctoral Fellow
Amy Dukes, Research Assistant
1991 B.A. Anthropology University of Colorado, Boulder CO
1995 PhD. Biology Northwestern University, Evanston IL
Post Doctoral Training
1995-1997 Duke University
Honors and Awards
2009 Innovation in Teaching Award, Georgia Health Sciences University Medical College of Georgia
2009 Exemplary Teaching Award, Georgia Health Sciences University Medical College of Georgia
2005 Outstanding Young Faculty Award, Basic Sciences, Georgia Health Sciences University Medical College of Georgia
The primary objective of our research program is to understand how soft tissues (muscle and fat) influence bone metabolism and bone strength. We are particularly interested in defining the molecular mechanisms by which muscle and fat regulate bone formation and bone loss, so that these pathways can be targeted therapeutically in order to prevent and treat bone fractures. In the area of muscle-bone interactions, it is recognized that myostatin (GDF8) is a powerful inhibitor of muscle growth and regeneration, and myostatin deficiency significantly increases muscle mass. We have shown that myostatin deficiency increases bone strength and biomineralization throughout the skeleton (Fig. 1) via direct effects on bone-marrow derived pharmacological agents to increase muscle mass, bone strength, and bone regeneration. In the area of fat-bone interactions, we have demonstrated that the fat-derived hormone leptin is a key regulator of bone mass, and leptin treatment significantly improves bone formation and bone strength in leptin-deficient animals (Fig. 2). Although weight loss reduces risk factors for and improves symptoms of obesity-related conditions, it is associated with bone loss. It is thought that the bone loss associated with decreased body weight is mediated in part by declining levels of leptin. Indeed, we have demonstrated that caloric restriction is associated with significant bone loss, leptin deficiency, and muscle atrophy, and leptin treatment can attenuate bone loss in fasting animals. The long-term goal of our research on fat-bone interactions is to explore leptin treatment as a novel therapeutic approach for improving muscle and bone health with aging and weight loss.
Fig. 1 . Left image: CT of fracture callus in normal mouse (orange) and mouse lacking myostatin (yellow). Right image: pQCT cross-sections through the distal femur of a normal mouse (top) and mouse lacking myostatin (bottom).
Experimental Approaches :
Much of our research utilizes animal models such as mice with targeted mutations in myostatin, leptin, and theirreceptors. We also use interventional approaches such as caloric restriction and high fat diets to alter certain metabolic parameters in laboratory rodents. More recently, we have established protocols for working with tissue samples discarded during orthopaedic procedures in order to better study myostatin- and leptin-signaling interactions in human musculoskeletal tissues. Standard procedures used by the lab include measurements of bone mass and density using micro-densitometry techniques such as dual energy x-ray absorptiometry (DEXA) and peripheral quantitative computed tomography (pQCT). Our lab also collaborates with the Savannah River National Laboratory, a national center of excellence for the development and application of unique and innovative technologies, on microCT imaging modalities for imaging bone tissue. We work with colleagues in the Departments of Orthopaedics and Oral Biology on testing the material properties of bones (e.g., bone strength, stiffness, and brittleness). Serum markers of bone formation are studied using radioimmunoassay and ELISA techniques, and many of these assays are performed by our collaborators in the Institute of Molecular Medicine and Genetics. Our lab uses histochemical and immunohistochemical methods to study the processes of bone formation, resorption, and regeneration at the cellular level. Finally, we monitor the expression of osteogenic, chondrogenic, and myogenic factors in musculoskeletal tissues and bone-marrow derived stem cells using molecular approaches.
Fig. 2 . Left column: fluorochrome labeled bone forming surfaces (white arrows) in lean mice receiving saline (top row), ob/ob mice receiving saline (middle row), and ob/ob mice receiving leptin (bottom row). The middle column is a merged image of the brightfield and fluorescent images. Note the increased bone formation in the ob/ob mouse receiving leptin. The column on the right shows brightfield micrographs of bone marrow sections (H&E) demonstrating the numerous, large adipocytes (asterisks) in bone marrow from the ob/ob mouse receiving saline (middle row) compared to the lean mouse (top row) and the ob/ob mouse receiving leptin (bottom row). All sections are from the proximal tibia.
Published Abstracts from Recent Professional Presentations:
Hamrick MW, Arounleut P, Kellum E, Cain M, Elkasrawy M, Stegall F, Immel D, Liang
Effects of recombinant myostatin propeptide on fracture repair in a fibula osteotomy model.
Transactions of the Orthopaedic Research Society 0936.
Kellum E, Fulzele S, Wenger K, Hamrick MW. Absence of myostatin (GDF-8) increases fracture callus size and expression of the chondrogenic factor Sox-5 during bone repair. 2008. Bone 43: S33.
Patterson S, Hill W, McNeil P, Isales C, Hamrick MW. 2008. Myostatin (GDF-8) regulates the
secretion of growth factors localized to the muscle-bone interface. Journal of Bone & Mineral
Research 23S: S278.
Hamrick MW, Shi X, Ding K, Isales CM. 2008. Leptin receptor expression in skeletal muscle
declines with aging: a mechanism linking altered leptin signaling with frailty and sarcopenia.
Calcified Tissue International 82: S229.
Hamrick MW, Ponnala S, Zumwalt A, Schmitt D. 2008. Myostatin deficiency increases cortical
bone formation independent of changes in ground reaction forces during normal locomotion.
Calcified Tissue International 82: S47.
Davis C, Dukes A, Fulzele S, Shi X, Hill W, Isales CM, Liu Y, Hamrick MW. 2015. Aging and caloric restriction significantly alter the microRNA cargo of exosomes and microvesicles in the bone marrow microenvironment. J Bone Miner Res FR0397.
Davis C, Balaji C, Periyasamy-Thandavan S, Fulzele S, Ruark R, Homlar K, Corpe R, Isales CM, Liu Y, Hill WD, Hamrick MW. 2015. Oxygen tension regulates the miRNA profile of extracellular vesicles secreted by human bone marrow-derived stem cells. J Extracellular Vesicles vol. 4: 27783.
Herberg S, Periyasamy-Thandavan S, Arounleut P, Upadhyay S, Dukes A, Davis C, Kondrikova G, Johnson M, Isales CM, Hill WD, Hamrick MW. 2014. Mediation of SDF-1/CXCR4 signaling in aged skeletal muscle by the adipokine leptin. J Bone Miner Res FR0197.
El Refaey M, Davis C, Arounleut P, Upadhyay S, Dukes A, Johnson M, Hill WD, Isales CM, Hamrick MW. 2014. The amino acid tryptophan increases skeletal muscle IGF-1 and follistatin in mice, and induces the expression of exercise-related factors. J Bone Miner Res MO0194.
Hamrick MW , Arounleut P, He H-Z, Herberg S, Shiver A, Qi R-Q, Zhou L, Isales
CM, Mi Q-S. (2010) The adipokine leptin increases skeletal muscle mass and
significantly alters skeletal muscle miRNA expression profile in aged mice.
Biochemical & Biophysical Research Communications 400: 379-83.
Hamrick MW, Arounleut P, Kellum E, Cain M, Immel D, Liang L. (2010) Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injury. Journal of Trauma 69: 579-83.
Hamrick MW , Della-Fera MA, Baile CA, Pollock NK, Lewis RD. 2009. Body fat as a regulator of bone mass: experimental evidence from animal models. Clinical Reviews in Bone & Mineral Metabolism 7: 224-229.
Kellum E, Starr H, Immel D, Arounleut P, Fulzele S, Wenger K, Hamrick MW. 2009. Myostatin (GDF-8) deficiency increases fracture callus size, Sox-5 expression, and callus bone volume . Bone 44: 17-23.
Hamrick MW , Ding K-H, Ponnala S, Ferrari SL, Isales CM. 2008. Caloric restriction decreases cortical bone mass but spares trabecular bone in the mouse skeleton: implications for the regulation of bone mass by body weight. Journal of Bone & Mineral Research 23: 870-879.
Hamrick MW, Ferrari SL. 2008. Leptin and the sympathetic connection of fat to bone. Osteoporosis
International 19: 905-912
Ravosa MJ, Lopez E, Stock S, Stack MS, Hamrick MW. 2008. Using mighty mouse to understand
masticatory plasticity: myostatin-deficient mice and musculoskeletal function. Journal of Integrative
and Comparative Biology 48: 345-359.
Hamrick MW, Dukes A, Arounleut P, Davis C, Periyasamy-Thandavan S, Mork S, Herberg S, Johnson MH, Isales CM, Hill WD, Otvos L, Belin de Chantemèle EJ. 2015. The adipokine leptin mediates muscle- and liver-derived IGF-1 in aged mice. Experimental Gerontology 70:92-96.
Dukes A, Davis C, El Refaey M, Upadhyay S, Mork S, Arounleut P, Johnson MH, Hill WD, Isales CM, Hamrick MW. 2015. The aromatic amino acid tryptophan stimulates skeletal muscle IGF1/p70s6k/mTor signaling in vivo and the expression of myogenic genes in vitro. Nutrition 31:1018-24.
Novotny S, Warren G, Hamrick MW. 2015. Aging and the muscle-bone relationship. Physiology 30: 8-16.
Co-Editor, Special Volume (2015): Bone Health & Nutrition, Molecular & Cellular Endocrinology.
Sanghavi P, Young P, Upadhyay, Hamrick MW. 2015. Exosomes for bone diseases. In Mesenchymal Stem Cell Derived Exosomes: The Potential for Translational Nanomedicine (Y. Tang & B. Dawn, eds), Ch. 10, pp. 207-221. Elsevier: New York.
Grant Support as Principal Investigator
2004-2009 National Institute of Arthritis, Musculoskeletal, and Skin Diseases (R01 AR049717-01A2) “Effects of Myostatin Deficiency on Bone Strength”.
2008-2011 Office of Naval Research (N00014-08-1-0197) “Myostatin Inhibitors to Accelerate Tissue Regeneration”.
2009-2010 Orthopaedic Trauma Association “The Effects of Suramin Treatment on Fracture Healing in a Rodent Model”
2010-2013 Department of the Army (USAMRAA-CDMRP) “Novel Therapeutic Strategy for the Prevention of Bone Fractures” (P.I., 40% FTE; Total costs $1,035,290).
2011-2016 National Institute on Aging (P01) “Age-Induced Impairment of Nutrient Signaling Results in Bone Loss” (P.I. Project 2 “The Leptin-IGF1 Axis in Musculoskeletal Aging; P.I. Core B, “Bone Biology Core” 10% FTE; Co-I, Core A, “Administrative Core”).