RESEARCH PROGRESS OF KEY SIGNALING PATHWAYS IN OSTEOBLAST DIFFERENTIATION AND BONE FORMATION REGULATION_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

XULian ,  KONGQingquan

Department of Orthopaedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P. R. China;

Corresponding author：

KONGQingquan, Email: kqqspine@126.com

Keywords：

Mesenchymal stem cells; Osteoblast differentiation; Bone formation; Signaling pathway

DOI：

10.7507/1002-1892.20140321

Video：

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Objective To review the mechanism and research progress of signal ing pathways which play key roles in the regulation of osteoblast differentiation and bone formation. Methods Recent articles about signal ing pathways of osteoblast differentiation and bone formation were reviewed and comprehensively analyzed. Results At present, multi ple signaling pathways have been found to be involved in the regulation of osteoblast differentiation and bone formation, among which bone morphogenetic protein-Smads, Wnt/β-catenin, Notch, Hedgehog, and fibroblast growth factor signaling pathways may play the most important roles. Not only each pathway has a complex regulatory mechanism itself, but also contacts and impacts with each other, thus they formed a more compl icated and sophisticated regulatory network, and regulate together osteoblast differentiation and bone formation. However, the mechanisms in detail of those pathways are still not very clear, because the animal experiment techniques are not yet mature as well as the relevant cl inical trials were carried out not too much. Conclusion The complete molecular mechanism of osteoblast differentiation and bone formation should be further investigated, so as to lay a theory foundation for preventing and treating the common bone diseases in cl inical which are involve in osteoblast differentiation and bone formation.

Citation： XULian, KONGQingquan. RESEARCH PROGRESS OF KEY SIGNALING PATHWAYS IN OSTEOBLAST DIFFERENTIATION AND BONE FORMATION REGULATION. Chinese Journal of Reparative and Reconstructive Surgery, 2014, 28(12): 1484-1489. doi: 10.7507/1002-1892.20140321 Copy

1.	Komori T. Regulation of osteoblast differentiation by transcri ption factors. J Cell Biochem, 2006, 99(5):1233-1239.
2.	Soltanoff CS, Yang S, Chen W, et al. Signaling networks that control the lineage commitment and differentiation of bone cells. Crit Rev Eukaryot Gene Expr, 2009, 19(1):1-46.
3.	Sampath TK, Nathanson MA, Reddi AH. In vitro transformation of mesenchymal cells derived from embryonic muscle into cartilage in response to extracellular matrix components of bone. Proc Natl Acad Sci U S A, 1984, 81(11):3419-3423.
4.	Zhang J, Li L. BMP signaling and stem cell regulation. Dev Bio, 2005, 284(1):1-11.
5.	Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 2003, 113(6):685-700.
6.	Varga AC, Wrana JL. The disparate role of BMP in stem cell biology. Oncogene, 2005, 24(37):5713-5721.
7.	Kang Q, Song WX, Luo Q, et al. A comprehensive analysis of the dual roles of BMPs in regulating adi pogenic and osteogenic differentiation of mesenchymal progenitor cells. Stem Cells and Dev, 2008, 18(4): 545-559.
8.	Muruganandan S, Roman AA, Sinal CJ. Adi pocyte differentiation of bone marrow-derived mesenchymal stem cells:cross talk with the osteoblastogenic program. Cell Mol Life Sci, 2009, 66(2):236-253.
9.	Beederman M, Lamplot J D, Nan G, et al. BMP signaling in mesenchymal stem cell differentiation and bone formation. Journal of Biomedical Science and Engineering, 2013, 6(8A):32-52.
10.	Leboy PS. Regulating bone growth and development with bone morphogenetic proteins. Ann N Y Acad Sci, 2006, 1068:14-18.
11.	Chen GQ, Deng CX, Li YP. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci, 2012, 8(2):272-288.
12.	Hong JH, Hwang ES, McManus MT, et al. TAZ, a transcri ptional modulator of mesenchymal stem cell differentiation. Science, 2005, 309(5737):1074-1078.
13.	Edgar AJ, Dover SL, Lodrick MN, et al. Bone morphogenetic protein-2 induces expression of murine zinc finger transcri ption factor ZNF450. J Cell Biochem, 2005, 94(1):202-215.
14.	Tachi K, Takami M, Sato H, et al. Enhancement of bone morphogenetic protein-2-induced ectopic bone formation by transforming growth factor-β1. Tissue Eng Part A, 2010, 17(5-6):597-606.
15.	Li S, Lu K, Wang J, et al. Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol Cell Biochem, 2010, 338(1-2):11-17.
16.	Krishnan V, Bryant HU, MacDougald OA. Regulation of bone mass by Wnt signal ing. J Clin Invest, 2006, 116(5):1202-1209.
17.	Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 1982, 31(1):99-109.
18.	Nusse R. Wnt signaling in disease and in development. Cell Res, 2005, 15(1):28-32.
19.	Clevers H, Nusse R. Wnt/β-catenin signal ing and disease. Cell, 2012, 149(6):1192-1205.
20.	Shi YC, Worton L, Esteban L, et al. Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic prol iferation and differentiation. Bone, 2007, 41(1):87-96.
21.	Glass DA 2nd, Bialek P, Ahn JD, et al. Canonical Wnt signal ing in differentiated osteoblasts controls osteoclast differentiation. Dev Cell, 2005, 8(5):751-764.
22.	Monroe DG, McGee-Lawrence ME, Oursler MJ, et al. Update on Wnt signaling in bone cell biology and bone disease. Gene, 2012, 492(1): 1-18.
23.	Liu W, Konermann A, Guo T, et al. Canonical Wnt signaling differently modulates osteogenic differentiation of mesenchymal stem cells derived from bone marrow and from periodontal ligament under inflammatory conditions. Biochim Biophys Acta, 2014, 1840(3):1125-1134.
24.	Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med, 2013, 19(2):179-192.
25.	Kim JH, Liu X, Wang J, et al. Wnt signaling in bone formation and its therapeutic potential for bone diseases. Ther Adv Musculoskelet Dis, 2013, 5(1):13-31.
26.	Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med, 2002, 346(20): 1513-1521.
27.	Tüysüz B, Bursalı A, Alp Z, et al. Osteoporosis-pseudoglioma syndrome: three novel mutations in the LRP5 gene and response to bisphosphonate treatment. Horm Res Paediatr, 2012, 77(2):115-120.
28.	Cui Y, Niziolek PJ, MacDonald BT, et al. Lrp5 functions in bone to regulate bone mass. Nat Med, 2011, 17(6):684-691.
29.	Joeng KS, Schumacher CA, Zylstra-Diegel CR, et al. Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. Dev Biol, 2011, 359(2):222-229.
30.	Qiu W, Andersen TE, Bollerslev J, et al. Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adi pogenesis of human mesenchymal stem cells. J Bone Miner Res, 2007, 22(11):1720-1731.
31.	Yadav VK, Arantes HP, Barros ER, et al. Genetic analysis of Lrp5 function in osteoblast progenitors. Calcif Tissue Int, 2010, 86(5):382-388.
32.	Javaheri B, Stern AR, Lara N, et al. Deletion of a single β-catenin allele in osteocytes abolishes the bone anabolic response to loading. J Bone Mineral Res, 2014, 29(3):705-715.
33.	Macsai CE, Foster BK, Xian CJ. Roles of Wnt signaling in bone growth, remodelling, skeletal disorders and fracture repair. J Cell Physiol, 2008, 215(3):578-587.
34.	Hill TP, Später D, Taketo MM, et al. Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell, 2005, 8(5):727-738.
35.	Kang S, Bennett CN, Gerin I, et al. Wnt signal ing stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/ enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. J Biol Chem, 2007, 282(19):14515-14524.
36.	Lai EC. Notch signal ing:control of cell communication and cell fate. Development, 2004, 131(5):965-973.
37.	Canalis E. Notch signaling in osteoblasts. Sci Signal, 2008, 1(17):pe17.
38.	Regan J, Long F. Notch signaling and bone remodeling. Curr Osteoporos Rep, 2013, 11(2):126-129.
39.	Liu W, Singh SR, Hou SX. JAK-STAT is restrained by Notch to control cell prol iferation of the Drosophila intestinal stem cells. J Cell Biochem, 2010, 109(5):992-999.
40.	Abe N, Hozumi K, Hirano K, et al. Notch ligands transduce different magnitudes of signaling critical for determination of T-cell fate. Eur J Immunol, 2010, 40(9):2608-2617.
41.	Zanotti S, Canalis E. Notch and the skeleton. Mol Cell Biol, 2010, 30(4):886-896.
42.	Mead TJ, Yutzey KE. Notch signal ing and the developing skeleton// Notch Signal ing in Embryology and Cancer. New York:Springer-Verlag New York Inc, 2012:114-130.
43.	Ugarte F, Ryser M, Thieme S, et al. Notch signal ing enhances osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells. Exp Hematol, 2009, 37(7):867-875. e1.
44.	Zanotti S, Smerdel-Ramoya A, Stadmeyer L, et al. Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology, 2008, 149(8):3890-3899.
45.	Engin F, Yao Z, Yang T, et al. Dimorphic effects of Notch signaling in bone homeostasis. Nat Med, 2008, 14(3):299-305.
46.	Watanabe K, Ikeda K. Osteoblast differentiation and bone formation. Nihon Rinsho, 2009, 67(5):879-886.
47.	Hilton MJ, Tu X, Wu X, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med, 2008, 14(3):306-314.
48.	Deregowski V, Gazzerro E, Priest L, et al. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signal ing. J Biol Chem, 2006, 281(10): 6203-6210.
49.	Zamurovic N, Cappellen D, Rohner D, et al. Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcri ptional activity. J Biol Chem, 2004, 279(36):37704-37715.
50.	McMahon AP, Ingham PW, Tabin CJ. Developmental roles and cl inical significance of hedgehog signal ing. Curr Top Dev Biol, 2003, 53: 1-114.
51.	Beachy PA, Hymowitz SG, Lazarus RA, et al. Interactions between Hedgehog proteins and their binding partners come into view. Genes Dev, 2010, 24(18):2001-2012.
52.	Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and princi ples. Genes Dev, 2001, 15(23):3059-3087.
53.	Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell, 2008, 15(6):801-812.
54.	Takahashi S, Kawashima N, Sakamoto K, et al. Differentiation of an ameloblast-lineage cell line (ALC) is induced by Sonic hedgehog signaling. Biochem Biophys Res Commun, 2007, 353(2):405-411.
55.	Fontaine C, Cousin W, Plaisant M, et al. Hedgehog signal ing alters adi pocyte maturation of human mesenchymal stem cells. Stem Cells, 2008, 26(4):1037-1046.
56.	Kim WK, Meliton V, Bourquard N, et al. Hedgehog signaling and osteogenic differentiation in multi potent bone marrow stromal cells are inhibited by oxidative stress. J Cell Biochem, 2010, 111(5):1199-1209.
57.	Cai JQ, Huang YZ, Chen XH, et al. Sonic hedgehog enhances the prol iferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell Biol Int, 2012, 36(4):349-355.
58.	Tu X, Joeng KS, Long F. Indian hedgehog requires additional effectors besides Runx2 to induce osteoblast differentiation. Dev Biol, 2012, 362(1):76-82.
59.	Yuasa T, Kataoka H, Kinto N, et al. Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP-2. J Cell Physiol, 2002, 193(2):225-232.
60.	Regard JB, Malhotra D, Gvozdenovic-Jeremic J, et al. Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat Med, 2013, 19(11):1505-1512.
61.	Shimoyama A, Wada M, Ikeda F, et al. Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Mol Biol Cell, 2007, 18(7):2411-2418.
62.	Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signal ing. Endocr Relat Cancer, 2000, 7(3):165-197.
63.	Zhang F, Zhang Z, Lin X, et al. Compositional analysis of heparin/heparan sulfate interacting with fibroblast growth factor· fibroblast growth factor receptor complexes. Biochemistry, 2009, 48(35):8379-8386.
64.	Marie PJ, Miraoui H, Sévère N. FGF/FGFR signaling in bone formation: progress and perspectives. Growth Factors, 2012, 30(2):117-123.
65.	Su N, Du X, Chen L. FGF signal ing:its role in bone development and human skeleton diseases. Front Biosci, 2007, 13:2842-2865.
66.	Fei Y, Xiao L, Doetschman T, et al. Fibroblast growth factor 2 stimulation of osteoblast differentiation and bone formation is mediated by modulation of the Wnt signaling pathway. J Biol Chem, 2011, 286(47): 40575-40583.
67.	Ito T, Sawada R, Fujiwara Y, et al. FGF-2 increases osteogenic and chondrogenic differentiation potentials of human mesenchymal stem cells by inactivation of TGF-beta signal ing. Cytotechnology, 2008, 56(1):1-7.
68.	Dailey L, Ambrosetti D, Mansukhani A, et al. Mechanisms underlying differential responses to FGF signal ing. Cytokine Growth Factor Rev, 2005, 16(2):233-247.
69.	Yin L, Du X, Li C, et al. A Pro253Arg mutation in fibroblast growth factor receptor 2(Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis. Bone, 2008, 42(4):631-643.
70.	Kodama N, Nagata M, Tabata Y, et al. A local bone anabolic effect of rhFGF2-impregnated gelatin hydrogel by promoting cell proliferation and coordinating osteoblastic differentiation. Bone, 2009, 44(4):699-707.
71.	Agas D, Sabbieti MG, Marchetti L, et al. FGF-2 enhances Runx-2/ Smads nuclear local ization in BMP-2 canonical signal ing in osteoblasts. J Cell Physiol, 2013, 228(11):2149-2158.
72.	Kim BG, Kim HJ, Park HJ, et al. Runx2 phosphorylation induced by fibroblast growth factor-2/protein kinase C pathways. Proteomics, 2006, 6(4):1166-1174.

1. Komori T. Regulation of osteoblast differentiation by transcri ption factors. J Cell Biochem, 2006, 99(5):1233-1239.
2. Soltanoff CS, Yang S, Chen W, et al. Signaling networks that control the lineage commitment and differentiation of bone cells. Crit Rev Eukaryot Gene Expr, 2009, 19(1):1-46.
3. Sampath TK, Nathanson MA, Reddi AH. In vitro transformation of mesenchymal cells derived from embryonic muscle into cartilage in response to extracellular matrix components of bone. Proc Natl Acad Sci U S A, 1984, 81(11):3419-3423.
4. Zhang J, Li L. BMP signaling and stem cell regulation. Dev Bio, 2005, 284(1):1-11.
5. Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell, 2003, 113(6):685-700.
6. Varga AC, Wrana JL. The disparate role of BMP in stem cell biology. Oncogene, 2005, 24(37):5713-5721.
7. Kang Q, Song WX, Luo Q, et al. A comprehensive analysis of the dual roles of BMPs in regulating adi pogenic and osteogenic differentiation of mesenchymal progenitor cells. Stem Cells and Dev, 2008, 18(4): 545-559.
8. Muruganandan S, Roman AA, Sinal CJ. Adi pocyte differentiation of bone marrow-derived mesenchymal stem cells:cross talk with the osteoblastogenic program. Cell Mol Life Sci, 2009, 66(2):236-253.
9. Beederman M, Lamplot J D, Nan G, et al. BMP signaling in mesenchymal stem cell differentiation and bone formation. Journal of Biomedical Science and Engineering, 2013, 6(8A):32-52.
10. Leboy PS. Regulating bone growth and development with bone morphogenetic proteins. Ann N Y Acad Sci, 2006, 1068:14-18.
11. Chen GQ, Deng CX, Li YP. TGF-β and BMP signaling in osteoblast differentiation and bone formation. Int J Biol Sci, 2012, 8(2):272-288.
12. Hong JH, Hwang ES, McManus MT, et al. TAZ, a transcri ptional modulator of mesenchymal stem cell differentiation. Science, 2005, 309(5737):1074-1078.
13. Edgar AJ, Dover SL, Lodrick MN, et al. Bone morphogenetic protein-2 induces expression of murine zinc finger transcri ption factor ZNF450. J Cell Biochem, 2005, 94(1):202-215.
14. Tachi K, Takami M, Sato H, et al. Enhancement of bone morphogenetic protein-2-induced ectopic bone formation by transforming growth factor-β1. Tissue Eng Part A, 2010, 17(5-6):597-606.
15. Li S, Lu K, Wang J, et al. Ubiquitin ligase Smurf1 targets TRAF family proteins for ubiquitination and degradation. Mol Cell Biochem, 2010, 338(1-2):11-17.
16. Krishnan V, Bryant HU, MacDougald OA. Regulation of bone mass by Wnt signal ing. J Clin Invest, 2006, 116(5):1202-1209.
17. Nusse R, Varmus HE. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell, 1982, 31(1):99-109.
18. Nusse R. Wnt signaling in disease and in development. Cell Res, 2005, 15(1):28-32.
19. Clevers H, Nusse R. Wnt/β-catenin signal ing and disease. Cell, 2012, 149(6):1192-1205.
20. Shi YC, Worton L, Esteban L, et al. Effects of continuous activation of vitamin D and Wnt response pathways on osteoblastic prol iferation and differentiation. Bone, 2007, 41(1):87-96.
21. Glass DA 2nd, Bialek P, Ahn JD, et al. Canonical Wnt signal ing in differentiated osteoblasts controls osteoclast differentiation. Dev Cell, 2005, 8(5):751-764.
22. Monroe DG, McGee-Lawrence ME, Oursler MJ, et al. Update on Wnt signaling in bone cell biology and bone disease. Gene, 2012, 492(1): 1-18.
23. Liu W, Konermann A, Guo T, et al. Canonical Wnt signaling differently modulates osteogenic differentiation of mesenchymal stem cells derived from bone marrow and from periodontal ligament under inflammatory conditions. Biochim Biophys Acta, 2014, 1840(3):1125-1134.
24. Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med, 2013, 19(2):179-192.
25. Kim JH, Liu X, Wang J, et al. Wnt signaling in bone formation and its therapeutic potential for bone diseases. Ther Adv Musculoskelet Dis, 2013, 5(1):13-31.
26. Boyden LM, Mao J, Belsky J, et al. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med, 2002, 346(20): 1513-1521.
27. Tüysüz B, Bursalı A, Alp Z, et al. Osteoporosis-pseudoglioma syndrome: three novel mutations in the LRP5 gene and response to bisphosphonate treatment. Horm Res Paediatr, 2012, 77(2):115-120.
28. Cui Y, Niziolek PJ, MacDonald BT, et al. Lrp5 functions in bone to regulate bone mass. Nat Med, 2011, 17(6):684-691.
29. Joeng KS, Schumacher CA, Zylstra-Diegel CR, et al. Lrp5 and Lrp6 redundantly control skeletal development in the mouse embryo. Dev Biol, 2011, 359(2):222-229.
30. Qiu W, Andersen TE, Bollerslev J, et al. Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adi pogenesis of human mesenchymal stem cells. J Bone Miner Res, 2007, 22(11):1720-1731.
31. Yadav VK, Arantes HP, Barros ER, et al. Genetic analysis of Lrp5 function in osteoblast progenitors. Calcif Tissue Int, 2010, 86(5):382-388.
32. Javaheri B, Stern AR, Lara N, et al. Deletion of a single β-catenin allele in osteocytes abolishes the bone anabolic response to loading. J Bone Mineral Res, 2014, 29(3):705-715.
33. Macsai CE, Foster BK, Xian CJ. Roles of Wnt signaling in bone growth, remodelling, skeletal disorders and fracture repair. J Cell Physiol, 2008, 215(3):578-587.
34. Hill TP, Später D, Taketo MM, et al. Canonical Wnt/β-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell, 2005, 8(5):727-738.
35. Kang S, Bennett CN, Gerin I, et al. Wnt signal ing stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/ enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. J Biol Chem, 2007, 282(19):14515-14524.
36. Lai EC. Notch signal ing:control of cell communication and cell fate. Development, 2004, 131(5):965-973.
37. Canalis E. Notch signaling in osteoblasts. Sci Signal, 2008, 1(17):pe17.
38. Regan J, Long F. Notch signaling and bone remodeling. Curr Osteoporos Rep, 2013, 11(2):126-129.
39. Liu W, Singh SR, Hou SX. JAK-STAT is restrained by Notch to control cell prol iferation of the Drosophila intestinal stem cells. J Cell Biochem, 2010, 109(5):992-999.
40. Abe N, Hozumi K, Hirano K, et al. Notch ligands transduce different magnitudes of signaling critical for determination of T-cell fate. Eur J Immunol, 2010, 40(9):2608-2617.
41. Zanotti S, Canalis E. Notch and the skeleton. Mol Cell Biol, 2010, 30(4):886-896.
42. Mead TJ, Yutzey KE. Notch signal ing and the developing skeleton// Notch Signal ing in Embryology and Cancer. New York:Springer-Verlag New York Inc, 2012:114-130.
43. Ugarte F, Ryser M, Thieme S, et al. Notch signal ing enhances osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells. Exp Hematol, 2009, 37(7):867-875. e1.
44. Zanotti S, Smerdel-Ramoya A, Stadmeyer L, et al. Notch inhibits osteoblast differentiation and causes osteopenia. Endocrinology, 2008, 149(8):3890-3899.
45. Engin F, Yao Z, Yang T, et al. Dimorphic effects of Notch signaling in bone homeostasis. Nat Med, 2008, 14(3):299-305.
46. Watanabe K, Ikeda K. Osteoblast differentiation and bone formation. Nihon Rinsho, 2009, 67(5):879-886.
47. Hilton MJ, Tu X, Wu X, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med, 2008, 14(3):306-314.
48. Deregowski V, Gazzerro E, Priest L, et al. Notch 1 overexpression inhibits osteoblastogenesis by suppressing Wnt/beta-catenin but not bone morphogenetic protein signal ing. J Biol Chem, 2006, 281(10): 6203-6210.
49. Zamurovic N, Cappellen D, Rohner D, et al. Coordinated activation of notch, Wnt, and transforming growth factor-beta signaling pathways in bone morphogenic protein 2-induced osteogenesis. Notch target gene Hey1 inhibits mineralization and Runx2 transcri ptional activity. J Biol Chem, 2004, 279(36):37704-37715.
50. McMahon AP, Ingham PW, Tabin CJ. Developmental roles and cl inical significance of hedgehog signal ing. Curr Top Dev Biol, 2003, 53: 1-114.
51. Beachy PA, Hymowitz SG, Lazarus RA, et al. Interactions between Hedgehog proteins and their binding partners come into view. Genes Dev, 2010, 24(18):2001-2012.
52. Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and princi ples. Genes Dev, 2001, 15(23):3059-3087.
53. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell, 2008, 15(6):801-812.
54. Takahashi S, Kawashima N, Sakamoto K, et al. Differentiation of an ameloblast-lineage cell line (ALC) is induced by Sonic hedgehog signaling. Biochem Biophys Res Commun, 2007, 353(2):405-411.
55. Fontaine C, Cousin W, Plaisant M, et al. Hedgehog signal ing alters adi pocyte maturation of human mesenchymal stem cells. Stem Cells, 2008, 26(4):1037-1046.
56. Kim WK, Meliton V, Bourquard N, et al. Hedgehog signaling and osteogenic differentiation in multi potent bone marrow stromal cells are inhibited by oxidative stress. J Cell Biochem, 2010, 111(5):1199-1209.
57. Cai JQ, Huang YZ, Chen XH, et al. Sonic hedgehog enhances the prol iferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell Biol Int, 2012, 36(4):349-355.
58. Tu X, Joeng KS, Long F. Indian hedgehog requires additional effectors besides Runx2 to induce osteoblast differentiation. Dev Biol, 2012, 362(1):76-82.
59. Yuasa T, Kataoka H, Kinto N, et al. Sonic hedgehog is involved in osteoblast differentiation by cooperating with BMP-2. J Cell Physiol, 2002, 193(2):225-232.
60. Regard JB, Malhotra D, Gvozdenovic-Jeremic J, et al. Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification. Nat Med, 2013, 19(11):1505-1512.
61. Shimoyama A, Wada M, Ikeda F, et al. Ihh/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function. Mol Biol Cell, 2007, 18(7):2411-2418.
62. Powers CJ, McLeskey SW, Wellstein A. Fibroblast growth factors, their receptors and signal ing. Endocr Relat Cancer, 2000, 7(3):165-197.
63. Zhang F, Zhang Z, Lin X, et al. Compositional analysis of heparin/heparan sulfate interacting with fibroblast growth factor· fibroblast growth factor receptor complexes. Biochemistry, 2009, 48(35):8379-8386.
64. Marie PJ, Miraoui H, Sévère N. FGF/FGFR signaling in bone formation: progress and perspectives. Growth Factors, 2012, 30(2):117-123.
65. Su N, Du X, Chen L. FGF signal ing:its role in bone development and human skeleton diseases. Front Biosci, 2007, 13:2842-2865.
66. Fei Y, Xiao L, Doetschman T, et al. Fibroblast growth factor 2 stimulation of osteoblast differentiation and bone formation is mediated by modulation of the Wnt signaling pathway. J Biol Chem, 2011, 286(47): 40575-40583.
67. Ito T, Sawada R, Fujiwara Y, et al. FGF-2 increases osteogenic and chondrogenic differentiation potentials of human mesenchymal stem cells by inactivation of TGF-beta signal ing. Cytotechnology, 2008, 56(1):1-7.
68. Dailey L, Ambrosetti D, Mansukhani A, et al. Mechanisms underlying differential responses to FGF signal ing. Cytokine Growth Factor Rev, 2005, 16(2):233-247.
69. Yin L, Du X, Li C, et al. A Pro253Arg mutation in fibroblast growth factor receptor 2(Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis. Bone, 2008, 42(4):631-643.
70. Kodama N, Nagata M, Tabata Y, et al. A local bone anabolic effect of rhFGF2-impregnated gelatin hydrogel by promoting cell proliferation and coordinating osteoblastic differentiation. Bone, 2009, 44(4):699-707.
71. Agas D, Sabbieti MG, Marchetti L, et al. FGF-2 enhances Runx-2/ Smads nuclear local ization in BMP-2 canonical signal ing in osteoblasts. J Cell Physiol, 2013, 228(11):2149-2158.
72. Kim BG, Kim HJ, Park HJ, et al. Runx2 phosphorylation induced by fibroblast growth factor-2/protein kinase C pathways. Proteomics, 2006, 6(4):1166-1174.

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