Understanding of stem cells in bone biology and translation into clinical applications

Abstract

Developments of stem cell biology provide new approaches for understanding the mechanisms of a number of diseases, including osteoporosis. In this mini-review, we highlight two areas that related to stem cells in bone biology. Recent discovery of the role of osteoclast and their stem cells leads to developing a new approach for treatment of osteoporosis with the initial stimulation of cells in osteoclast lineage and followed by sequentially enhanced bone formation. Stimulation on both sides in bone remodeling is expected to achieve a long term effect on bone formation. For bone regeneration, multiple disciplinary collaborations among bone biologists, stem cell biologists and biomaterial scientists are necessary to successfully develop an integrated stem cell therapy that should include stem cells, suitable scaffolds and bioactive factors/small molecular compounds.

Key words： Stem cells; bone regeneration; osteoporosis; scaffolds; small molecules

References

1 Alkhiary Y M, Gerstenfeld L C, Krall E, Westmore M, Sato M, Mitlak B H, Einhorn T A (2005). Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1-34). J Bone Joint Surg Am, 87(4): 731-741

2 Aoi T, Yae K, Nakagawa M, Ichisaka T, Okita K, Takahashi K, Chiba T, Yamanaka S (2008). Generation of pluripotent stem cells from adult mouse liver and stomach cells. Science (New York, N. Y), 321: 699-702

3 Bedogni A, Bettini G, Totola A, Saia G, Nocini P F (2010). Oral bisphosphonate-associated osteonecrosis of the jaw after implant surgery: a case report and literature review. J Oral Maxillofac Surg, 68(7): 1662-1666

4 Beloti M M, Bellesini L S, Rosa A L (2005a). Purmorphamine enhances osteogenic activity of human osteoblasts derived from bone marrow mesenchymal cells. Cell Biol Int, 29(7): 537-541

5 Beloti M M, Bellesini L S, Rosa A L (2005b). The effect of purmorphamine on osteoblast phenotype expression of human bone marrow mesenchymal cells cultured on titanium. Biomaterials, 26(20): 4245-4248

6 Bennett J H, Joyner C J, Triffitt J T, Owen M E (1991). Adipocytic cells cultured from marrow have osteogenic potential. J Cell Sci, 99(Pt 1): 131-139

7 Blackwell K A, Raisz L G, Pilbeam C C (2010). Prostaglandins in bone: bad cop, good cop? Trends in endocrinology and metabolism: TEM, 21, 294-301

8 Bodine P V (2008). Wnt signaling control of bone cell apoptosis. Cell Res, 18(2): 248-253

9 Bolós V, Grego-Bessa J, de la Pompa J L (2007). Notch signaling in development and cancer. Endocr Rev, 28(3): 339-363

10 Bonyadi M, Waldman S D, Liu D, Aubin J E, Grynpas M D, Stanford W L (2003). Mesenchymal progenitor self-renewal deficiency leads to age-dependent osteoporosis in Sca-1/Ly-6A null mice. Proc Natl Acad Sci U S A, 100(10): 5840-5845

11 Brown S E, Tong W, Krebsbach P H (2009). The derivation of mesenchymal stem cells from human embryonic stem cells. Cells Tissues Organs, 189(1-4): 256-260

12 Buckbinder L, Crawford D T, Qi H, Ke H Z, Olson L M, Long K R, Bonnette P C, Baumann A P, Hambor J E, Grasser W A 3rd, Pan L C, Owen T A, Luzzio M J, Hulford C A, Gebhard D F, Paralkar V M, Simmons H A, Kath J C, Roberts W G, Smock S L, Guzman-Perez A, Brown T A, Li M (2007). Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis. Proc Natl Acad Sci U S A, 104(25): 10619-10624

13 Bueno E M, Glowacki J (2009). Cell-free and cell-based approaches for bone regeneration. Nat Rev Rheumatol, 5(12): 685-697

14 Cameron K O, Lefker B A, Chu-Moyer M Y, Crawford D T, Jardine P D, DeNinno S L, Gilbert S, Grasser W A, Ke H, Lu B, Owen T A, Paralkar V M, Qi H, Scott D O, Thompson D D, Tjoa C M, Zawistoski M P (2006). Discovery of highly selective EP4 receptor agonists that stimulate new bone formation and restore bone mass in ovariectomized rats. Bioorg Med Chem Lett, 16(7): 1799-1802

15 Canalis E (2008). Notch signaling in osteoblasts. Sci Signal, 1(17): pe17

16 Chai G, Zhang Y, Hu X J, Wang M, Liu W, Cui L, Cao Y L (2006). Repair alveolar cleft bone defects with bone marrow stromal cells. Zhonghua Zhengxing Waike Zazhi, 22, 409-411

17 Chen Y, Alman B A (2009). Wnt pathway, an essential role in bone regeneration. J Cell Biochem, 106(3): 353-362

18 Cipriano C A, Issack P S, Shindle L, Werner C M, Helfet D L, Lane J M (2009). Recent advances toward the clinical application of PTH (1-34) in fracture healing. HSS J, 5(2): 149-153

19 Cunningham V J, D'Apice M R, Licata N, Novelli G, Cundy T (2010). Skeletal phenotype of mandibuloacral dysplasia associated with mutations in ZMPSTE24. Bone, 47(3): 591-597

20 Daley G Q (2010). Stem cells: roadmap to the clinic. J Clin Invest, 120(1): 8-10

21 De Kok I J, Hicok K C, Padilla R J, Young R G, Cooper L F (2006). Effect of vitamin D pretreatment of human mesenchymal stem cells on ectopic bone formation. J Oral Implantol, 32(3): 103-109

22 Delmas P D, Vergnaud P, Arlot M E, Pastoureau P, Meunier P J, Nilssen M H (1995). The anabolic effect of human PTH (1-34) on bone formation is blunted when bone resorption is inhibited by the bisphosphonate tiludronate—is activated resorption a prerequisite for the in vivo effect of PTH on formation in a remodeling system? Bone, 16(6): 603-610

23 Derubeis A R, Mastrogiacomo M, Cancedda R, Quarto R (2003). Osteogenic potential of rat spleen stromal cells. Eur J Cell Biol, 82(4): 175-181

24 Ding G, Liu Y, An Y, Zhang C, Shi S, Wang W, Wang S (2010). Suppression of T cell proliferation by root apical papilla stem cells in vitro. Cells Tissues Organs, 191(5): 357-364

25 Duailibi M T, Duailibi S E, Young C S, Bartlett J D, Vacanti J P, Yelick P C (2004). Bioengineered teeth from cultured rat tooth bud cells. J Dent Res, 83(7): 523-528

26 Duan X, Tu Q, Zhang J, Ye J, Sommer C, Mostoslavsky G, David K, Yang P, Chen J (2010). Application of induced pluripotent stem (iPS) cells in periodontal tissue regeneration. J Cellular Physiol, DOI: 10.1002/jcp.22316

27 Elçin Y M, Inanç B, Elçin A E (2010). Human embryonic stem cell differentiation on periodontal ligament fibroblasts. Methods Mol Biol, 584: 269-281

28 Fang D, Seo B M, Liu Y, Sonoyama W, Yamaza T, Zhang C, Wang S, Shi S (2007). Transplantation of mesenchymal stem cells is an optimal approach for plastic surgery. Stem cells, (Dayton, Ohio), 25, 1021-1028

29 Ferrari S (2009). [Bone remodeling: new therapeutic approaches]. Rev Med Suisse, 5(207): 1325-1328

30 Fracon R N, Teófilo J M, Satin R B, Lamano T (2008). Prostaglandins and bone: potential risks and benefits related to the use of nonsteroidal anti-inflammatory drugs in clinical dentistry. J Oral Sci, 50(3): 247-252

31 Friedenstein A J, Chailakhjan R K, Lalykina K S (1970). The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet, 3(4): 393-403

32 Friedenstein A J, Petrakova K V, Kurolesova A I, Frolova G P (1968). Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation, 6(2): 230-247

33 Friedenstein A J, Piatetzky-Shapiro I I, Petrakova K V (1966). Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol, 16(3): 381-390

34 Gronthos S, Mankani M, Brahim J, Robey P G, Shi S (2000). Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A, 97(25): 13625-13630

35 Heitz-Mayfield L J, Lang N P (2004). Antimicrobial treatment of peri-implant diseases. Int J Oral Maxillofac Implants, 19(Suppl): 128-139

36 Hoeppner L H, Secreto F J, Westendorf J J (2009). Wnt signaling as a therapeutic target for bone diseases. Expert Opin Ther Targets, 13(4): 485-496

37 Holmes C, Khan T S, Owen C, Ciliberti N, Grynpas M D, Stanford W L (2007). Longitudinal analysis of mesenchymal progenitors and bone quality in the stem cell antigen-1-null osteoporotic mouse. J Bone Miner Res, 22(9): 1373-1386

38 Horwitz E M, Gordon P L, Koo W K, Marx J C, Neel M D, McNall R Y, Muul L, Hofmann T (2002). Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci U S A, 99(13): 8932-8937

39 Huang K Y, Chang J K, Ling S Y, Endo N, Takahashi H E (2000). Epidemiology of cervical and trochanteric fractures of the proximal femur in 1996 in Kaohsiung City, Taiwan. J Bone Miner Metab, 18(2): 89-95

40 Itasaki N, Hoppler S (2010). Crosstalk between Wnt and bone morphogenic protein signaling: a turbulent relationship. Dev Dyn, 239(1): 16-33

41 Jethva R, Otsuru S, Dominici M, Horwitz E M (2009). Cell therapy for disorders of bone. Cytotherapy, 11(1): 3-17

42 Johnson M L (2004). The high bone mass family—the role of Wnt/Lrp5 signaling in the regulation of bone mass. J Musculoskelet Neuronal Interact, 4(2): 135-138

43 Jung Y, Song J, Shiozawa Y, Wang J, Wang Z, Williams B, Havens A, Schneider A, Ge C, Franceschi R T, McCauley L K, Krebsbach P H, Taichman R S (2008). Hematopoietic stem cells regulate mesenchymal stromal cell induction into osteoblasts thereby participating in the formation of the stem cell niche. Stem Cells, 26(8): 2042-2051

44 Kaback L A, Soung Y, Naik A, Geneau G, Schwarz E M, Rosier R N, O’Keefe R J, Drissi H (2008). Teriparatide (1-34 human PTH) regulation of osterix during fracture repair. J Cell Biochem, 105(1): 219-226

45 Kärner E, Unger C, Cerny R, Ahrlund-Richter L, Ganss B, Dilber M S, Wendel M (2009). Differentiation of human embryonic stem cells into osteogenic or hematopoietic lineages: a dose-dependent effect of osterix over-expression. J Cell Physiol, 218(2): 323-333

46 Karsdal M A, Neutzsky-Wulff A V, Dziegiel M H, Christiansen C, Henriksen K (2008). Osteoclasts secrete non-bone derived signals that induce bone formation. Biochem Biophys Res Commun, 366(2): 483-488

47 Katoh M (2007). Networking of WNT, FGF, Notch, BMP, and Hedgehog signaling pathways during carcinogenesis. Stem Cell Rev, 3(1): 30-38

48 Khan A A, Sándor G K, Dore E, Morrison A D, Alsahli M, Amin F, Peters E, Hanley D A, Chaudry S R, Lentle B, Dempster D W, Glorieux F H, Neville A J, Talwar R M, Clokie C M, Mardini M A, Paul T, Khosla S, Josse R G, Sutherland S, Lam D K, Carmichael R P, Blanas N, Kendler D, Petak S, Ste-Marie L G, Brown J, Evans A W, Rios L, Compston J E, and the Canadian Taskforce on Osteonecrosis of the Jaw (2009). Bisphosphonate associated osteonecrosis of the jaw. J Rheumatol, 36(3): 478-490

49 Kim S, Kim S S, Lee S H, Eun Ahn S, Gwak S J, Song J H, Kim B S, Chung H M (2008). In vivo bone formation from human embryonic stem cell-derived osteogenic cells in poly(d,l-lactic-co-glycolic acid)/hydroxyapatite composite scaffolds. Biomaterials, 29(8): 1043-1053

50 Klüppel M, Wrana J L (2005). Turning it up a Notch: cross-talk between TGF beta and Notch signaling. Bioessays, 27(2): 115-118

51 Koh A J, Demiralp B, Neiva K G, Hooten J, Nohutcu R M, Shim H, Datta N S, Taichman R S, McCauley L K (2005). Cells of the osteoclast lineage as mediators of the anabolic actions of parathyroid hormone in bone. Endocrinology, 146(11): 4584-4596

52 Kubota T, Michigami T, Ozono K (2009). Wnt signaling in bone metabolism. J Bone Miner Metab, 27(3): 265-271

53 Lee K W, Yook J Y, Son M Y, Kim M J, Koo D B, Han Y M, Cho Y S (2010). Rapamycin promotes the osteoblastic differentiation of human embryonic stem cells by blocking the mTOR pathway and stimulating the BMP/Smad pathway. Stem Cells Dev, 19(4): 557-568

54 Li F, Bronson S, Niyibizi C (2010). Derivation of murine induced pluripotent stem cells (iPS) and assessment of their differentiation toward osteogenic lineage. J Cell Biochem, 109(4): 643-652

55 Li M, Ke H Z, Qi H, Healy D R, Li Y, Crawford D T, Paralkar V M, Owen T A, Cameron K O, Lefker B A, Brown T A, Thompson D D (2003). A novel, non-prostanoid EP2 receptor-selective prostaglandin E2 agonist stimulates local bone formation and enhances fracture healing. J Bone Miner Res, 18(11): 2033-2042

56 Li M, Thompson D D, Paralkar V M (2007). Prostaglandin E(2) receptors in bone formation. Int Orthop, 31(6): 767-772

57 Liu B, Wang J, Chan K M, Tjia W M, Deng W, Guan X, Huang J D, Li K M, Chau P Y, Chen D J, Pei D, Pendas A M, Cadiñanos J, López-Otín C, Tse H F, Hutchison C, Chen J, Cao Y, Cheah K S, Tryggvason K, Zhou Z (2005). Genomic instability in laminopathy-based premature aging. Nat Med, 11(7): 780-785

58 Liu X, Pettway G J, McCauley L K, Ma P X (2007). Pulsatile release of parathyroid hormone from an implantable delivery system. Biomaterials, 28(28): 4124-4131

59 Liu Y, Zheng Y, Ding G, Fang D, Zhang C, Bartold P M, Gronthos S, Shi S, Wang S (2008). Periodontal ligament stem cell-mediated treatment for periodontitis in miniature swine. Stem Cells, 26(4): 1065-1073

60 Luo L Z, Xu L (2005). Study on direct economic-burden and its risk factors of osteoporotic hip fracture. Zhonghua Liuxingbingxue Zazhi, 26, 669-672

61 Mahmood A, Harkness L, Schrøder H D, Abdallah B M, Kassem M (2010). Enhanced differentiation of human embryonic stem cells to mesenchymal progenitors by inhibition of TGF-beta/activin/nodal signaling using SB-431542. J Bone Miner Res, 25(6): 1216-1233

62 Marsell R, Jonsson K B, Cho T J, Einhorn T A, Ohlsson C, Schipani E (2007). Mice expressing a constitutively active PTH/PTHrP receptor in osteoblasts show reduced callus size but normal callus morphology during fracture healing. Acta Orthop, 78(1): 39-45

63 Martin T J, Seeman E (2008). Bone remodelling: its local regulation and the emergence of bone fragility. Best Prac Res, 22, 701-722

64 Martin T, Gooi J H, Sims N A (2009). Molecular mechanisms in coupling of bone formation to resorption. Crit Rev Eukaryot Gene Expr, 19(1): 73-88

65 Mendes S C, Tibbe J M, Veenhof M, Both S, Oner F C, van Blitterswijk C A, de Bruijn J D (2004). Relation between in vitro and in vivo osteogenic potential of cultured human bone marrow stromal cells. J Mater Sci Mater Med, 15(10): 1123-1128

66 Méndez-Ferrer S, Michurina T V, Ferraro F, Mazloom A R, Macarthur B D, Lira S A, Scadden D T, Ma’ayan A, Enikolopov G N, Frenette P S (2010). Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature, 466(7308): 829-834

67 Miura M, Gronthos S, Zhao M, Lu B, Fisher L W, Robey P G, Shi S (2003). SHED: stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci U S A, 100(10): 5807-5812

68 Miura Y, Miura M, Gronthos S, Allen M R, Cao C, Uveges T E, Bi Y, Ehirchiou D, Kortesidis A, Shi S, Zhang L (2005). Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis. Proc Natl Acad Sci U S A, 102(39): 14022-14027

69 Mizoguchi F, Izu Y, Hayata T, Hemmi H, Nakashima K, Nakamura T, Kato S, Miyasaka N, Ezura Y, Noda M (2010). Osteoclast-specific Dicer gene deficiency suppresses osteoclastic bone resorption. J Cell Biochem, 109(5): 866-875

70 Mukherjee S, Raje N, Schoonmaker J A, Liu J C, Hideshima T, Wein M N, Jones D C, Vallet S, Bouxsein M L, Pozzi S, Chhetri S, Seo Y D, Aronson J P, Patel C, Fulciniti M, Purton L E, Glimcher L H, Lian J B, Stein G, Anderson K C, Scadden D T (2008). Pharmacologic targeting of a stem/progenitor population in vivo is associated with enhanced bone regeneration in mice. J Clin Invest, 118(2): 491-504

71 Murray P E, Garcia-Godoy F (2004). Stem cell responses in tooth regeneration. Stem Cells Dev, 13(3): 255-262

72 Nakagawa M, Koyanagi M, Tanabe K, Takahashi K, Ichisaka T, Aoi T, Okita K, Mochiduki Y, Takizawa N, Yamanaka S (2008). Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat Biotechnol, 26(1): 101-106

73 Ohazama A, Courtney J M, Tucker A S, Naito A, Tanaka S, Inoue J, Sharpe P T (2004). Traf6 is essential for murine tooth cusp morphogenesis. Dev Dyn, 229(1): 131-135

74 Okita K, Nakagawa M, Hyenjong H, Ichisaka T, Yamanaka S (2008). Generation of mouse induced pluripotent stem cells without viral vectors. Science, 322(5903): 949-953

75 Paralkar V M, Borovecki F, Ke H Z, Cameron K O, Lefker B, Grasser W A, Owen T A, Li M, DaSilva-Jardine P, Zhou M, Dunn R L, Dumont F, Korsmeyer R, Krasney P, Brown T A, Plowchalk D, Vukicevic S, Thompson D D (2003). An EP2 receptor-selective prostaglandin E2 agonist induces bone healing. Proc Natl Acad Sci U S A, 100(11): 6736-6740

76 Park S H, Wang H L (2005). Implant reversible complications: classification and treatments. Implant Dent, 14(3): 211-220

77 Raaijmakers M H, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker J A, Ebert B L, Al-Shahrour F, Hasserjian R P, Scadden E O, Aung Z, Matza M, Merkenschlager M, Lin C, Rommens J M, Scadden D T (2010). Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature, 464(7290): 852-857

78 Raisz L G (1999). Prostaglandins and bone: physiology and pathophysiology. Osteoarthritis and cartilage/OARS. Osteoarthritis Research Society, 7: 419-421

79 Raisz L G (2005). Pathogenesis of osteoporosis: concepts, conflicts, and prospects. J Clin Invest, 115(12): 3318-3325

80 Rivas D, Li W, Akter R, Henderson J E, Duque G (2009). Accelerated features of age-related bone loss in zmpste24 metalloproteinase-deficient mice. J Gerontology, 64A, 1015-1024

81 Rowe D, Lichtler A (2002). A strategy for identifying osteoporosis risk genes. Endocrine, 17(1): 67-75

82 Rozen N, Lewinson D, Bick T, Jacob Z C, Stein H, Soudry M (2007). Fracture repair: modulation of fracture-callus and mechanical properties by sequential application of IL-6 following PTH 1-34 or PTH 28-48. Bone, 41(3): 437-445

83 Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, Tagliafico E, Ferrari S, Robey P G, Riminucci M, Bianco P (2007). Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell, 131(2): 324-336

84 Sahlgren C, Lendahl U (2006). Notch signaling and its integration with other signaling mechanisms. Regen Med, 1(2): 195-205

85 Secreto F J, Hoeppner L H, Westendorf J J (2009). Wnt signaling during fracture repair. Curr Osteoporos Rep, 7(2): 64-69

86 Seo B M, Miura M, Gronthos S, Bartold P M, Batouli S, Brahim J, Young M, Robey P G, Wang C Y, Shi S (2004). Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet, 364(9429): 149-155

87 Shi S, Bartold P M, Miura M, Seo B M, Robey P G, Gronthos S (2005). The efficacy of mesenchymal stem cells to regenerate and repair dental structures. Orthod Craniofac Res, 8(3): 191-199

88 Sonoyama W, Liu Y, Fang D, Yamaza T, Seo B M, Zhang C, Liu H, Gronthos S, Wang C Y, Wang S, Shi S (2006). Mesenchymal stem cell-mediated functional tooth regeneration in swine. PLoS One, 1: e79

89 Stevenson K, McGlynn L, Shiels P G (2009). Stem cells: outstanding potential and outstanding questions. Scott Med J, 54(4): 35-37

90 Sudo K, Kanno M, Miharada K, Ogawa S, Hiroyama T, Saijo K, Nakamura Y (2007). Mesenchymal progenitors able to differentiate into osteogenic, chondrogenic, and/or adipogenic cells in vitro are present in most primary fibroblast-like cell populations. Stem Cells, 25(7): 1610-1617

91 Takada I, Kouzmenko A P, Kato S (2009). Wnt and PPARgamma signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol, 5(8): 442-447

92 Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, Yamanaka S (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5): 861-872

93 Takahashi K, Yamanaka S (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4): 663-676

94 Tamaoki N, Takahashi K, Tanaka T, Ichisaka T, Aoki H, Takeda-Kawaguchi T, Iida K, Kunisada T, Shibata T, Yamanaka S, Tezuka K (2010). Dental pulp cells for induced pluripotent stem cell banking. J Dent Res, 89(8): 773-778

95 Tamura M, Nemoto E, Sato M M, Nakashima A, Shimauchi H (2010). Role of the Wnt signaling pathway in bone and tooth. Frontiers in bioscience (Elite edition), 2: 1405-1413

96 Tanaka M, Sakai A, Uchida S, Tanaka S, Nagashima M, Katayama T, Yamaguchi K, Nakamura T (2004). Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats. Bone, 34(6): 940-948

97 Thesleff I (2003). Developmental biology and building a tooth. Quintessence Int, 34(8): 613-620

98 Thyagarajan B, Scheyhing K, Xue H, Fontes A, Chesnut J, Rao M, Lakshmipathy U (2009). A single EBV-based vector for stable episomal maintenance and expression of GFP in human embryonic stem cells. Regen Med, 4(2): 239-250

99 Tong W, Brown S E, Krebsbach P H (2007). Human Embryonic Stem Cells Undergo Osteogenic Differentiation in Human Bone Marrow Stromal Cell Microenvironments. J Stem Cells, 2, 139-147

100 Van den Wyngaert T, Huizing M T, Vermorken J B (2006). Bisphosphonates and osteonecrosis of the jaw: cause and effect or a post hoc fallacy? Ann Oncol, 17(8): 1197-1204

101 Vassiliou V, Tselis N, Kardamakis D (2010). Osteonecrosis of the jaws: clinicopathologic and radiologic characteristics, preventive and therapeutic strategies. Strahlenther Onkol, 186(7): 367-373

102 Walker E C, McGregor N E, Poulton I J, Pompolo S, Allan E H, Quinn J M, Gillespie M T, Martin T J, Sims N A (2008). Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling. J Bone Miner Res, 23(12): 2025-2032

103 Wang S, Liu Y, Fang D, Shi S (2007). The miniature pig: a useful large animal model for dental and orofacial research. Oral Dis, 13(6): 530-537

104 Warden S J, Komatsu D E, Rydberg J, Bond J L, Hassett S M (2009). Recombinant human parathyroid hormone (PTH 1-34) and low-intensity pulsed ultrasound have contrasting additive effects during fracture healing. Bone, 44(3): 485-494

105 Wataru S, Kazuomi S, Yoshikazu N, Hiroaki I, Takaharu Y, Hideki Y (2005). Three-dimensional morphological analysis of humeral heads: a study in cadavers. Acta Orthop, 76(3): 392-396

106 Weber J M, Calvi L M (2010). Notch signaling and the bone marrow hematopoietic stem cell niche. Bone, 46(2): 281-285

107 Wei G, Pettway G J, McCauley L K, Ma P X (2004). The release profiles and bioactivity of parathyroid hormone from poly(lactic-co-glycolic acid) microspheres. Biomaterials, 25(2): 345-352

108 Woo D G, Shim M S, Park J S, Yang H N, Lee D R, Park K H (2009). The effect of electrical stimulation on the differentiation of hESCs adhered onto fibronectin-coated gold nanoparticles. Biomaterials, 30(29): 5631-5638

109 Wu X, Ding S, Ding Q, Gray N S, Schultz P G (2002). A small molecule with osteogenesis-inducing activity in multipotent mesenchymal progenitor cells. J Am Chem Soc, 124(49): 14520-14521

110 Xu C, Jiang J, Sottile V, McWhir J, Lebkowski J, Carpenter M K (2004). Immortalized fibroblast-like cells derived from human embryonic stem cells support undifferentiated cell growth. Stem Cells, 22(6): 972-980

111 Xu L, Lu A, Zhao X, Chen X, Cummings S R (1996). Very low rates of hip fracture in Beijing, People’s Republic of China the Beijing Osteoporosis Project. Am J Epidemiol, 144(9): 901-907

112 Yadav V K, Ducy P (2010). Lrp5 and bone formation : A serotonin-dependent pathway. Ann N Y Acad Sci, 1192(1): 103-109

113 Yan L, Zhou B, Prentice A, Wang X, Golden M H (1999). Epidemiological study of hip fracture in Shenyang, People’s Republic of China. Bone, 24(2): 151-155

114 Yan X, Qin H, Qu C, Tuan R S, Shi S, Huang G T (2010). iPS cells reprogrammed from human mesenchymal-like stem/progenitor cells of dental tissue origin. Stem Cells Dev, 19(4): 469-480

115 Yin D, Wang Z, Gao Q, Sundaresan R, Parrish C, Yang Q, Krebsbach P H, Lichtler A C, Rowe D W, Hock J, Liu P (2009). Determination of the fate and contribution of ex vivo expanded human bone marrow stem and progenitor cells for bone formation by 2.3ColGFP. Mol Ther, 17(11): 1967-1978

116 Young C S, Abukawa H, Asrican R, Ravens M, Troulis M J, Kaban L B, Vacanti J P, Yelick P C (2005). Tissue-engineered hybrid tooth and bone. Tissue Eng, 11(9-10): 1599-1610

117 Young C S, Terada S, Vacanti J P, Honda M, Bartlett J D, Yelick P C (2002). Tissue engineering of complex tooth structures on biodegradable polymer scaffolds. J Dent Res, 81(10): 695-700

118 Zanotti S, Canalis E (2010). Notch and the skeleton. Mol Cell Biol, 30(4): 886-896

119 Zhao X Y, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Guo C L, Ma Q W, Wang L, Zeng F, Zhou Q (2009). iPS cells produce viable mice through tetraploid complementation. Nature, 461(7260): 86-90

120 Zhao X Y, Li W, Lv Z, Liu L, Tong M, Hai T, Hao J, Wang X, Wang L, Zeng F, Zhou Q (2010a). Viable fertile mice generated from fully pluripotent iPS cells derived from adult somatic cells. Stem Cell Rev, 6(3): 390-397

121 Zhao X Y, Lv Z, Li W, Zeng F, Zhou Q (2010b). Production of mice using iPS cells and tetraploid complementation. Nat Protoc, 5(5): 963-971

122 Zheng Y, Liu Y, Zhang C M, Zhang H Y, Li W H, Shi S, Le A D, Wang S L (2009). Stem cells from deciduous tooth repair mandibular defect in swine. J Dent Res, 88(3): 249-254

123 Zhu H, Zhang Y, Ge H, (2004). Investigation of milk product consuming and the prevalence of spine fracture in elderly women. Proceeding of the 3rd. Shanghai Osteoporosis Symposium, 7: 146

124 Zippel N, Schulze M, Tobiasch E (2010). Biomaterials and mesenchymal stem cells for regenerative medicine. Recent Pat Biotechnol, 4(1): 1-22