The mechanisms linking nutrient intake to altered bone formation are poorly understood. Although most research has focused on the calcium-PTH-Vitamin D axis, our laboratory has a longstanding interest defining the mechanisms utilized by enteric hormones to modulate bone turnover. During the conduct of our research, we observed that nutrients not only affect bone turnover by indirect mechanisms (e.g. by modulating release ofbone acfive hormones such as IGF-1, GLP-2, GIP or by modulating the activity of the innervation in bone) but also exert direct effects on bone marrow stem cells (BMSCs). Although it has been known for some time that nutrients can modulate osteoblastic and osteoclastic activity, direct nutrient effects on BMSCs have not been demonstrated. Preliminary data presented in this proposal support a role for direct, receptor-mediated nutrient effects on BMSC proliferation, specifically: (1) BMSC do not grow or differentiate in growth mediums with low amino acid concentrations;(2) BMSC express extracellular L-type amino acid sensors [the calcium sensing receptor (CasR) and the taste receptor (Tl R1/T1R3)];(3) aromafic amino acids increase intracellular calcium;(4) aromatic amino acids and glutamate activate the MAPK signaling pathway;(5) expression and funcfion of speciflc extracellular amino acid sensors vary in an age-dependent manner;and (6) aging C57BI6 mice fed a low protein diet lose bone and this loss is prevented by dietary supplementafion of aromafic amion acids. We hypothesize that direct nutrient effects on BMSCs play an important role in preserving bone mass. This proposal focuses on defining the contribution of direct nutrient effects on BMSCs to bone formation using interrelated in vivo and in vitro studies. Therefore, the specific aims of the proposal are: (1) To define the molecular mechanisms involved in direct amino acid induced BMSC/Osteoprogenitor cell activation in vitro;and (2) To define the effect of dietary nutrients (protein) on bone mass in vivo. Findings from the proposed experiments should help reveal and define the mechanistic links between nutrient ingesfion and bone formation and result in new targets for therapeutics, particularly those targeted to age-dependent alterations in bone formafion. This project also will explore the interactions between amino acid effects on BMSC with the fat and muscle derived hormones, lepfin and IGF-1 and the cytokine SDF-1 and thus provides a unique opportunity to examine nutrient effects on bone in a comprehensive manner.

Public Health Relevance

Nutrition has long been known to be important for the maintenance of bone health although the pathophysiological mechanisms is not know. The proposed studies will for the first time shed some light on how to maximize nutrient effects on bone mass.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01AG036675-04
Application #
8663787
Study Section
Special Emphasis Panel (ZAG1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Georgia Regents University
Department
Type
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
El Refaey, Mona; Zhong, Qing; Hill, William D et al. (2014) Aromatic amino acid activation of signaling pathways in bone marrow mesenchymal stem cells depends on oxygen tension. PLoS One 9:e91108
Herberg, Samuel; Kondrikova, Galina; Periyasamy-Thandavan, Sudharsan et al. (2014) Inkjet-based biopatterning of SDF-1? augments BMP-2-induced repair of critical size calvarial bone defects in mice. Bone 67:95-103
Pan, Guodong; Cao, Jay; Yang, Nianlan et al. (2014) Role of glucocorticoid-induced leucine zipper (GILZ) in bone acquisition. J Biol Chem 289:19373-82
Refaey, Mona El; Zhong, Qing; Ding, Ke-Hong et al. (2014) Impact of dietary aromatic amino acids on osteoclastic activity. Calcif Tissue Int 95:174-82
Herberg, Samuel; Shi, Xingming; Johnson, Maribeth H et al. (2013) Stromal cell-derived factor-1? mediates cell survival through enhancing autophagy in bone marrow-derived mesenchymal stem cells. PLoS One 8:e58207
Arounleut, Phonepasong; Bialek, Peter; Liang, Li-Fang et al. (2013) A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength. Exp Gerontol 48:898-904
Bollag, Wendy B; Isales, Carlos M (2013) GRowing an epidermal tumor. J Invest Dermatol 133:2659-62
Fulzele, Sadanand; Chothe, Paresh; Sangani, Rajnikumar et al. (2013) Sodium-dependent vitamin C transporter SVCT2: expression and function in bone marrow stromal cells and in osteogenesis. Stem Cell Res 10:36-47
Herberg, Samuel; Fulzele, Sadanand; Yang, Nianlan et al. (2013) Stromal cell-derived factor-1* potentiates bone morphogenetic protein-2-stimulated osteoinduction of genetically engineered bone marrow-derived mesenchymal stem cells in vitro. Tissue Eng Part A 19:1-13
Bowser, Matthew; Herberg, Samuel; Arounleut, Phonepasong et al. (2013) Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells. Exp Gerontol 48:290-7

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