Background and Objective: The importance of β-adrenergic signals in bone formation and resorption has been well investigated. However, little is known about the role of β -adrenergic signals in osteoblastic differentiation of mesenchymal stem cells (MSCs), which is critically important in bone physiology and pharmacology. In this study, RUNX2 and Osteocalcin gene expression were quantified in MSCs differentiated by osteoblastic differentiation medium (ODM) and Isoproterenol (ISO). Materials and Methods: In this experimental study, human mesenchymal stem cells were treated by osteoblastic differentiation medium and ISO. RNA extraction was carried out from both osteoblastic differentiation medium at 4 and 21 days of differentiation and from undifferentiated MSCs. RUNX2 and osteocalcin gene expression were quantified by quantitative Real Time-PCR. Results: Isoproterenol decreased the expression of RUNX2 and osteocalcin genes at 4 and 21 days of osteoblastic differentiation. Statistically significant difference was found at 21 days of differentiation (P<0.05). Conclusion: Isoproterenol negatively affects MSC osteogenesis. These findings suggest that human mesenchymal stem cell is also a target for β-adrenergic and may provide valuable treatment option in bone diseases. References 1- Serre CM, Farlay D, Delmas PD, Chenu C. Evidence for a dense and intimate innervation of the bone tissue, including glutamate-containing fibers. Bone. 1999 25: 623-9. 2- Togari A, Mogi M, Arai M, Yamamoto S, Koshihara Y. Expression of mRNA for axon guidance molecules,such as semaphorin-III,netrins and neurotrophins,in human osteoblasts and osteoclasts. Brain Res. 2000 29 878: 204-9. 3- Cuscito C, Colaianni G, Tamma R, et al. Adrenergic stimulation decreases osteoblast oxytocin synthesis. Ann N Y Acad Sci. 2011 1237: 53-7. 4- Bonnet N, Pierroz D, Ferrari L. Adrenergic control of bone remodeling and its implications for the treatment of osteoporosis. J Musculoskelet Neuronal Interact. 2008 8: 94-104 5- Takeda S, Elefteriou F, Levasseur R, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell. 2002 111: 305-317. 6- Kondo H, Takeuchi S, Togari A. Beta-adrenergic signaling stimulates osteoclastogenesis via reactive oxygen species. Am J Physiol Endocrinol Metab. 2013 304: E507-15. 7- Qin W, Bauman WA, Cardozo CP. Evolving concepts in neurogenic osteoporosis. Curr Osteoporos Rep. 2010 8: 212-8. 8- Rejnmark L, Vestergaard P, Mosekilde L. Treatment with beta-blockers, ACE inhibitors,and calciumchannel blockers is associated with a reduced fracture risk: a nationwide case-control study. J Hypertens. 2006 24: 581-9. 9- Yan L, Vatner DE, O’Connor JP, et al. Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell. 2007 130: 247-58. 10- Patricia Ducy, Thorsten Schinke, Gerard Karsenty. The osteoblast: A sophisticated fibroblast under central surveillance. Science. 2000 289: 1501-4. 11- Stein G, Lian J, Stein J, Wijnen A, Montecino M. Transcriptional control of osteoblast growth and differentiation. Physiol Rev. 1996 76: 593-629. 12- Celeste A, Rosen V, Buecker J, Kriz R, Wang E, Wozney A. Isolation of the human gene for bone gla protein utilizing mouse and rat cDNA clones . J M EMBO J .1986 5: 1885-90. 13- Lee TC, Lee TH, Huang YH, Chang NK, Lin YJ. Comparison of surface markers between human and rabbit mesenchymal stem cells. PLoS ONE. 2014 9: e111390 14- Aitken SJ, Landao-Bassonga E, Ralston SH, Idris AI. Beta 2-adrenoreceptor ligands regulate osteoclast differentiation in vitro by direct and indirect mechanisms. Arch of Biochem and Biophysics. 2009 482: 96-103. 15- Farshdousti Hagh M, Noruzinia M, Mortazavi Y, et al. Comparison of quantitative expression of runx2 in mesenchymal stem cells (mscs) differentiated by osteoblastic differentiation medium and zoledronic acid. J Rafsanjan Univ Med Scie. 2012 11: 377-90. 16- Haifang Li, Chichun Fong, Yao Chen, Guoping Cai, Mengsu Yang. Beta 2 and Beta 3 but not Beta 1 adrenergic receptors are involved in osteogenesis of mouse mesenchymal stem cells via cAMP/PKA signaling. Arch of Biochem and Biophysics. 2010 496: 77-83. 17- Ma Y, Krueger JJ, Redmon SN, et al. Extracellular norepinephrine clearance by the norepinephrine transporter is required for skeletal homeostasis. J Biol Chem. 2013 18 288: 30105-13. 18- Hirai T, Tanaka K, Togari A. β-adrenergic receptor signaling regulates Ptgs2 by driving circadian gene expression in osteoblasts. J Cell Sci. 2014 1127: 3711-9. 19- Dominique D, Bonnet N, Bianchi N, et al. Deletion of B-adrenergic receptor 1, 2, or both leads to different bone phenotypes and response to mechanical stimulation. J Bone Miner Res. 2012 27: 1252-62. 20- Pierroz DD, Bouxsein ML, Muzzin P, Rizzoli R, Ferrari SL. Bone loss following ovariectomy is maintained in absence of adrenergic receptor beta1 and beta2 signaling. J Bone Miner Res. 2005 20: S277. 21- Yirmiya R, Goshen I, Bajayo A, et al. Depression induces bone loss through stimulation of the sympathetic nervous system. PNAS. 2006 103: 16876-16881. 22- Bonnet N, Benhamou CL, Brunet-Imbault B, et al. Severe bone alterations under beta 2 agonist treatment: bone mass, microarchitecture and strength analyses in female rats. Bone. 2005 37: 622-33. 23- Kitaura T, Tsunekawa N, Kraemer WJ. Inhibited longitudinal growth of bones in young male rats by clenbuterol. Med Sci Sports Exerc. 2002 34: 267-73. 24- Hamrick MW, Della-Fera MA, Choi YH, Pennington C, Hartzell D, Baile CA. Leptin treatment induces loss of bone marrow adipocytes and increases bone formation in leptin-deficient ob/ob mice. J Bone Miner Res. 2005 20: 994-1001. 25- Hamrick MW, Pennington C, Newton D, Xie D, Isales C. Leptin deficiency produces contrasting phenotypes in bones of the limb and spine. Bone . 2004 34: 376-83. 26- De Vries F, Pouwels S, Bracke M, et al. Use of beta-2 agonists and risk of hip/femur fracture: a population based case-control study. Pharmaco epidemiol Drug Saf. 2007 16: 612-29. 27- Schwartzman RJ. New treatments for reflex sympathetic dystrophy. N Engl J Med. 2000 343: 1811-2. 28- Collomp K, Le Panse B, Portier H, et al. Effects of acute salbutamol intake during a wingate test. Int J Sports Med. 2005 26: 513-7. 29- Veldhuis-Vlug AG, El Mahdiui M, Endert E, et al. Bone resorption is increased in pheochromocytoma patients and normalizes following adrenalectomy. J Clin Endocrinol Metab. 2012 97: E2093-E2097. 30- Shui C, Spelsberg TC, Riggs BL, Khosla S. Changes in runx2/Cbfa1 expression and activity during osteoblastic differentiation of human bone marrow stromal cells. J Bone Miner Res. 2003 18: 213-221. 31- Liu F, Akiyama Y, Tai S, Maruyama K, Muramatsu K, Yamaguchi K. Changes in the expression of CD106, osteogenic genes and transcription factors involved in the osteogenic differentiation of human bone marrow mesenchymal stem cells. J Bone Muner Metab. 2008 26: 312-20. 32- Brann DW, Hendry LB, Mahesh VB. Emerging diversities in the mechanism of action of steroid hormones. J Steroid Biochem Mol Biol. 1995 52: 113-33 33- Byers BAPavlath GK, Murphy TJ, Karsenty G, Garcia AJ. Cell type dependent up- regulation of in vitro mineralization after overexpression of the osteoblast specific transcription factor RUNX2.cbfa1. J Bone Miner Res. 2002 17: 1931-44. 34- Aubin JE. Bone stem cells. Journal of Cellular Biochemistry. 1998 73-82. 35- Kulterer B, Friedl G, Jandrositz A, et al. Gene expression profiling of human mesenchymal stem cells derived from bone marrow during expansion and osteoblast differentiation. BMC Genomics. 2007 8:70.
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