RESEARCH PROGRESS OF Hedgehog SIGNALING PATHWAY IN REGULATING BONE FORMATION AND OSTEOGENIC DIFFERENTIATION OF BONE MESENCHYMAL STEM CELLS_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

CHIBojing ¹ , LIUGuangyuan ² ,  XINGLei ³ ,  TIANFaming ⁴

1. Graduate School, North China University of Science and Technology, Tangshan Hebei, 063000, P. R. China;
2. Hebei Medical University, Tangshan Hebei, 063000, P. R. China;
3. Geriatrics Department, Affiliated Hospital, North China University of Science and Technology, Tangshan Hebei, 063000, P. R. China;
4. Medical Research Center, North China University of Science and Technology, Tangshan Hebei, 063000, P. R. China;

Corresponding author：

XINGLei, Email: Xlpangdun001@163.com; TIANFaming, Email: tfm9911316@163.com

Keywords：

Hedgehog signaling pathway; Bone marrow mesenchymal stem cells; Osteogenic differentiation; Bone formation

DOI：

10.7507/1002-1892.20160318

Video：

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Objective To summarize the research progress of the effects and mechanisms of Hedgehog signaling pathway in regulating bone formation and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). Methods The related literature concerning the regulations and mechanism of Hedgehog signaling pathway in osteogenic differentiation of BMSCs and bone formation in vivo, in vitro, and ex vivo studies in recent years was analyzed and summarized. Results The in vitro studies indicate that Hedgehog signaling pathway can promote osteogenic differentiation of BMSCs via activation of key molecules Smoothened (Smo) and Gli1 which are downstream of Hedgehog signaling, and Hedgehog signaling can activate mTORC2-Akt signaling by upregulation of insulin-like growth factor which has similar effects. Hedgehog signaling regulates osteoblast differentiation via activation of Hh-Smo-Ptch1-Gli signaling pathway and inhibition of Hh-Gαi-RhoA stress fibre signaling. Hedgehog signaling can regulate key molecules of osteogenesis Runx2 for promoting osteogenic differentiation and matrix mineralization by synergism of bone morphogenetic protein and Wnt signaling, and promotes bone formation and repair and healing for bone defect and bone graft model in vivo. Conclusion Hedgehog signaling can regulate bone formation and osteogenic differentiation of BMSCs via activation of Hedgehog signaling and other signaling pathways. Hedgehog signaling pathway may be a potential target for developing treatment for bone related diseases of osteoporosis and fracture healing disorders.

Citation： CHIBojing, LIUGuangyuan, XINGLei, TIANFaming. RESEARCH PROGRESS OF Hedgehog SIGNALING PATHWAY IN REGULATING BONE FORMATION AND OSTEOGENIC DIFFERENTIATION OF BONE MESENCHYMAL STEM CELLS. Chinese Journal of Reparative and Reconstructive Surgery, 2016, 30(12): 1545-1550. doi: 10.7507/1002-1892.20160318 Copy

1.	Aaseth J, Boivin G, Andersen O. Osteoporosis and trace elements--an overvie. J Trace Elem Med Biol, 2012, 26(2-3):149-152.
2.	中华医学会骨质疏松和骨矿盐疾病分会.原发性骨质疏松症诊治指南(2011年).中华骨质疏松和骨矿盐疾病杂志, 2011, 4(1):2-17.
3.	Donoso O, Pino AM, Seitz G, et al. Osteoporosis-associated alteration in the signalling status of BMP-2 in human MSCs under adipogenic conditions. J Cell Biochem, 2015, 116(7):1267-1277.
4.	Liu H, Xia X, Li B. Mesenchymal stem cell aging:Mechanisms and influences on skeletal and non-skeletal tissues. Exp Biol Med (Maywood), 2015, 240(8):1099-1106.
5.	罗明, 黄宏兴, 黄红, 等. Hedgehog信号通路与骨质疏松症.中国骨伤, 2014, 27(2):169-172.
6.	Yao E, Chuang PT. Hedgehog signaling:From basic research to clinical applications. J Formos Med Assoc, 2015, 114(7):569-576.
7.	Ehlen HW, Buelens LA, Vortkamp A. Hedgehog signaling in skeletal development. Birth Defects Rest C Embryo Today, 2006, 78(3):267-279.
8.	Briscoe J, Thérond P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol, 2013, 14(7):416-429.
9.	蔡加琴, 邓力. Hedgehog信号通路对MSCs的调控.中国修复重建外科杂志, 2010, 24(8):993-996.
10.	Varjosalo M, Taipale J. Hedgehog:functions and mechanisms. Genes Dev, 2008, 22(18):2454-2472.
11.	Chen Y, Jiang J. Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res, 2013, 23(2):186-200.
12.	Varjosalo M, Taipale J. Hedgehog signaling. J Cell Sci, 2007, 120(Pt 1):3-6.
13.	Carbone A, Carballo C, Ma R, et al. Indian hedgehog signaling and the role of graft tension in tendon-to-bone healing:Evaluation in a rat ACL reconstruction model. J Orthop Res, 2016, 34(4):641-649.
14.	Felber K, Croucher P, Roehl HH. Hedgehog signalling is required for perichondral osteoblast differentiation in zebrafish. Mech Dev, 2011, 128(1-2):141-152.
15.	Baht GS, Silkstone D, Nadesan P, et al. Activation of hedgehog signaling during fracture repair enhances osteoblastic-dependent matrix formation. J Orthop Res, 2014, 32(4):581-586.
16.	Wang Q, Huang C, Zeng F, et al. Activation of the Hh pathway in periosteum-derived mesenchymal stem cells induces bone formation in vivo:implication for postnatal bone repair. Am J Pathol, 2010, 177(6):3100-3111.
17.	Kitaura Y, Hojo H, Komiyama Y, et al. Gli1 haploinsufficiency leads to decreased bone mass with an uncoupling of bone metabolism in adult mice. PLoS One, 2014, 9(10):e109597.
18.	Shi Y, Chen J, Karner CM, et al. Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation. Proc Natl Acad Sci U S A, 2015, 112(15):4678-4683.
19.	Laurie LE, Kokubo H, Nakamura M, et al. The transcription factor hand1 is involved in Runx2-Ihh-Regulated endochondral ossification. PLoS One, 2016, 11(2):e0150263.
20.	Funato N, Chapman SL, Mckee MD, et al. Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2. Development, 2009, 136(4):615-625.
21.	Amano K, Densmore M, Fan Y, et al. Ihh and PTH1R signaling in limb mesenchyme is required for proper segmentation and subsequent formation and growth of digit bones. Bone, 2015, 83:256-266.
22.	Kim EJ, Cho SW, Shin JO, et al. Ihh and Runx2/Runx3 signaling interact to coordinate early chondrogenesis:a mouse model. PLoS One, 2013, 8(2):e55296.
23.	Tian F, Wu M, Deng L, et al. Core binding factor beta (Cbfβ) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation. J Bone Miner Res, 2014, 29(7):1564-1574.
24.	Cai JQ, Huang YZ, Chen XH, et al. Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell Biol Int, 2012, 36(4):349-355.
25.	韩磊, 张晓玲, 李晅, 等. Hedgehog通路对成骨细胞增殖和分化的作用.上海口腔医学, 2009, 18(3):287-290.
26.	Plaisant M, Giorgetti-Peraldi S, Gabrielson M, et al. Inhibition of hedgehog signaling decreases proliferation and clonogenicity of human mesenchymal stem cells. PLoS One, 2011, 6(2):e16798.
27.	张雪萍, 马晓丽, 汪运山, 等.大鼠骨髓间充质干细胞成骨分化过程中Hedgehog信号分子的表达.中国组织工程研究与临床康复, 2011, 15(14):2487-2490.
28.	James AW, Pang S, Askarinam A, et al. Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. Stem Cells Dev, 2012, 21(12):2170-2178.
29.	Montgomery SR, Nargizyan T, Meliton V, et al. A novel osteogenic oxysterol compound for therapeutic development to promote bone growth:activation of hedgehog signaling and osteogenesis through smoothened binding. J Bone Miner Res, 2014, 29(8):1872-1885.
30.	Yalom A, Hokugo A, Sorice S, et al. In vitro osteoinductive effects of hydroxycholesterol on human adipose-derived stem cells are mediated through the hedgehog signaling pathway. Plast Reconstr Surg, 2014, 134(5):960-968.
31.	Reichert JC, Schmalzl J, Prager P, 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.
32.	Oliveira FS, Bellesini LS, Defino HLA, et al. Hedgehog signaling and osteoblast gene expression are regulated by purmorphamine in human mesenchymal stem cells. J Cell Biochem, 2012, 113(1):204-208.
33.	Lin YC, Roffler SR, Yan YT, et al. Disruption of Scube2, Impairs Endochondral Bone Formation. J Bone Miner Res, 2015, 30(7):1255-1267.
34.	Li L, Dong Q, Wang Y, et al. Hedgehog signaling is involved in the BMP9-induced osteogenic differentiation of mesenchymal stem cells. Int J Mol Med, 2015, 35(6):1641-1650.
35.	Nakamura T, Naruse M, Chiba Y, et al. Novel hedgehog agonists promote osteoblast differentiation in mesenchymal stem cells. J Cell Physiol, 2015, 230(4):922-929.
36.	Yang S, Wang C. The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis. Bone, 2012, 51(3):407-417.
37.	Yuan X, Cao J, He X, et al. Ciliary IFT80 balances canonical versus non-canonical hedgehog signalling for osteoblast differentiation. Nat Commun, 2016, 7:11024.
38.	Jiang Q, Du J, Yin X, et al. Shh signaling, negatively regulated by BMP signaling, inhibits the osteo/dentinogenic differentiation potentials of mesenchymal stem cells from apical papilla. Mol Cell Biochem, 2013, 383(1-2):85-93.
39.	Plaisant M, Fontaine C, Cousin W, et al. Activation of hedgehog signaling inhibits osteoblast differentiation of human mesenchymal stem cells. Stem Cells, 2009, 27(3):703-713.
40.	Huang C, Tang M, Yehling E, et al. Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model. Mol Ther, 2014, 22(2):430-439.

1. Aaseth J, Boivin G, Andersen O. Osteoporosis and trace elements--an overvie. J Trace Elem Med Biol, 2012, 26(2-3):149-152.
2. 中华医学会骨质疏松和骨矿盐疾病分会.原发性骨质疏松症诊治指南(2011年).中华骨质疏松和骨矿盐疾病杂志, 2011, 4(1):2-17.
3. Donoso O, Pino AM, Seitz G, et al. Osteoporosis-associated alteration in the signalling status of BMP-2 in human MSCs under adipogenic conditions. J Cell Biochem, 2015, 116(7):1267-1277.
4. Liu H, Xia X, Li B. Mesenchymal stem cell aging:Mechanisms and influences on skeletal and non-skeletal tissues. Exp Biol Med (Maywood), 2015, 240(8):1099-1106.
5. 罗明, 黄宏兴, 黄红, 等. Hedgehog信号通路与骨质疏松症.中国骨伤, 2014, 27(2):169-172.
6. Yao E, Chuang PT. Hedgehog signaling:From basic research to clinical applications. J Formos Med Assoc, 2015, 114(7):569-576.
7. Ehlen HW, Buelens LA, Vortkamp A. Hedgehog signaling in skeletal development. Birth Defects Rest C Embryo Today, 2006, 78(3):267-279.
8. Briscoe J, Thérond P. The mechanisms of Hedgehog signalling and its roles in development and disease. Nat Rev Mol Cell Biol, 2013, 14(7):416-429.
9. 蔡加琴, 邓力. Hedgehog信号通路对MSCs的调控.中国修复重建外科杂志, 2010, 24(8):993-996.
10. Varjosalo M, Taipale J. Hedgehog:functions and mechanisms. Genes Dev, 2008, 22(18):2454-2472.
11. Chen Y, Jiang J. Decoding the phosphorylation code in Hedgehog signal transduction. Cell Res, 2013, 23(2):186-200.
12. Varjosalo M, Taipale J. Hedgehog signaling. J Cell Sci, 2007, 120(Pt 1):3-6.
13. Carbone A, Carballo C, Ma R, et al. Indian hedgehog signaling and the role of graft tension in tendon-to-bone healing:Evaluation in a rat ACL reconstruction model. J Orthop Res, 2016, 34(4):641-649.
14. Felber K, Croucher P, Roehl HH. Hedgehog signalling is required for perichondral osteoblast differentiation in zebrafish. Mech Dev, 2011, 128(1-2):141-152.
15. Baht GS, Silkstone D, Nadesan P, et al. Activation of hedgehog signaling during fracture repair enhances osteoblastic-dependent matrix formation. J Orthop Res, 2014, 32(4):581-586.
16. Wang Q, Huang C, Zeng F, et al. Activation of the Hh pathway in periosteum-derived mesenchymal stem cells induces bone formation in vivo:implication for postnatal bone repair. Am J Pathol, 2010, 177(6):3100-3111.
17. Kitaura Y, Hojo H, Komiyama Y, et al. Gli1 haploinsufficiency leads to decreased bone mass with an uncoupling of bone metabolism in adult mice. PLoS One, 2014, 9(10):e109597.
18. Shi Y, Chen J, Karner CM, et al. Hedgehog signaling activates a positive feedback mechanism involving insulin-like growth factors to induce osteoblast differentiation. Proc Natl Acad Sci U S A, 2015, 112(15):4678-4683.
19. Laurie LE, Kokubo H, Nakamura M, et al. The transcription factor hand1 is involved in Runx2-Ihh-Regulated endochondral ossification. PLoS One, 2016, 11(2):e0150263.
20. Funato N, Chapman SL, Mckee MD, et al. Hand2 controls osteoblast differentiation in the branchial arch by inhibiting DNA binding of Runx2. Development, 2009, 136(4):615-625.
21. Amano K, Densmore M, Fan Y, et al. Ihh and PTH1R signaling in limb mesenchyme is required for proper segmentation and subsequent formation and growth of digit bones. Bone, 2015, 83:256-266.
22. Kim EJ, Cho SW, Shin JO, et al. Ihh and Runx2/Runx3 signaling interact to coordinate early chondrogenesis:a mouse model. PLoS One, 2013, 8(2):e55296.
23. Tian F, Wu M, Deng L, et al. Core binding factor beta (Cbfβ) controls the balance of chondrocyte proliferation and differentiation by upregulating Indian hedgehog (Ihh) expression and inhibiting parathyroid hormone-related protein receptor (PPR) expression in postnatal cartilage and bone formation. J Bone Miner Res, 2014, 29(7):1564-1574.
24. Cai JQ, Huang YZ, Chen XH, et al. Sonic hedgehog enhances the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell Biol Int, 2012, 36(4):349-355.
25. 韩磊, 张晓玲, 李晅, 等. Hedgehog通路对成骨细胞增殖和分化的作用.上海口腔医学, 2009, 18(3):287-290.
26. Plaisant M, Giorgetti-Peraldi S, Gabrielson M, et al. Inhibition of hedgehog signaling decreases proliferation and clonogenicity of human mesenchymal stem cells. PLoS One, 2011, 6(2):e16798.
27. 张雪萍, 马晓丽, 汪运山, 等.大鼠骨髓间充质干细胞成骨分化过程中Hedgehog信号分子的表达.中国组织工程研究与临床康复, 2011, 15(14):2487-2490.
28. James AW, Pang S, Askarinam A, et al. Additive effects of sonic hedgehog and Nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. Stem Cells Dev, 2012, 21(12):2170-2178.
29. Montgomery SR, Nargizyan T, Meliton V, et al. A novel osteogenic oxysterol compound for therapeutic development to promote bone growth:activation of hedgehog signaling and osteogenesis through smoothened binding. J Bone Miner Res, 2014, 29(8):1872-1885.
30. Yalom A, Hokugo A, Sorice S, et al. In vitro osteoinductive effects of hydroxycholesterol on human adipose-derived stem cells are mediated through the hedgehog signaling pathway. Plast Reconstr Surg, 2014, 134(5):960-968.
31. Reichert JC, Schmalzl J, Prager P, 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.
32. Oliveira FS, Bellesini LS, Defino HLA, et al. Hedgehog signaling and osteoblast gene expression are regulated by purmorphamine in human mesenchymal stem cells. J Cell Biochem, 2012, 113(1):204-208.
33. Lin YC, Roffler SR, Yan YT, et al. Disruption of Scube2, Impairs Endochondral Bone Formation. J Bone Miner Res, 2015, 30(7):1255-1267.
34. Li L, Dong Q, Wang Y, et al. Hedgehog signaling is involved in the BMP9-induced osteogenic differentiation of mesenchymal stem cells. Int J Mol Med, 2015, 35(6):1641-1650.
35. Nakamura T, Naruse M, Chiba Y, et al. Novel hedgehog agonists promote osteoblast differentiation in mesenchymal stem cells. J Cell Physiol, 2015, 230(4):922-929.
36. Yang S, Wang C. The intraflagellar transport protein IFT80 is required for cilia formation and osteogenesis. Bone, 2012, 51(3):407-417.
37. Yuan X, Cao J, He X, et al. Ciliary IFT80 balances canonical versus non-canonical hedgehog signalling for osteoblast differentiation. Nat Commun, 2016, 7:11024.
38. Jiang Q, Du J, Yin X, et al. Shh signaling, negatively regulated by BMP signaling, inhibits the osteo/dentinogenic differentiation potentials of mesenchymal stem cells from apical papilla. Mol Cell Biochem, 2013, 383(1-2):85-93.
39. Plaisant M, Fontaine C, Cousin W, et al. Activation of hedgehog signaling inhibits osteoblast differentiation of human mesenchymal stem cells. Stem Cells, 2009, 27(3):703-713.
40. Huang C, Tang M, Yehling E, et al. Overexpressing sonic hedgehog peptide restores periosteal bone formation in a murine bone allograft transplantation model. Mol Ther, 2014, 22(2):430-439.

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RESEARCH PROGRESS OF Hedgehog SIGNALING PATHWAY IN REGULATING BONE FORMATION AND OSTEOGENIC DIFFERENTIATION OF BONE MESENCHYMAL STEM CELLS

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