George G. Weiss Research Professor
Institute of Molecular Medicine & Genetics
Office: R&E Building, CB1116
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MEMBERS OF THE LABORATORY:
Ling Ruan, PhD., Senior Research Associate
Bharati Mendhe, Research Assistant
Khairat El-Baradie, Postdoctorial Fellow
Helen Kaiser, Graduate Student
Emily Parker, Graduate Student
Andrew Khayrullin, Student 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
2018 Outstanding Basic Science Research Award, Medical College of Georgia
2018 Distinguished Research Award, College of Graduate Studies
2015 Exemplary Teaching Award, School of Medicine
2010 Exemplary Teaching Award, School of Medicine
2009 Exemplary Teaching Award, School of Medicine
2009 Innovation in Teaching Award, School of Medicine
2005 Outstanding Young Faculty Award, Basic Sciences, School of Medicine
The primary objective of our research program is to improve human health by discovering new therapeutic approaches for preventing muscle and bone loss with aging and enhancing muscle and bone repair after injury. We are particularly interested in defining the cellular and molecular mechanisms of crosstalk among bone and soft tissues such as muscle and fat 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, and blocking myostatin can improve bone repair after injury (Fig. 1). Absence of myostatin increases bone deposition after injury, whereas myostatin treatment will directly inhibit bone repair after injury (Fig. 2). 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. 3). 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. More recently we are studying extracellular vesicles (exosomes and microvesicles) secreted by muscle and bone cells with aging to determine the role of these vesicles and their microRNA cargo in muscle and bone degeneration.
Figure 1. Left panel: (a) Faxitron radiographs of the humerus in wild type (top row) and myostatin-deficient mice (bottom row) showing the expanded deltoid crest (asterisk) and transverse dimension of the diaphysis (arrows) in the mice lacking myostatin. (b) Radiographs of the femur in normal (top row) and myostatin-deficient mice (bottom row) showing the expanded third trochanter (asterisk) and transverse dimension of the diaphysis (arrows) in mice lacking myostatin. J Exp Zool A Ecol Genet Physiol.
2010 Jul 1;313(6):339-51. Right panel: MicroCT reconstructions show a myostatin inhibitor (PROP) enhances bone repair after injury. J Trauma. 2010 Sep;69(3):579-83.
Figure 2. Left panel: microCT reconstruction of fracture callus in normal mouse (orange) and mouse lacking myostatin (yellow) showing increased bone deposition in the absence of myostatin. Bone 2009 Jan;44(1):17-23. Right Panel: MicroCT images showing impaired fracture healing with increasing local administration of exogenous myostatin (GDF-8). J Histochem Cytochem. 2012 Jan;60(1):22-30.
Figure 3. 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. J Bone Miner Res. 2005 Jun;20(6):994-1001.
Much of our research utilizes animal models such as aged mice and/or mice with targeted mutations. We also use interventional approaches such as caloric restriction, exercise, and high fat diets to alter certain metabolic parameters in laboratory rodents. 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 micro-computed tomography (microCT). Our group recently acquired an Aurora muscle testing system for in vivo and ex vivo assessment of muscle contractile strength in mice and rats. Our lab uses histochemical and immunohistochemical methods to study the processes of bone formation, resorption, and regeneration at the cellular level. We monitor the expression of osteogenic, chondrogenic, and myogenic factors in musculoskeletal tissues and bone-marrow derived stem cells using molecular approaches. Our work with extracellular vesicles involves isolation techniques such as size-exclusion chromatography and tangential flow filtration, exosome production using a hollow-fiber bioreactor system, and exosome imaging using membrane and mRNA labeling and in vivo tracking with Ami X spectral imaging in the Georgia Cancer Center Small Animal Imaging Center (Figure 4).
Figure 4. Figure 4. Left panel: Extracellular vesicles labeled with exo-red. Right panel: Ami
X imaging of DiR-labeled extracellular vesicles 24 hrs following tail vein injection.
Arrow indicates vesicles homing to bone.
2018 Bettis T, Kim BJ, Hamrick MW. Impact of muscle atrophy on bone metabolism and bone strength: implications for muscle-bone crosstalk with aging and disuse. Osteoporosis International 29:1713-1720.
2017 Murphy C, Withrow J, Hunter M, Liu Y, Tang YL, Fulzele S, Hamrick MW. Emerging role of extracellular vesicles in musculoskeletal diseases. Molecular Aspects of Medicine doi: 10.1016/j.mam.2017.09.006.
2017 Davis C, Dukes A, Drewry M, Helwa I, Johnson MH, Isales CM, Hill WD, Liu Y, Shi X, Fulzele S, Hamrick MW. MicroRNA-183-5p increases with age in bone-derived extracellular vesicles, suppresses bone marrow stromal (stem) cell proliferation, and induces stem cell senescence. Tissue Engineering 23:1231-1240.
2016 Hamrick MW, McGee-Lawrence ME, Frechette D. Fatty infiltration of skeletal muscle: mechanisms and comparisons with bone marrow adiposity. Frontiers in Endocrinology 7:69.
2016 Khayrullin A, Mistry D, Dukes A, Pan YA, Hamrick MW. Chronic alcohol exposure induces muscle atrophy (myopathy) in zebrafish and alters the expression of microRNAs targeting the Notch pathway in skeletal muscle. Biochemical Biophysical Research Communications 479(3):590-595.
Recent Grant Support:
2018-2021 Department of the Army (USAMRAA-CDMRP) “Exosome Therapy for Stabilization of Extremity Injury” (P.I., 25% FTE; Total costs $1,277,516).
2017-2022 National Institute on Aging (P01) “Age-Induced Impairment of Nutrient Signaling Results in Bone Loss” (P.I. Project 2 “Role of bone-derived exosomes in musculoskeletal aging”, 25% FTE; P.I. Core B, “Bone Biology Core” 5% FTE; Co-I, Core A, “Administrative Core” 10% FTE; Total costs $11,290,000.
2017-2020 National Science Foundation “Mechanosensation in Bone through Osteocyte Plasma Membrane Disruptions” (Co-I, 1%FTE; P.I. Meghan McGee-Lawrence; Total costs $449,738).
2016-2021 National Institute of Arthritis, Musculoskeletal, and Skin Diseases (R01) “Innovative Approaches to Treat Duchenne Muscular Dystrophy Using iPSC-Derived Muscle Progenitors” (Co-I, 5% FTE; P.I. Yao Liang Tang; Total costs $2,100,000).
2013-2018 National Institute on Aging (R01) “Inflammation and Bone Loss with Aging" (Co-I, 5% FTE; P.I. Xingming Shi, Total costs $1,100,000).