title: Aromatic amino acid activation of signaling pathways in bone marrow mesenchymal stem cells depends on oxygen tension.
abstract: The physiologic oxygen pressures inside the bone marrow environment are much lower than what is present in the peripheral circulation, ranging from 1-7%, compared to values as high as 10-13% in the arteries, lungs and liver. Thus, experiments done with bone marrow mesenchymal stem cells (BMMSCs) using standard culture conditions may not accurately reflect the true hypoxic bone marrow microenvironment. However, since aging is associated with an increased generation of reactive oxygen species, experiments done under 21%O2 conditions may actually more closely resemble that of the aging bone marrow environment. Aromatic amino acids are known to be natural anti-oxidants. We have previously reported that aromatic amino acids are potent agonists for stimulating increases in intracellular calcium and phospho-c-Raf and in promoting BMMSC differentiation down the osteogenic pathway. Our previous experiments were performed under normoxic conditions. Thus, we next decided to compare a normoxic (21% O2) vs. a hypoxic environment (3% O2) alone or after treatment with aromatic amino acids. Reverse-phase protein arrays showed that 3% O2 itself up-regulated proliferative pathways. Aromatic amino acids had no additional effect on signaling pathways under these conditions. However, under 21%O2 conditions, aromatic amino acids could now significantly increase these proliferative pathways over this "normoxic" baseline. Pharmacologic studies are consistent with the aromatic amino acids activating the extracellular calcium-sensing receptor. 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.
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Mona
authors.initials: M
authors.lastname: El Refaey
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhong
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Hill
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Department of Pathology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Xing-Ming
authors.initials: XM
authors.lastname: Shi
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Hamrick
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Lakiea
authors.initials: L
authors.lastname: Bailey
authors.affiliation: Department of Biostatistics, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Maribeth
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Jianrui
authors.initials: J
authors.lastname: Xu
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America; Department of Physiology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Charlie Norwood VA Medical Center, Augusta, Georgia, United States of America.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Bollag
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Norman
authors.initials: N
authors.lastname: Chutkan
authors.affiliation: Institute for Regenerative and Reparative Medicine, Georgia Regents University, Augusta, Georgia, United States of America; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Department of Orthopaedic Surgery, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America; Department of Cellular Biology and Anatomy, Medical College of Georgia, Georgia Regents University, Augusta, Georgia, United States of America.
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Isales
mesh_terms: D024322:Amino Acids, Aromatic / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D024322:Amino Acids, Aromatic; D010100:Oxygen
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