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The Role of Signaling Pathway on Osteoprogenitor Cell Behavior and Bone Formation

Maedeh Hashemi 1 , Vahid Shakeri 2 , Haleh Mosallaei 3 , Mona Kholdebarin 4 , Mohamad Bakhtiari 5 , Masoomeh Mohamadpour 6 , Saeed Gholami 3 and Seyed Amir Yazdanparast 7 , *
Authors Information
1 Anatomy Department, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
2 Department of Orthopedic, Arak University of Medical Sciences, Arak, Iran
3 Iran University of Medical Sciences, Tehran, Iran
4 Science and Research Branch, Islamic Azad University, Tehran, Iran
5 Anatomy Department, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
6 Neuroscience Research Center, School of Advanced Medical Sciences and Technologies, Iran University of Medical Sciences, Tehran, Iran
7 Mycology Department, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
Article information
  • Thrita: June 2018, 7 (1); e81485
  • Published Online: August 19, 2018
  • Article Type: Review Article
  • Received: June 29, 2018
  • Revised: July 9, 2018
  • Accepted: July 9, 2018
  • DOI: 10.5812/thrita.81485

To Cite: Hashemi M , Shakeri V , Mosallaei H , Kholdebarin M , Bakhtiari M , et al. The Role of Signaling Pathway on Osteoprogenitor Cell Behavior and Bone Formation, Thrita. 2018 ; 7(1):e81485. doi: 10.5812/thrita.81485.

Copyright © 2018, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
1. Context
2. Evidence Acquisition
3. Results
4. Conclusions
  • 1. Shao J, Zhang W, Yang T. Using mesenchymal stem cells as a therapy for bone regeneration and repairing. Biol Res. 2015;48:62. doi: 10.1186/s40659-015-0053-4. [PubMed: 26530042]. [PubMed Central: PMC4630918].
  • 2. Zheng AQ, Xiao J, Xie J, Lu PP, Ding X. bFGF enhances activation of osteoblast differentiation and osteogenesis on titanium surfaces via PI3K/Akt signaling pathway. Int J Clin Exp Pathol. 2016;9(4):4680-92.
  • 3. Pogozhykh O, Pogozhykh D, Neehus AL, Hoffmann A, Blasczyk R, Muller T. Molecular and cellular characteristics of human and non-human primate multipotent stromal cells from the amnion and bone marrow during long term culture. Stem Cell Res Ther. 2015;6:150. doi: 10.1186/s13287-015-0146-6. [PubMed: 26297012]. [PubMed Central: PMC4546288].
  • 4. Anam K, Davis TA. Comparative analysis of gene transcripts for cell signaling receptors in bone marrow-derived hematopoietic stem/progenitor cell and mesenchymal stromal cell populations. Stem Cell Res Ther. 2013;4(5):112. doi: 10.1186/scrt323. [PubMed: 24405801]. [PubMed Central: PMC3854681].
  • 5. Alvarez-Viejo M, Menendez-Menendez Y, Otero-Hernandez J. CD271 as a marker to identify mesenchymal stem cells from diverse sources before culture. World J Stem Cells. 2015;7(2):470-6. doi: 10.4252/wjsc.v7.i2.470. [PubMed: 25815130]. [PubMed Central: PMC4369502].
  • 6. Campbell SL, Khosravi-Far R, Rossman KL, Clark GJ, Der CJ. Increasing complexity of Ras signaling. Oncogene. 1998;17(11 Reviews):1395-413. doi: 10.1038/sj.onc.1202174. [PubMed: 9779987].
  • 7. Vojtek AB, Der CJ. Increasing complexity of the ras signaling pathway. J Biol Chem. 1998;273(32):19925-8. doi: 10.1074/jbc.273.32.19925.
  • 8. Mitin N, Rossman KL, Der CJ. Signaling interplay in Ras superfamily function. Curr Biol. 2005;15(14):R563-74. doi: 10.1016/j.cub.2005.07.010. [PubMed: 16051167].
  • 9. Ory S, Morrison DK. Signal transduction: implications for Ras-dependent ERK signaling. Curr Biol. 2004;14(7):R277-8. doi: 10.1016/j.cub.2004.03.023. [PubMed: 15062121].
  • 10. Hancock JF. Ras proteins: different signals from different locations. Nat Rev Mol Cell Biol. 2003;4(5):373-84. doi: 10.1038/nrm1105. [PubMed: 12728271].
  • 11. Schindeler A, Little DG. Ras-MAPK signaling in osteogenic differentiation: friend or foe? J Bone Miner Res. 2006;21(9):1331-8. doi: 10.1359/jbmr.060603.
  • 12. Rahman MS, Akhtar N, Jamil HM, Banik RS, Asaduzzaman SM. TGF-beta/BMP signaling and other molecular events: regulation of osteoblastogenesis and bone formation. Bone Res. 2015;3:15005. doi: 10.1038/boneres.2015.5. [PubMed: 26273537]. [PubMed Central: PMC4472151].
  • 13. Wu M, Chen G, Li YP. TGF-beta and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009. doi: 10.1038/boneres.2016.9. [PubMed: 27563484]. [PubMed Central: PMC4985055].
  • 14. Beederman M, Lamplot JD, Nan G, Wang J, Liu X, Yin L, et al. BMP signaling in mesenchymal stem cell differentiation and bone formation. J Biomed Sci Eng. 2013;6(8A):32-52. doi: 10.4236/jbise.2013.68A1004. [PubMed: 26819651]. [PubMed Central: PMC4725591].
  • 15. Botchkarev VA. Bone morphogenetic proteins and their antagonists in skin and hair follicle biology. J Invest Dermatol. 2003;120(1):36-47. doi: 10.1046/j.1523-1747.2003.12002.x. [PubMed: 12535196].
  • 16. Lechleider RJ, Ryan JL, Garrett L, Eng C, Deng C, Wynshaw-Boris A, et al. Targeted mutagenesis of Smad1 reveals an essential role in chorioallantoic fusion. Dev Biol. 2001;240(1):157-67. doi: 10.1006/dbio.2001.0469. [PubMed: 11784053].
  • 17. Zhao GQ. Consequences of knocking out BMP signaling in the mouse. Genesis. 2003;35(1):43-56. doi: 10.1002/gene.10167. [PubMed: 12481298].
  • 18. Urist MR. Bone morphogenetic protein: the molecularization of skeletal system development. J Bone Miner Res. 1997;12(3):343-6. doi: 10.1359/jbmr.1997.12.3.343. [PubMed: 9076576].
  • 19. Carreira AC, Lojudice FH, Halcsik E, Navarro RD, Sogayar MC, Granjeiro JM. Bone morphogenetic proteins: facts, challenges, and future perspectives. J Dent Res. 2014;93(4):335-45. doi: 10.1177/0022034513518561. [PubMed: 24389809].
  • 20. Feng XH, Derynck R. Specificity and versatility in tgf-beta signaling through Smads. Annu Rev Cell Dev Biol. 2005;21:659-93. doi: 10.1146/annurev.cellbio.21.022404.142018. [PubMed: 16212511].
  • 21. Balemans W, Van Hul W. Extracellular regulation of BMP signaling in vertebrates: a cocktail of modulators. Dev Biol. 2002;250(2):231-50. [PubMed: 12376100].
  • 22. Moustakas A, Heldin CH. The regulation of TGFbeta signal transduction. Development. 2009;136(22):3699-714. doi: 10.1242/dev.030338. [PubMed: 19855013].
  • 23. Schmierer B, Hill CS. TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol. 2007;8(12):970-82. doi: 10.1038/nrm2297. [PubMed: 18000526].
  • 24. Guo L, Zhao RC, Wu Y. The role of microRNAs in self-renewal and differentiation of mesenchymal stem cells. Exp Hematol. 2011;39(6):608-16. doi: 10.1016/j.exphem.2011.01.011. [PubMed: 21288479].
  • 25. Bessa PC, Casal M, Reis RL. Bone morphogenetic proteins in tissue engineering: the road from the laboratory to the clinic, part I (basic concepts). J Tissue Eng Regen Med. 2008;2(1):1-13. doi: 10.1002/term.63. [PubMed: 18293427].
  • 26. Pan A, Chang L, Nguyen A, James AW. A review of hedgehog signaling in cranial bone development. Front Physiol. 2013;4:61. doi: 10.3389/fphys.2013.00061. [PubMed: 23565096]. [PubMed Central: PMC3613593].
  • 27. Horikiri Y, Shimo T, Kurio N, Okui T, Matsumoto K, Iwamoto M, et al. Sonic hedgehog regulates osteoblast function by focal adhesion kinase signaling in the process of fracture healing. PLoS One. 2013;8(10). e76785. doi: 10.1371/journal.pone.0076785. [PubMed: 24124594]. [PubMed Central: PMC3790742].
  • 28. Reichert JC, Schmalzl J, Prager P, Gilbert F, Quent VM, Steinert AF, et al. Synergistic effect of Indian hedgehog and bone morphogenetic protein-2 gene transfer to increase the osteogenic potential of human mesenchymal stem cells. Stem Cell Res Ther. 2013;4(5):105. doi: 10.1186/scrt316. [PubMed: 24004723]. [PubMed Central: PMC3854715].
  • 29. Kim JH, Liu X, Wang J, Chen X, Zhang H, Kim SH, et al. Wnt signaling in bone formation and its therapeutic potential for bone diseases. Ther Adv Musculoskelet Dis. 2013;5(1):13-31. doi: 10.1177/1759720X12466608. [PubMed: 23514963]. [PubMed Central: PMC3582304].
  • 30. Issack PS, Helfet DL, Lane JM. Role of Wnt signaling in bone remodeling and repair. HSS J. 2008;4(1):66-70. doi: 10.1007/s11420-007-9072-1. [PubMed: 18751865]. [PubMed Central: PMC2504275].
  • 31. Terada K, Misao S, Katase N, Nishimatsu S, Nohno T. Interaction of Wnt Signaling with BMP/Smad Signaling during the Transition from Cell Proliferation to Myogenic Differentiation in Mouse Myoblast-Derived Cells. Int J Cell Biol. 2013;2013:616294. doi: 10.1155/2013/616294. [PubMed: 23864860]. [PubMed Central: PMC3705783].
  • 32. Lin GL, Hankenson KD. Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J Cell Biochem. 2011;112(12):3491-501. doi: 10.1002/jcb.23287. [PubMed: 21793042]. [PubMed Central: PMC3202082].
  • 33. Davies J, Warwick J, Totty N, Philp R, Helfrich M, Horton M. The osteoclast functional antigen, implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. J Cell Biol. 1989;109(4 Pt 1):1817-26. [PubMed: 2477382]. [PubMed Central: PMC2115816].
  • 34. Di Capite J, Ng SW, Parekh AB. Decoding of cytoplasmic Ca(2+) oscillations through the spatial signature drives gene expression. Curr Biol. 2009;19(10):853-8. doi: 10.1016/j.cub.2009.03.063. [PubMed: 19375314].
  • 35. Hwang SY, Putney JW. Calcium signaling in osteoclasts. Mol Cell Res. 2011;1813(5):979-83. doi: 10.1016/j.bbamcr.2010.11.002.
  • 36. Sun X, McLamore E, Kishore V, Fites K, Slipchenko M, Porterfield DM, et al. Mechanical stretch induced calcium efflux from bone matrix stimulates osteoblasts. Bone. 2012;50(3):581-91. doi: 10.1016/j.bone.2011.12.015. [PubMed: 22227434].
  • 37. Jung H, Best M, Akkus O. Microdamage induced calcium efflux from bone matrix activates intracellular calcium signaling in osteoblasts via L-type and T-type voltage-gated calcium channels. Bone. 2015;76:88-96. doi: 10.1016/j.bone.2015.03.014. [PubMed: 25819792].
  • 38. Kanno T, Takahashi T, Tsujisawa T, Ariyoshi W, Nishihara T. Mechanical stress-mediated Runx2 activation is dependent on Ras/ERK1/2 MAPK signaling in osteoblasts. J Cell Biochem. 2007;101(5):1266-77. doi: 10.1002/jcb.21249. [PubMed: 17265428].
  • 39. Jung H, Akkus O. Activation of intracellular calcium signaling in osteoblasts colocalizes with the formation of post-yield diffuse microdamage in bone matrix. Bonekey Rep. 2016;5:778. doi: 10.1038/bonekey.2016.5. [PubMed: 26962448]. [PubMed Central: PMC4774084].
  • 40. Gruber J, Yee Z, Tolwinski NS. Developmental drift and the role of wnt signaling in aging. Cancers (Basel). 2016;8(8). doi: 10.3390/cancers8080073. [PubMed: 27490570]. [PubMed Central: PMC4999782].
  • 41. Shi J, Chi S, Xue J, Yang J, Li F, Liu X. Emerging role and therapeutic implication of wnt signaling pathways in autoimmune diseases. J Immunol Res. 2016;2016:9392132. doi: 10.1155/2016/9392132. [PubMed: 27110577]. [PubMed Central: PMC4826689].
  • 42. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest. 2006;116(5):1202-9. doi: 10.1172/JCI28551. [PubMed: 16670761]. [PubMed Central: PMC1451219].
  • 43. Ray S, Khassawna TE, Sommer U, Thormann U, Wijekoon ND, Lips K, et al. Differences in expression of Wnt antagonist Dkk1 in healthy versus pathological bone samples. J Microsc. 2017;265(1):111-20. doi: 10.1111/jmi.12469. [PubMed: 27580425].
  • 44. Ransom RC, Hunter DJ, Hyman S, Singh G, Ransom SC, Shen EZ, et al. Axin2-expressing cells execute regeneration after skeletal injury. Sci Rep. 2016;6:36524. doi: 10.1038/srep36524. [PubMed: 27853243]. [PubMed Central: PMC5113299].
  • 45. Kimura T, Kuwata T, Ashimine S, Yamazaki M, Yamauchi C, Nagai K, et al. Targeting of bone-derived insulin-like growth factor-II by a human neutralizing antibody suppresses the growth of prostate cancer cells in a human bone environment. Clin Cancer Res. 2010;16(1):121-9. doi: 10.1158/1078-0432.CCR-09-0982. [PubMed: 20028742]. [PubMed Central: PMC2802676].
  • 46. Arvidson K, Abdallah BM, Applegate LA, Baldini N, Cenni E, Gomez-Barrena E, et al. Bone regeneration and stem cells. J Cell Mol Med. 2011;15(4):718-46. doi: 10.1111/j.1582-4934.2010.01224.x. [PubMed: 21129153]. [PubMed Central: PMC3922662].
  • 47. Guo Y, Tang CY, Man XF, Tang HN, Tang J, Zhou CL, et al. Insulin-like growth factor-1 promotes osteogenic differentiation and collagen I alpha 2 synthesis via induction of mRNA-binding protein LARP6 expression. Dev Growth Differ. 2017;59(2):94-103. doi: 10.1111/dgd.12342. [PubMed: 28211947].
  • 48. Elias WY. Assessment of the osteogenic potential of morphogenetic protein-2 and insulin-like growth factor-I on adipose tissuederived stem cells. J Biomed Sci. 2016;5(1):1-6.
  • 49. Majidinia M, Sadeghpour A, Yousefi B. The roles of signaling pathways in bone repair and regeneration. J Cell Physiol. 2018;233(4):2937-48. doi: 10.1002/jcp.26042. [PubMed: 28590066].
  • 50. Iwamoto T, Nakamura T, Doyle A, Ishikawa M, de Vega S, Fukumoto S, et al. Pannexin 3 regulates intracellular ATP/cAMP levels and promotes chondrocyte differentiation. J Biol Chem. 2010;285(24):18948-58. doi: 10.1074/jbc.M110.127027. [PubMed: 20404334]. [PubMed Central: PMC2881817].
  • 51. Hung CT, Allen FD, Mansfield KD, Shapiro IM. Extracellular ATP modulates [Ca2+]i in retinoic acid-treated embryonic chondrocytes. Am J Physiol. 1997;272(5 Pt 1):C1611-7. doi: 10.1152/ajpcell.1997.272.5.C1611. [PubMed: 9176153].
  • 52. Ishikawa M, Iwamoto T, Nakamura T, Doyle A, Fukumoto S, Yamada Y. Pannexin 3 functions as an ER Ca(2+) channel, hemichannel, and gap junction to promote osteoblast differentiation. J Cell Biol. 2011;193(7):1257-74. doi: 10.1083/jcb.201101050. [PubMed: 21690309]. [PubMed Central: PMC3216329].
  • 53. Ishikawa M, Williams GL, Ikeuchi T, Sakai K, Fukumoto S, Yamada Y. Pannexin 3 and connexin 43 modulate skeletal development through their distinct functions and expression patterns. J Cell Sci. 2016;129(5):1018-30. doi: 10.1242/jcs.176883. [PubMed: 26759176]. [PubMed Central: PMC4813316].
  • 54. Koga T, Matsui Y, Asagiri M, Kodama T, de Crombrugghe B, Nakashima K, et al. NFAT and Osterix cooperatively regulate bone formation. Nat Med. 2005;11(8):880-5. doi: 10.1038/nm1270. [PubMed: 16041384].
  • 55. Ishikawa M, Yamada Y. The role of pannexin 3 in bone biology. J Dent Res. 2016;96(4):372-9. doi: 10.1177/0022034516678203.
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