Age-Induced Impairment of Nutrient Signaling Results in Bone Loss

Summary

Principal Investigator: CARLOS MIGUEL ISALES
Abstract: DESCRIPTION (provided by applicant): One out of every six adults over the age of sixty-five consumes less than 1,000 calories/day, and in the case of older, institutionalized populations the prevalence of malnutrition increases to between twenty-three to sixty percent. It Is precisely this population that is at greatest risk for bone fractures. We hypothesize that a decline in musculoskeletal function with age is due in large part to a decline in nutrient-activated anabolic signals. This Program Project application is focused on defining the role of nutrients in age-dependent bone loss. The proposal consists of three Projects and three Core facilities. The three research projects will define the molecular mechanisms involved in nutrient modulation of bone marrow stromal cell (BMSC) differentiation and proliferation, and will determine how these mechanisms are altered with aging. The three Core facilities will add value to the program as a whole by providing essential support to the Projects while at the same time promoting aging and bone research at the Medical College of Georgia. The overall specific aims of the proposal are: (1) To determine how aging alters the response of bone-derived progenitor cells to amino acids;(2) To determine how aging alters the response of bone-and muscle-derived stem cells to nutrition-related hormones (e.g., IGF-1 and leptin);and (3) To determine how aging and nutrient-related stimuli alter the transcriptional regulation of BMSC differentiation mediated by stromal derived factor-1. Major strengths of this application include: (1) a multidisciplinary team of investigators with diverse backgrounds in molecular biology, physiology, endocrinology, and bone biology, who will bring new perspectives to solve a common problem;(2) a strong clinical-translational focus, with both M.D. clinician scientists and Ph.D. research scientists playing key roles;(3) a mixture of investigators of diverse background and training who have been working together for five years;(4) outstanding institutional support from both clinical and research departments, as well as from the MCG administration;and (5) the coordinated use of a common model of aging mice (C57BL/6) across highly integrated project components. This tight integration among the different projects makes this proposal truly synergistic and unique. Ultimately, we expect the Program Project to identify new therapeutic strategies and develop specific countermeasures for age-associated declines in musculoskeletal function.
Funding Period: 2011-05-01 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Glucocorticoid-induced leucine zipper (GILZ) antagonizes TNF-α inhibition of mesenchymal stem cell osteogenic differentiation
    Linlin He
    Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, Georgia, United States of America
    PLoS ONE 7:e31717. 2012
  2. pmc GRowing an epidermal tumor
    Wendy B Bollag
    1 Charlie Norwood VA Medical Center, One Freedom Way, Augusta, Georgia, USA 2 Department of Physiology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 3 Department of Medicine Dermatology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 4 Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 5 Department of Orthopaedic Surgery, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 6 Institute of Regenerative and Reparative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA
    J Invest Dermatol 133:2659-62. 2013
  3. pmc CXCR4 in epidermal keratinocytes: crosstalk within the skin
    Wendy B Bollag
    1 Charlie Norwood VA Medical Center, One Freedom Way, Augusta, Georgia, USA 2 Department of Physiology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 3 Department of Medicine Dermatology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 4 Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 5 Department of Orthopaedic Surgery, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 6 Institute of Regenerative and Reparative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA
    J Invest Dermatol 133:2505-8. 2013
  4. pmc Absence of functional leptin receptor isoforms in the POUND (Lepr(db/lb)) mouse is associated with muscle atrophy and altered myoblast proliferation and differentiation
    Phonepasong Arounleut
    Georgia Regents University, Augusta, Georgia, United States of America
    PLoS ONE 8:e72330. 2013
  5. pmc A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength
    Phonepasong Arounleut
    Georgia Regents University, Augusta, GA 30912, USA
    Exp Gerontol 48:898-904. 2013
  6. pmc Stromal cell-derived factor-1β mediates cell survival through enhancing autophagy in bone marrow-derived mesenchymal stem cells
    Samuel Herberg
    Charlie Norwood VA Medical Center, Augusta, Georgia, USA
    PLoS ONE 8:e58207. 2013
  7. pmc Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells
    Matthew Bowser
    Georgia Health Sciences University, Augusta, GA 30912, USA
    Exp Gerontol 48:290-7. 2013
  8. pmc Sodium-dependent vitamin C transporter SVCT2: expression and function in bone marrow stromal cells and in osteogenesis
    Sadanand Fulzele
    Department of Orthopaedic Surgery, Georgia Health Science University, Augusta, GA 30912, USA
    Stem Cell Res 10:36-47. 2013
  9. pmc Stromal cell-derived factor-1β potentiates bone morphogenetic protein-2-stimulated osteoinduction of genetically engineered bone marrow-derived mesenchymal stem cells in vitro
    Samuel Herberg
    Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
    Tissue Eng Part A 19:1-13. 2013
  10. pmc Aromatic amino acid activation of signaling pathways in bone marrow mesenchymal stem cells depends on oxygen tension
    Mona El Refaey
    Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America
    PLoS ONE 9:e91108. 2014

Detail Information

Publications10

  1. pmc Glucocorticoid-induced leucine zipper (GILZ) antagonizes TNF-α inhibition of mesenchymal stem cell osteogenic differentiation
    Linlin He
    Institute of Molecular Medicine and Genetics, Georgia Health Sciences University, Augusta, Georgia, United States of America
    PLoS ONE 7:e31717. 2012
    ..These results suggest that GILZ may have therapeutic potential as a novel anti-inflammation therapy...
  2. pmc GRowing an epidermal tumor
    Wendy B Bollag
    1 Charlie Norwood VA Medical Center, One Freedom Way, Augusta, Georgia, USA 2 Department of Physiology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 3 Department of Medicine Dermatology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 4 Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 5 Department of Orthopaedic Surgery, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 6 Institute of Regenerative and Reparative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA
    J Invest Dermatol 133:2659-62. 2013
    ..demonstrate that mice lacking GR in the epidermis exhibit increased vulnerability to chemical carcinogenesis. Evidence supporting an involvement of GR signaling in physiological and pathophysiological processes in skin is discussed. ..
  3. pmc CXCR4 in epidermal keratinocytes: crosstalk within the skin
    Wendy B Bollag
    1 Charlie Norwood VA Medical Center, One Freedom Way, Augusta, Georgia, USA 2 Department of Physiology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 3 Department of Medicine Dermatology, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 4 Department of Cellular Biology and Anatomy, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 5 Department of Orthopaedic Surgery, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA 6 Institute of Regenerative and Reparative Medicine, Medical College of Georgia at Georgia Regents University, Augusta, Georgia, USA
    J Invest Dermatol 133:2505-8. 2013
    ..Nevertheless, CXCR4 and its ligand SDF-1 have been implicated in skin wound healing, systemic lupus erythematosus, and basal cell carcinoma tumor angiogenesis. Further study is merited. ..
  4. pmc Absence of functional leptin receptor isoforms in the POUND (Lepr(db/lb)) mouse is associated with muscle atrophy and altered myoblast proliferation and differentiation
    Phonepasong Arounleut
    Georgia Regents University, Augusta, Georgia, United States of America
    PLoS ONE 8:e72330. 2013
    ..Here we utilized a novel mouse model lacking all functional leptin receptor isoforms (POUND mouse, Lepr(db/lb)) to determine the role of leptin in skeletal muscle...
  5. pmc A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength
    Phonepasong Arounleut
    Georgia Regents University, Augusta, GA 30912, USA
    Exp Gerontol 48:898-904. 2013
    ....
  6. pmc Stromal cell-derived factor-1β mediates cell survival through enhancing autophagy in bone marrow-derived mesenchymal stem cells
    Samuel Herberg
    Charlie Norwood VA Medical Center, Augusta, Georgia, USA
    PLoS ONE 8:e58207. 2013
    ..Taken together, we provide novel evidence that the SDF-1/CXCR4 axis, specifically activated by the SDF-1β isoform, plays a critical role in regulating BMSC survival under oxidative stress through increasing autophagy...
  7. pmc Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells
    Matthew Bowser
    Georgia Health Sciences University, Augusta, GA 30912, USA
    Exp Gerontol 48:290-7. 2013
    ..Myostatin appears to play a particularly important role in the impaired proliferative capacity of muscle and bone progenitor cells from aged mice...
  8. pmc Sodium-dependent vitamin C transporter SVCT2: expression and function in bone marrow stromal cells and in osteogenesis
    Sadanand Fulzele
    Department of Orthopaedic Surgery, Georgia Health Science University, Augusta, GA 30912, USA
    Stem Cell Res 10:36-47. 2013
    ..Our findings could be relevant to bone tissue engineering and bone related diseases such as osteoporosis in which oxidative stress and aging plays important role...
  9. pmc Stromal cell-derived factor-1β potentiates bone morphogenetic protein-2-stimulated osteoinduction of genetically engineered bone marrow-derived mesenchymal stem cells in vitro
    Samuel Herberg
    Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia, USA
    Tissue Eng Part A 19:1-13. 2013
    ..Taken together, these data support that SDF-1β can play an important role in BMP-2-stimulated osteogenic differentiation of BMSCs and may exert its biological activity in both an autocrine and paracrine fashion...
  10. pmc Aromatic amino acid activation of signaling pathways in bone marrow mesenchymal stem cells depends on oxygen tension
    Mona El Refaey
    Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America
    PLoS ONE 9:e91108. 2014
    ..The effects of aromatic amino acids on BMMSC function in the 21% O2 environment is consistent with a potential role for these amino acids in an aging environment as functional anti oxidants. ..