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Study on therapeutic effects of porcine induced pluripotent stem cells in preclinical models of osteoporosis
|關鍵字:||誘導多能性幹細胞;成骨細胞;骨質疏鬆症;大鼠;蘭嶼豬;induced pluripotent stem cells;osteoblasts;osteoporosis;rats;Lanyu pigs||引用:||石力、郭紘志。2011。建立多能性幹細胞株的方式與技術發展。中國畜牧學會會誌。40（3）：141–157。 陳立人、吳明哲、王建平。1991a。哺乳動物胚幹細胞之體外培養（II）小鼠與豬囊胚衍生物之體外培養。中國畜牧學會會誌。20（3）：327–339。 陳立人、吳明哲、許登造。1991b。分離小鼠與豬囊胚內細胞群之兔抗血清的製備。中國畜牧學會會誌。20（1）：61–67。 楊鎮榮。2012。豬胚幹細胞應用於帕金森氏症治療之研究。農業生技產業季刊。31: 44-51。 錢宗良。2008。幹細胞學。幹細胞與組織工程教學資源中心。台北市。 Adinoff, A. D., and J. R. Hollister. 1983. Steroid-induced fractures and bone loss in patients with asthma. N. Engl. J. Med. 309:265–268. Ahn, S. E., S. Kim, K. H. Park, S. H. Moon, H. J. Lee, G. J. Kim, Y. J. Lee, K. H. Park, K. Y. Cha, and H. M. Chung. 2006. Primary bone-derived cells induce osteogenic differentiation without exogenous factors in human embryonic stem cells. Biochem. Biophys. Res. Commun. 340:403–408. Akahoshi S., A. Sakai, S. Arita, S. Ikeda, Y. Morishita, H. Tsutsumi, M. Ito, A. Shiraishi, and T. Nakamura. 2005. Modulation of bone turnover by alfacalcidol and/or alendronate does not prevent glucocorticoid-induced osteoporosis in growing minipigs. J. Bone Miner. Metab. 23:341–350. Allen, N. D., S. C. Barton, K. Hilton, M. L. Norris, and M. A. Surani. 1994. A functional analysis of imprinting in parthenogenetic embryonic stem cells. Development 120:1473–1482. Ammann, P., and R. Rizzoli. 2003. Bone strength and its determinants. Osteoporos. Int. 14:S13–S18. Anderson, G. B., S. J. Choi, and R. H. Bondurant. 1994. Survival of porcine inner cell masses in culture and after injection into blastocysts. Theriogenology 42:204–212. Antebi, B., G. Pelled, and D. Gazit. 2014. Stem Cell Therapy for Osteoporosis. Curr. Osteoporos. Rep. 12:41–47. AOAC. 2016. Official Methods of Analysis. 20th ed. Assoc. Offic. Anal. Chem., Arlington, VA, USA. Arpornmaeklong, P., Z. Wang, M. J. Pressler, S. E. Brown, and P. H. KrEBbach. 2010. Expansion and characterization of human embryonic stem cell-derived osteoblast-like cells. Cell. Reprogram. 12:377–389. Arrigoni, E., S. Lopa, L. de Girolamo, D. Stanco, and A. T. Brini. 2009. Isolation, characterization and osteogenic differentiation of adiposederived stem cells: from small to large animal models. Cell Tissue Res. 338:401–411. Bagi, C. M., M. Mecham, J. Weis, and S. C. Miller. 1993. Comparative morphometric changes in rat cortical bone following ovariectomy and/ or immobilization. Bone 14:877–883. Baofeng, L., Y. Zhi, C. Bei, M. Guolin, Y. Qingshui, and L. Jian. 2010. Characterization of a rabbit osteoporosis model induced by ovariectomy and glucocorticoid. Acta Orthop. 81:396–401. Bauss, F., and R. Schimmer. 2006. Ibandronate: the first once-monthly oral bisphosphonate for treatment of postmenopausal osteoporosis. Ther. Clin. Risk Manag. 2:3-18. Bielby, R. C., A. R. Boccaccini, J. M. Polak, and L. D. Buttery. 2004. In vitro differentiation and in vivomineralization of osteogenic cells derived from human embryonic stem cells. Tissue Eng. 10:1518–1525. Birkebaek, N. H., G. Esberg, K. Andersen, O. Wolthers, and C. Hassager. 1995. Bone and collagen turnover during treatment with inhaled dry powder budesonide and beclomethasone dispropionate. Arch. Dis. Child. 73:524–527. Blum, B., and N. Benvenisty. 2008. The tumorigenicity of human embryonic stem cells. Adv. Cancer. Res. 100:133–158. Bock, C., E. Kiskinis, G. Verstappen, H. Gu, G. Boulting, Z. D. Smith, M. Ziller, G. F. Croft, M. W. Amoroso, D. H. Oakley, A. Gnirke, K. Eggan, and A. Meissner. 2011. Reference maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines. Cell 144:439–452. Bone, H. G., D. Hosking, J. P. Devogelaer, J. R. Tucci, R. D. Emkey, R. P. Tonino, J. A. Rodriguez-Portales, R. W. Downs, J. Gupta, A. C. Santora, and U. A. Liberman. 2004. Alendronate phase III osteoporosis treatment study group ten years' experience with alendronate for osteoporosis in post-menopausal women. N. Engl. J. Med. 350:1189–1199. Bonjour, J. P., P. Ammann, and R. And Rizzoli. 1999. Importance of preclinical studies in the development of drugs for treatment of osteoporosis: a review related to the 1998 WHO guidelines. Osteoporos. Int. 9:379–393. Boonen, S., and A. J. Singer. 2008. Osteoporosis management: impact of fracture type on cost and quality of life in patients at risk for fracture I. Curr. Med. Res. Opin. 24:1781–1788. Borah, B., T. E. Dufresne, P. A. Chmielewski, G. J. Gross, M. C. Prenger, and R. J. Phipps. 2002. Risedronate preserves trabecular architecture and increases bone strength in vertebra of ovariectomized minipigs as measured by three-dimensional microcomputed tomography. J. Bone Miner. Res. 17:1139–1147. Bouchard, G. F., R. W. Boyce, C. L. Paddock, E. Durham, and C. S. Reddy. 1996. Evaluation of Sinclair miniature swine as an osteopenia model. Page 647–651 in Advances in Swine in Biomedical Research. Tumbleson, M. E., and L. B. Schook, eds. Plenum Press, NY, USA. Boulting, G. L., E. Kiskinis, G. F. Croft, M. W. Amoroso, D. H. Oakley, B. J. Wainger, D. J. Williams, D. J. Kahler, M. Yamaki, L. Davidow, C. T. Rodolfa, J. T. Dimos, S. Mikkilineni, A. B. MacDermott, C. J. Woolf, C. E. Henderson, H. Wichterle, and K. Eggan. 2011. A functionally characterized test set of human induced pluripotent stem cells. Nat. Biotechnol. 29:279–286. Bouvard, B., E. Legrand, M. Audran, and D. Chappard. 2010. Glucocorticoid-induced osteoporosis: a review. Clinic. Rev. Bone Miner. Metab. 8:15–26. Bouxsein, M. L., S. K. Boyd, B. A. Christiansen, R. E. Guldberg, K. J. Jepsen, and R. Müller. 2010. Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. J. Bone Miner. Res. 25:1468–1486. Brack, A. S., and T. A. Rando. 2007. Intrinsic changes and extrinsic influences of myogenic stem cell function during aging. Stem Cell Rev. 3:226–237. Brandl, U., S. Michel, M. Erhardt, P. Brenner, L. Burdorf, H. Jöckle, I. Bittmann, M. Rössle, V. Mordstein, H. Baschnegger, A. Bauer, C. Hammer, B. Reichart, and M. Schmoeckel. 2007. Transgenic animals in experimental xenotransplantation models: Orthotopic heart transplantation in the pig-to-baboon model. Transplant. Proc. 39:577–578. Breton, A., R. Sharma, A. C. Diaz, A. G. Parham, A. Graham, C. Neil, C. B. Whitelaw, E. Milne, and F. X. Donadeu. 2013. Derivation and characterization of induced pluripotent stem cells from equine fibroblasts. Stem Cells Dev. 22:611–621. Brevini, T. A., and F. Gandolfi. 2008. Parthenotes as a source of embryonic stem cells. Cell Prolif. 41:20–30. Brevini, T. A. L., S. Antonini, F. Cillo, M. Crestan, and F. Gandolfi. 2007. Porcine embryonic stem cells: Facts, challenges and hopes. Theriogenology 68S:S206–S213. Cao, T., B. C. Heng, C. P. Ye, H. Liu, W. S. Toh, P. Robson, P. Li, Y. H. Hong, and L. W. Stanton. 2005. Osteogenic differentiation within intact human embryoid bodies result in a marked increase in osteocalcin secretion after 12 days of in vitro culture, and formation of morphologically distinct nodule-like structures. Tissue Cell. 37:325–334. Celil, A. B., and P. G. Campbell. 2005. BMP-2 and insulin-like growth factor-I mediate Osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways. J. Biol. Chem. 280:31353–31359. Chen, L. R., Y. L. Shiue, L. Bertolini, J. F. Merdrano, R. H. BonDurant, and G. B. Anderson. 1999. Establishment of pluripotent cell lines from porcine preimplantation embryos. Theriogenology 52:195–212. Chen, Y., M. Shimizu, K. Sato, M. Koto, K. Tsunemi, T. Yoshida, and Y. Yoshikawa. 2000. Effects of aging on bone mineral content and bone biomarkers in female cynomolgus monkeys. Exp. Anim. 49:163–170. Chin, M. H., M. J. Mason, W. Xie, S. Volinia, M. Singer, C. Peterson, G. Ambartsumyan, O. Aimiuwu, L. Richter, J. Zhang, I. Khvorostov, V. Ott, M. Grunstein, N. Lavon, N. Benvenisty, C. M. Croce, A. T. Clark, T. Baxter, A. D. Pyle, M. A. Teitell, M. Pelegrini, K. Plath, and W. E. Lowry. 2009. Induced pluripotent stem cells and embryonic stem cells are distinguished by gene expression signatures. Cell Stem Cell 5:111–123. Chung, Y., I. Klimanskaya, S. Becker, J. Marh, S. J. Lu, J. Johnson, L. Meisner, and R. Lanza. 2006. Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres. Nature 439:216–219. Creedon, A., and K. D. Cashman. 2001. The effect of calcium intake on bone composition and bone resorption in the young growing rat. Br. J. Nutr. 86: 453–459. Cummings, S. R., and L. J. Melton. 2002. Epidemiology and outcomes of osteoporotic fractures. Lancet 359:1761–1767. Cushing, H. 1994. The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism). 1932. Obes. Res. 2:486–508. Dalle Carbonare, L., M. E. Arlot, P. M. Chavassieux, J. P. Roux, N. R. Portero, and P. J. Meunier. 2001. Comparison of trabecular bone microarchitecture and remodeling in glucocorticoid-induced and postmenopausal osteoporosis. J. Bone Miner. Res. 16:97–103. Dalle Carbonare, L., M. T. Valenti, F. Bertoldo, M. Zanatta, S. Zenari, G. Realdi, V. Lo Cascio, and S. Giannini. 2005. Bone microarchitecture evaluated by histomorphometry. Micron 36:609–616. Dani, C., A. G. Smith, S. Dessolin, P. Leroy, L. Staccini, P. Villageois, C. Darimont, and G. Ailhaud. 1997. Differentiation of embryonic stem cells into adipocytes in vitro. J. Cell Sci. 110:1279–1285. Davis, R. L., H. Weintraub, and A. B. Lassar. 1987. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell 51:987–1000. De Vos, P., R. Saladin, J. Auwerx, and B. Staels. 1995. Induction of ob gene expression by corticosteroids is accompanied by body weight loss and reduced food intake. J. Biol. Chem. 270:15958–15961. Dempster, D. 2002. Bone remodeling. Page 315–343 in Disorders of Bone and Mineral Metabolism. Coe, F., and M. Favus, eds. Lippincott Williams & Wilkins, Baltimore, MD, USA. Dempster, D., and R. Lindsay. 1993. Pathogenesis of osteoporosis. Lancet 341:797–801. Deng, J., R. Shoemaker, B. Xie, A. Gore, E. M. LeProust, J. Antosiewicz-Bourget, D. Egli, N. Maherali, I. H. Park, J. Yu, G. Q. Daley, K. Eggan, K. Hochedlinger, J. Thomson, W. Wang, Y. Gao, and K. Zhang. 2009. Targeted bisulfate sequencing reveals changes in DNA methylation associated with nuclear reprogramming. Nat. Biotechnol. 27:353–360. Dennison, E., Z. Cole, and C. Cooper. 2005. Diagnosis and epidemiology of osteoporosis. Curr. Opin. Rheumatol. 17:456–461. Desponts, C., and S. Ding. 2010. Using small molecules to improve generation of induced pluripotent stem cells from somatic cells. Methods Mol. Biol. 636:207–218. Dimitriou, R., E. Tsiridis, and P. V. Giannoudis. 2005. Current concepts of molecular aspects of bone healing. Injury 36:1392–1404. Ding, M., L. Cheng, P. Bollen, P. Schwarz, and S. Overgaard. 2010. Glucocorticoid induced osteopenia in cancellous bone of sheep: validation of large animal model for spine fusion and biomaterial research. Spine (Phila Pa 1976) 35:363–370. Doi, A., I. H. Park, B. Wen, P. Murakami, M. J. Aryee, R. Irizarry, B. Herb, C. Ladd-Acosta, J. Rho, S. Loewer, J. Miller, T. Schlaeger, G. Q. Daley, and A. P. Feinberg. 2009. Differential methylation of tissue- and cancer-specific CpG island shores distinguishes human induced pluripotent stem cells, embryonic stem cells and fibroblasts. Nat. Genet. 41:1350–1353. Duplomb, L., M. Dagouassat, P. Jourdon, and D. Heymann. 2007a. Differentiation of osteoblasts from mouse embryonic stem cells without generation of embryoid body. In Vitro Cell Dev. Biol. Anim. 43:21–24. Duplomb, L., M. Dagouassat, P. Jourdon, and D. Heymann. 2007b. Concise review: embryonic stem cells: a new tool to study osteoblast and osteoclast differentiation. Stem Cells 25:544–552. Einhorn, T. A. 2005. The science of fracture healing. J. Orthop. Trauma 19:S4–S6. Eriksen, E. 1986. Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease. Endocr. Rev. 7:379–408. Ersek, A., A. I. Santo, Y. Vattakuzhi, S. George, A. R. Clark, and N. J. Horwood. 2016. Strain dependent differences in glucocorticoid-induced bone loss between C57BL/6J and CD-1 mice. Sci. Rep. 6:36513. Esteban, M. A., J. Xu, J. Yang, M. Peng, D. Qin, W. Li, Z. Jiang, J. Chen, K. Deng, M. Zhong, J. Cai, L. Lai, and D. Pei. 2009. Generation of induced pluripotent stem cell lines from tibetan miniature pig. J. Biol. Chem. 284:17634–17640. Evans, M. J., and M. H. Kaufman. 1981. Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156. Ezashi, T., B. P. Telugu, A. P. Alexenko, S. Sachdev, S. Sinha, and R. M. Roberts. 2009. Derivation of induced pluripotent stem cells from pig somatic cells. Proc. Natl. Acad. Sci. U S A. 106:10993–10998. Ezashi, T., Y. Yuan, and R. M. Roberts. 2015. Pluripotent stem cells from domesticated mammals. Annu. Rev. Anim. Biosci. 4:223–253. Fujishiro, S., K. Nakano, Y. Mizukami, T. Azami, Y. Arai, H. Matsunari, R. Ishino, T. Nishimura, M. Watanabe, T. Abe, Y. Furukawa, K. Umeyama, S. Yamanaka, M. Ema, H. Nagashima, and Y. Hanazono. 2013. Generation of naive-like porcine induced pluripotent stem cells capable of contributing to embryonic and fetal development. Stem Cells Dev. 22:473–482. Gadelete, S. J., A. L. Boskey, E. Paschalis, C. Carlson, F. Menschik, T. Baldini, M. Peterson, and C. M. Rimnac. 2000. A physical, chemical, and mechanical study of lumbar vertebrae from normal, ovariectomized, and Nandrolone Decanoate-treated cynomolgus monkeys (Macaca fascicularis). Bone 27:541–550. Gao, X., W. Ma, H. Dong, Z. Yong, and R. Su. 2014. Establishing a rapid animal model of osteoporosis with ovariectomy plus low calcium diet in rats. Int. J. Clin. Exp. Pathol. 7:5123–5128. Gasser, J. A., J. R. Green, V. Shen, P. Ingold, A. Rebman, A. S. Bhatnagar, and D. B. Evans. 2006. A single intravenous administration of zoledronic acid prevents the bone loss and mechanical compromise induced by aromatase inhibition in rats. Bone 39:787–795. Gatti, D., O. Viapiana, E. Fracassi, L. Idolazzi, C. Dartizio, M. R. Povino, S. Adami, and M. Rossini. 2012. Sclerostin and DKK1 in postmenopausal osteoporosis treated with denosumab. J. Bone Miner. Res. 27:2259–2263 . Ghilzon, R., C. A. McCulloch, and R. Zohar. 1999. Stromal mesenchymal progenitor cells. Leuk Lymphoma 32:211–221. Ghosh, Z., K. D. Wilson, Y. Wu, S. Hu, T. Quertermous, and J. C. Wu. 2010. Persistent donor cell gene expression among human induced pluripotent stem cells contributes to differences with human embryonic stem cells. PLoS ONE 5:e8975. Glüer, C. C., K. E. Scholz-Ahrens, A. Helfenstein, G. Delling, W. Timm, Y. Açil, R. Barkmann, J. Hassenpflug, B. Stampa, F. Bauss, and J. Schrezenmeir. 2007. Ibandronate treatment reverses glucocorticoid-induced loss of bone mineral density and strength in minipigs. Bone 40:645–655. Gottlieb, D. I., and J. E. Huettner. 1999. An in vitro pathway from embryonic stem cells to neurons and glia. Cells Tissues Organs 165:165–172. Gropp, M., V. Shilo, G. Vainer, M. Gov, Y. Gil, H. Khaner, L. Matzrafi, M. Idelson, J. Kopolovic, N. B. Zak, and B. E. Reubinoff. 2012. Standardization of the teratoma assay for analysis of pluripotency of human ES cells and biosafety of their differentiated progeny. PLoS One 7:e45532. Guenther, M. G., G. M. Frampton, F. Soldner, D. Hockemeyer, M. Mitalipova, R. Jaenisch, and R. A. Young. 2010. Chromatin structure and gene expression programs of human embryonic and induced pluripotent stem cells. Cell Stem Cell 7:249–257. Gurdon, J. B. 1962. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10:622–640. Hadjidakis, D. J., and I. I. Androulakis. 2006. Bone remodeling. Ann. N. Y. Acad. Sci. 1092:385–396. Hall, V. J., M. Kristensen, M. A. Rasmussen, O. Ujhelly, A. Dinnyés, and P. Hyttel. 2012. Temporal repression of endogenous pluripotency genes during reprogramming of porcine induced pluripotent stem cells. Cell. Reprogram. 14: 204–216. Harvey, N., E. Dennison, and C. Cooper. 2010. Osteoporosis: impact on health and economics. Nat. Rev. Rheumatol. 6:99–105. Heino, T. J., J. J. Alm, N. Moritz, and H. T. Aro. 2012. Comparison of the osteogenic capacity of minipig and human bone marrow-derived mesenchymal stem cells. J. Orthop. Res. 30:1019–1025. Hentze, H., P. L. Soong, S. T. Wang, B. W. Phillips, T. C. Putti, and N. R. Dunn. 2009. Teratoma formation by human embryonic stem cells: evaluation of essential parameters for future safety studies. Stem Cell Res. 2:198–210. Ho, P. J., M. L. Yen, J. D. Lin, L. S. Chen, H. I. Hu, C. K. Yeh, C. Y. Peng, C. Y. Lin, S. F. Yet, and B. L. Yen. 2010. Endogenous KLF4 expression in human fetal endothelial cells allows for reprogramming to pluripotency with just OCT3/4 and SOX2--brief report. Arterioscler. Thromb. Vasc. Biol. 30:1905–1907. Hochereau-de Reviers, M. T., and C. Perreau. 1993. In vitro culture of embryonic disc cells from porcine blastocysts. Reprod. Nutr. Dev. 33:475–483. Hsiao, F. S., C. C. Cheng, S. Y. Peng, H. Y. Huang, W. S. Lian, M. L. Jan, Y. T. Fang, E. C. Cheng, K. H. Lee, W. T. Cheng, S. P. Lin, and S. C. Wu. 2010. Isolation of therapeutically functional mouse bone marrow mesenchymal stem cells within 3 h by an effective singlestep plastic-adherent method. Cell Prolif. 43:235–248. Hsieh, Y. C., P. Intawicha, N. W. Lo, K. H. Lee, and J. C. Ju. 2010. Characterization and applications of embryonic stem cells derived from parthenogenetically activated embryos- A review. J. Agri. Assoc. China 11:580–601. Hu, B. Y., J. P. Weick, J. Yu, L. X. Ma, X. Q. Zhang, J. A. Thomsonm, and S. C. Zhang. 2010. Neural differentiation of human induced pluripotent stem cells follows developmental principles but with variable potency. Proc. Natl. Acad. Sci. USA 107:4335–4340. Hwang, Y. S., W. L. Randle, R. C. Bielby, J. M. Polak, and A. Mantalaris. 2006. Enhanced derivation of osteogenic cells from murine embryonic stem cells after treatment with hepG2-conditioned medium and modulation of the embryoid body formation period: application to skeletal tissue engineering. Tissue Eng. 12:1381–1392. Ikeda, S., Y. Morishita, H. Tsutsumi, M. Ito, A. Shiraishi, S. Arita, S. Akahoshi, K. Narusawa, and T. Nakamura. 2003. Reductions in bone turnover, mineral, and structure associated with mechanical properties of lumbar vertebra and femur in glucocorticoid-treated growing minipigs. Bone 33:779–787. Itoh, F., M. Kojima, H. Furihata-Komatsu, S. Aoyagi, H. Kusama, H. Komatsu, and T. Nakamura. 2002. Reductions in bone mass, structure, and strength in axial and appendicular skeletons associated with increased turnover after ovariectomy in mature cynomolgus monkeys and preventive effects of Clodronate. J. Bone Miner. Res. 17:534–543. Jayo, M. J., C. P. Jerome, C. J. Lees, S. E. Rankin, and D. S. Weaver. 1994. Bone mass in female cynomolgus macaques: A cross-sectional and longitudinal study by age. Calcif. Tissue Int. 54:231–236. Jee, W. S. S., and W. Yao. 2001. Overview: animal models of osteopenia and osteoporosis. J. Musculoskelet. Neuronal Interact. 1:193–207. Jerome, C. P. 1998. Primate models of osteoporosis. Lab. Anim. Sci. 48:618–622. Jerome, C. P., and P. E. Peterson. 2001. Nonhuman primate models in skeletal research. Bone 29:1–6. Jerome, C. P., C. S. Carlson, T. C. Register, F. T. Bain, M. J. Jayo, D. S. Weaver, and M. R. Adams. 1994. Bone functional changes in intact, ovariectomized, and ovariectomized, hormone- supplemented adult cynomolgus monkeys (Macaca fascicularis) evaluated by serum markers and dynamic histomorphometry. J. Bone Miner. Res. 9:527–540. Jerome, C. P., C. S. Johnson, H. T. Vafai, K. C. Kaplan, J. Bailey, B. Capwell, F. Fraser, L. Hansen, H. Ramsay, M. Shadoan, C. J. Lees, and J. S. Thomsen, 1999. Effect of treatment for 6 months with human parathyroid hormone (1–34) peptide in ovariectomozed cynomolgus monkeys (Macaca fascicularis). Bone 25:301–309. Jia, F., K. D. Wilson, N. Sun, D. M. Gupta, M. Huang, Z. Li, N. J. Panetta, Z. Y. Chen, R. C. Robbins, M. A. Kay, M. T. Longaker, and J. C. Wu. 2010. A nonviral minicircle vector for deriving human iPS cells. Nat. Methods 7:197–199. Kanis, J. A., F. Borgstrom, C. De Laet, H. Johansson, O. Johnell, P. Jonsson, A. Oden, N. Zethraeus, B. Pfleger, and N. Khaltaev. 2005. Assessment of fracture risk. Osteoporos. Int. 16:581–589. Kanke, K., H. Masaki, T. Saito, Y. Komiyama, H. Hojo, H. Nakauchi, A. C. Lichtler, T. Takato, U. I. Chung, and S. Ohba. 2014. Stepwise differentiation of pluripotent stem cells into osteoblasts using four small molecules under serum-free and feeder-free conditions. Stem Cell Reports. 2:751–760. Kao, C. F., C. Y. Chuang, C. H. Chen, and H. C. Kuo. 2008. Human pluripotent stem cells: Current status and future perspectives. Chin. J. Physiol. 51:214–225. Karp, J. M., L. S. Ferreira, A. Khademhosseini, A. H. Kwon, J. Yeh, and R. S. Langer. 2006. Cultivation of human embryonic stem cells without the embryoid body step enhances osteogenesis in vitro. Stem Cells 24:835–843. Kawaguchi, J., P. J. Mee, and A. G. Smith. 2005. Osteogenic and chondrogenic differentiation of embryonic stem cells in response to specific growth factors. Bone 36:758–769. Kiernan, J., S. Hu, M. D. Grynpas, J. E. Davies, and W. L. Stanford. 2016. Systemic mesenchymal stromal cell transplantation prevents functional bone loss in a mouse model of age-related osteoporosis. Stem Cells Transl. Med. 5:683–693. Kim, D., C. H. Kim, J. I. Moon, Y. G. Chung, M. Y. Chang, B. S. Han, S. Ko, E. Yang, K. Y. Cha, R. Lanza, and K. S. Kim. 2009. Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472–476. Kim, H. S., S. K. Oh, Y. B. Park, H. J. Ahn, K. C. Sung, M. J. Kang, L. A. Lee, C. S. Suh, S. H. Kim, D. W. Kim, and S. Y. Moon. 2005. Methods for derivation of human embryonic stem cells. Stem cells. 23:1228–1233. Kim, K., R. Zhao, A. Doi, K. Ng, J. Unternaehrer, P. Cahan, H. Huo, Y. H. Loh, M. J. Aryee, M. W. Lensch, H. Li, J. J. Collins, A. P. Feinberg, and G. Q. Daley. 2011. Donor cell type can influence the epigenome and differentiation potential of human induced pluripotent stem cells. Nat. Biotechnol. 29:1117–1119. Kim, S. W., K. S. Kim, C. D. Solis, M. S. Lee, and B. H. Hyun. 2013. Development of osteoporosis animal model using micropigs. Lab. Anim. Res. 29:174–177. Kimmel, D. B. 1996. Animal models for in vivo experimentation in osteoporosis research. Page 671–690 in Osteoporosis. Marcus, R., D. Feldman, and J. Kelsey, eds. Academic Press, NY, USA. Kimmel, D. B., and T. J. Wronski. 1990. Nondestructive measurement of bone mineral in femurs from ovariectomized rats. Calcif. Tissue Int. 46:101–110. Kues, W. A., D. Herrmann, B. Barg-Kues, S. Haridoss, M. Nowak-Imialek, T. Buchholz, M. Streeck, A. Grebe, I. Grabundzija, S. Merkert, U. Martin, V. J. Hall, M. A. Rasmussen, Z. Ivics, P. Hyttel, and H. Niemann. 2013. Derivation and characterization of sleeping beauty transposon-mediated porcine induced pluripotent stem cells. Stem Cells Dev. 22:124–135. Kumar, D., T. R. Talluri, T. Anand, and W. A. Kues. 2015. Induced pluripotent stem cells: Mechanisms, achievements and perspectives in farm animals. World J. Stem Cells 7:315–328. Lane, N. E. 2006. Epidemiology, etiology, and diagnosis of osteoporosis. Am. J. Obstet. Gynecol. 194:S3–S11. Larsen, T., J. A .Fernández, and R. M. Engberg. 2000. Bone turnover in growing pigs fed three levels of dietary calcium. Can. J. Anim. Sci. 80:547–557. Lee, A. S., C. Tang, F. Cao, X. Xie, K. van der Bogt, A. Hwang, A. J. Connolly, R. C. Robbins, and J. C. Wu. 2009. Effects of cell number on teratoma formation by human embryonic stem cells. Cell Cycle 8:2608–2612. Lee, C. J., T. C. Register, C. H. Turner, T. Wang, M. Stancill, and C. P. Jerome. 2002. Effects of raloxifene on bone density, biomarkers, and histomorphometric and biomechanical measures in ocariectomized cynomolgus monkeys. J. North Am. Menopause Soci. 9:320–328. Lee, J. H., K. J. Chun, H. S. Kim, S. H. Kim, P. Han, Y. Jun, and D. Lim. 2012. Alteration patterns of trabecular bone microarchitectural characteristics induced by osteoarthritis over time. Clin. Interv. Aging 7:303–312. Lelovas, P. P., T. T. Xanthos, S. E. Thoma, G. P. Lyritis, and I. A. Dontas. 2008. The laboratory rat as an animal model for osteoporosis research. Comp. Med. 58:424–430. Leung, K. S., W. S. Siu, N. M. Cheung, P. Y. Lui, D. H. Chow, A. James, and L. Qin. 2001. Goats as an osteopenic animal model. J. Bone Miner. Res. 16:2348–2255. Li, F., C. Zhou, L. Xu, S. Tao, J. Zhao, and Q. Gu. 2016. Effect of stem cell therapy on bone mineral density: a meta-analysis of preclinical studies in animal models of osteoporosis. PLoS One 11:e0149400. Li, M., Y. Shen, and T. J. Wronski. 1997. Time course of femoral neck osteopenia in ovariectomizd rats. Bone 20:55–61. Li, M., Y. Shen, H. Qi, and T. J. Wronski. 1996. Comparison study of skeletal response to estrogen depletion at red and yellow marrow sites in rats. Anat. Rec. 245:472–480. Li, X. J., and W. S. Jee. 1991. Adaptation of diaphyseal structure to aging and decreased mechanical loading in the adult rat: a densinometric and histomorpohometric study. Anat. Rec. 229:291–297. Liao, J., C. Cui, S. Chen, J. Ren, J. Chen, Y. Gao, H. Li, N. Jia, L. Cheng, H. Xiao, and L. Xiao. 2009. Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem Cell 4:11–15. Liao, Y. J., C. H. Liao, J. W. Liao, K. Yuan, Y. Z. Liu, Y. S. Chen, L. R. Chen, and J. R. Yang. 2014. Establishment and characterization of novel porcine induced pluripotent stem cells expressing hrGFP. J. Stem Cell Res. Ther. 4:208. Lien, C. Y., K. Chih-Yuan Ho, O. K. Lee, G. W. Blunn, and Y. Su. 2009. Restoration of bone mass and strength in glucocorticoid-treated mice by systemic transplantation of CXCR4 and cbfa-1 co-expressing mesenchymal stem cells. J. Bone Miner. Res. 24:837–848. Lin, S., J. Huang, L. Zheng, Y. Liu, G. Liu, N. Li, K. Wang, L. Zou, T. Wu, L. Qin, L. Cui, and G. Li. 2014. Glucocorticoid-induced osteoporosis in growing rats. Calcif. Tissue Int. 95:362–373. Lippuner, K. 2012. The future of osteoporosis treatment - a research update. Swiss Med. Wkly. 142:w13624. Lister, R., M. Pelizzola, Y. S. Kida, R. D. Hawkins, J. R. Nery, G. Hon, J. Antosiewicz-Bourget, R. O'Malley, R. Castanon, S. Klugman, M. Downes, R. Yu, R. Stewart, B. Ren, J. A. Thomson, R. M. Evans, and J. R. Ecker. 2011. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature 471:68–73. Liu, H., F. Zhu, J. Yong, P. Zhang, P. Hou, H. Li, W. Jiang, J. Cai, M. Liu, K. Cui, X. Qu, T. Xiang, D. Lu, X. Chi, G. Gao, W. Ji, M. Ding, and H. Deng. 2008. Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 3:587–590. Liu, X. Y., J. H. Shi, W. H. Du, Y. P. Fan, X. L. Hu, C. C. Zhang, H. B. Xu, Y. J. Miao, H. Y. Zhou, P. Xiang, and F. L. Chen. 2011. Glucocorticoids decrease body weight and food intake and inhibit appetite regulatory peptide expression in the hypothalamus of rats. Exp. Ther. Med. 2:977–984. Liu, Y., J. Wu, Y. Zhu, and J. Han. 2014. Therapeutic application of mesenchymal stem cells in bone and joint diseases. Clin. Exp. Med. 14:13–24. Lysdah, H., A. Baatrup, C. B. Foldager, and C. Bünger. 2014. Preconditioning human Mesenchymal stem cells with a low concentration of BMP2 stimulates proliferation and osteogenic differentiation in vitro. Biores. Open Access 3:278–285. Ma, Y. F., H. Z. Ke, and W. S. S. Jee. 1994. Prostagladin E2 adds bone to a cancellous bone site with a growth plate and low bone turnover in ovariectomized rats. Bone 15:137–146. Marchetto, M. C., G. W. Yeo, O. Kainohana, M. Marsala, F. H. Gage, and A. R. Muotri. 2009. Transcriptional signature and memory retention of human-induced pluripotent stem cells. PLoS ONE 4:e7076. Maron-Gutierrez, T., I. Araujo, M. M. Morales, C. S. Garcia, and P. R. Rocco. 2009. Stem cell therapy in acute respiratory distress syndrome. Rev. Bras. Ter. Intensiva. 21:51–57. Martı´nez-Gonza´lez, J. M., J. Cano-Sa´nchez, J. Campo-Trapero, J. C. Gonzalo-Lafuente, J. Díaz-Regañón, and M. T. Vázquez-Piñeiro. 2005. Evaluation of minipigs as an animal model for alveolar distraction. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 99:11–16. Martı´nez-Lorenzo, M. J., M. Royo-Can˜as, E. Alegre-Aguaro´n, P. Desportes, T. Castiella, F. García-Alvarez, and L. Larrad. 2009. Phenotype and chondrogenic differentiation of mesenchymal cells from adipose tissue of different species. J. Orthop. Res. 27:1499–1507. Martin, G. R. 1981. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc. Natl. Acad. Sci. USA 78:7634–7638. Martiniakova´, M., B. Grosskopf, R. Omelka, M. Vondráková, and M. Bauerová. 2006. Differences among species in compact bone tissue microstructure of mammalian skeleton: use of a discriminant function analysis for species identification. J. Forensic Sci. 51:1235–1239. Miller, J. D., and T. M. Schlaeger. 2011. Generation of induced pluripotent stem cell lines from human fibroblasts via retroviral gene transfer. Methods Mol. Biol. 767:55–65. Miller, S. C., B. M. Bowman, and W. S. S. Jee. 1995. Available animal models of osteopenia-Small and large. Bone 17:117S-123S. Miller, S. C., B. M. Bowman, M. A. Miller, and C. M. Bagi. 1991. Calcium absorption and osseous organ-, tissue-, and envelops-specific changes following ovariectomy in rats. Bone 12:439–446. Miura, K., Y. Okada, T. Aoi, A. Okada, K. Takahashi, K. Okita, M. Nakagawa, M. Koyanagi, K. Tanabe, M. Ohnuki, D. Ogawa, E. Ikeda, H. Okano, and S. Yamanaka. 2009. Variation in the safety of induced pluripotent stem cell lines. Nat. Biotechnol. 27:743–745. Miyakoshi, N., K. Sato, T. Tsuchida, Y. Tamura, and T. Kudo. 1999. Histomorphometric evaluation of the effects of ovariectomy on bone turnover in rat caudal vertebrae. Calcif. Tissue Int. 64:318–324. Montserrat, N., E. G. Bahima, L. Batlle, S. Häfner, A. M. Rodrigues, F. González, and J. C. Izpisúa Belmonte. 2011. Generation of pig iPS cells: a model for cell therapy. J. Cardiovasc. Transl. Res. 4:121–130. Moore, K., and J. A. Piedrahita. 1997. The effects of human leukemia inhibitory factor (hLIF) and culture medium on in vitro differentiation of cultured porcine inner cell mass (pICM). In Vitro Cell Dev. Biol. Anim. 33:62–71. Morey, E. R. 1979. Spaceflight and bone turnover: correlation with a new rat model of weightlessness. Bioscience 29:168–172. Mosekilde, L. 1995. Assessing bone quality-Animal models in preclinical osteoporosis research. Bone 17:343S-352S. Mosekilde, L., J. Kragstrup, and A. Richards. 1987. Compressive strength, ash weight, and volume of vertebral trabecular bone in experimental fluorosis in pigs. Calcif. Tissue Int. 40:318–322. Mosekilde, L., S. E. Weisbrode, J. A. Safron, H. F. Stills, M. L. Jankowsky, D. C. Ebert, C. C. Danielsen, C. H. Søgaard, A. F. Franks, and M. L. Stevens. 1993a. Calcium restricted ovariectomized Sinclair S-1 minipigs: an animal model of osteopenia and trabecular plate perforation. Bone 14:379–382. Mosekilde, L., S. E. Weisbrode, J. A. Safron, H. F. Stills, M. L. Jankowsky, D. C. Ebert, C. C. Danielsen. C. H. Søgaard, A. F. Franks, and M. L. Stevens. 1993b. Evaluation of the skeletal effects of combined mild dietary calcium restriction and ovariectomy in Sinclair S-1 Minipigs: A pilot study. J. Bone Mineral. Res. 8:1311–1321. Muschler, G. F., H. Nitto, C. A. Boehm, and K. A. Easley. 2001. Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J. Orthop. Res. 19:117–125. Nakamura, T. 1999. The front line of bone histomorphometry. Clin. Calcium 9:478–483 (in Japanese). Newman, A. M., and J. B. Cooper. 2010. Lab-specific gene expression signatures in pluripotent stem cells. Cell Stem Cell 7:258–262. Nussbaum, J., E. Minami, M. A. Laflamme, J. A. Virag, C. B. Ware, A. Masino, V. Muskheli, L. Pabon, H. Reinecke, and C. E. Murry. 2007. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J. 21(7):1345–1357. Ocarino Nde, M., J. N. Boeloni, V. Jorgetti, D. A. Gomes, A. M. Goes, and R. Serakides. 2010. Intra-bone marrow injection of mesenchymal stem cells improves the femur bone mass of osteoporotic female rats. Connect. Tissue Res. 51:426–433. Ohi, Y., H. Qin, C. Hong, L. Blouin, J. M. Polo, T. Guo, Z. Qi, S. L. Downey, P. D. Manos, D. J. Rossi, J. Yu, M. Hebrok, K. Hochedlinger, J. F. Costello, J. S. Song, and M. Ramalho-Santos. 2011. Incomplete DNA methylation underlies a transcriptional memory of somatic cells in human iPS cells. Nat. Cell Biol. 13:541–549. Okita, K., H. Hong, K. Takahashi, and S. Yamanaka. 2010. Generation of mouse induced pluripotent stem cells with plasmid vectors. Nat. Protoc. 5:418–428. Okumura, H., T. Yamamuro, R. Kassai, T. Hirashi, K. Tada, and Y. Nishii. 1987. Effect of 1 alpha-hydroxyvitamin D3 on osteoporosis induced by immobilization combined with ovariectomy in rats. Bone 8:351–355. Parfitt, A. M. 1984. The cellular basis of bone remodeling: the quantum concept reexamined in light of recent advances in the cell biology of bone. Calcif. Tissue Int. 36:S37–S45. Park, I. H., R. Zhao, J. A. West, A. Yabuuchi, H. Huo, T. A. Ince, P. H. Lerou, M. W. Lensch, and G. Q. Daley. 2008. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146. Paschalis, E. P., D. B. Burr, R. Mendelsohn, J. M. Hock, and A. L. Boskey. 2003. Bone mineral and collagen quality in humeri of ovariectomized cynomolgus monkeys given rhPTH (1–34) for 18 months. J. Bone Miner. Res. 18:769–775. Phillips, B. W., N. Belmonte, C. Vernochet, G. Ailhaud, and C. Dani. 2001. Compactin enhances osteogenesis in murine embryonic stem cells. Biochem. Biophys. Res. Commun. 284:478–484. Phimphilai, M., Z. Zhao, H. Boules, H. Roca, and R. T. Franceschi. 2006. BMP signaling is required for RUNX2-dependent induction of the osteoblast phenotype. J. Bone Miner. Res. 21:637–646. Piedrahita, J. A., and B. Mir. 2004. Cloning and transgenesis in mammals: Implications for xenotransplantation. Am. J. Transplant. 4:43–50. Piedrahita, J. A., G. B. Anderson, and R. H. Bondurant. 1990. On the isolation of embryonic stem cells: comparative behavior of murine, porcine and ovine embryos. Theriogenology 34:879–901. Prado, R. F., V. Á. Silveira, R. F. Rocha, L. M. Vasconcellos, and Y. R. Carvalho. 2012. Effects of experimental osteoporosis and low calcium intake on postextraction sockets of rats. Int. J. Exp. Pathol. 93:139–147. Prather, R. S., R. J. Hawley, D. B. Carter, L. Lai, and J. L. Greenstein. 2003. Transgenic swine for biomedicine and agriculture. Theriogenology 59:115-123. Rawadi, G., B. Vayssiere, F. Dunn, R. Baron, and S. Roman-Roman. 2003. BMP-2 controls alkaline phosphatase expression and osteoblast mineralization by a Wnt autocrine loop. J. Bone Miner. Res. 18:1842–1853. Revazova, E. S., N. A. Turovets, O. D. Kochetkova, L. B. Kindarova, L. N. Kuzmichev, J. D. Janus, and M. V. Pryzhkova. 2007. Patient-specific stem cell lines derived from human parthenogenetic blastocysts. Cloning Stem Cells 9:432–449. Rodan, G. A. 1992. Introduction to bone biology. Bone 13:S3–S6. Rodgers, J. B., M. C. Monier-Faugere, and H. Malluche. 1993. Animal models for the study of bone loss after cessation of ovarian function. Bone 14:369–377. Roschger, P., P. Fratzl, K. Klaushofer, and G. Rodan. 1997. Mineralization of cancellous bone after Alendronate andsodium fluoride treatment: a quantitative backscattered electron imaging study on minipig ribs. Bone 20:393–397. SAS. 2016. User's guide: statistics. version 9.4. SAS Institute. Cary, NC, USA. Schneuwly, S., R. Klemenz, and W. J. Gehring. 1987. Redesigning the body plan of Drosophila by ectopic expression of the homoeotic gene Antennapedia. Nature 325:816–818. Scholz-Ahrens, K. E., G. Delling, B. Stampa, A. Helfenstein, H. J. Hahne, Y. Açil, W. Timm, R. Barkmann, J. Hassenpflug, J. Schrezenmeir, and C. C. Glüer. 2007. Glucocorticosteroid-induced osteoporosis in adult primiparous Göttingen miniature pigs: effects on bone mineral and mineral metabolism. Am. J. Physiol. Endocrinol. Metab. 293:E385–E395. Scudellari, M. 2016. A decade of iPS cells. Nature 534:310–312. Sethe, S., A. Scutt, and A. Stolzing. 2006. Aging of mesenchymal stem cells. Ageing Res. Rev. 5:91–116. Seto, H., K. Aoki, S. Kasugai, and K. Ohya. 1996. Trabecular bone turnover, bone marrow cell development, and gene expression of bone matrix proteins after low calcium feeding in rats. Bone 25:687–695. Smith, A. G., J. K. Heath, D. D. Donaldson, G. G. Wong, J. Moreau, M. Stahl, and D. Rogers. 1988. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature 336:688–690. Solter, D., and B. B. Knowles. 1975. Immunosurgery of mouse blastocyst. Proc. Natl. Acad. Sci. USA. 72:5099–5102. Sottile, V., A. Thomson, and J. McWhir. 2003. In vitro osteogenic differentiation of human ES cells. Cloning Stem Cells 5:149–155. Sreenivas, S. D., A. S. Rao, S. S. Satyavani, B. H. Reddy, and S. Vasudevan. 2011. Where will the stem cells lead us? Prospects for dentistry in the 21st century. J. Indian Soc. Periodontol. 15:199–204. Stadtfeld, M., and K. Hochedlinger. 2010. Induced pluripotency: history, mechanisms, and applications. Genes Dev. 24:2239–2263. Stahn, C., M. Löwenberg, D. W. Hommes, and F. Buttgereit. 2007. Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists. Mol. Cell Endocrinol. 275:71–78. Stellon, A. J., A. Davis, J. Compston, and R. Williams. 1985. Bone loss in autoimmune chronic active hepatitis on maintenance corticosteroid therapy. Gastroenterology 89:1078–1083. Sui, B., C. Hu, X. Zhang, P. Zhao, T. He, C. Zhou, X. Qiu, N. Chen, X. Zhao, and Y. Jin. 2016. Allogeneic mesenchymal stem cell therapy promotes osteoblastogenesis and prevents glucocorticoid-induced osteoporosis. Stem Cells Transl. Med. 5:1238–1246. Suzuki, A., C. Ghayor, J. Guicheux, D. Magne, S. Quillard, A. Kakita, Y. Ono, Y. Miura, Y. Oiso, M. Itoh, and J. Caverzasio. 2006. Enhanced expression of the inorganic phosphate transporter Pit-1 is involved in BMP-2-induced matrix mineralization in osteoblast- like cells. J. Bone Miner. Res. 21:674–683. Szulc, P., E. Seeman, and P. D. Delmas. 2000. Biochemical measurements of bone turnover in children and adolescents. Osteoporos. Int. 11:281–294. Tada, M., Y. Takahama, K. Abe, N. Nakatsuji, and T. Tada. 2001. Nuclear reprogramming of somatic cells by in vitro hybridization with ES cells. Curr. Biol. 11:1553–1558. Tai, N., and D. Inoue. 2014. Anti-Dickkopf1 (Dkk1) antibody as a bone anabolic agent for the treatment of osteoporosis. Clin. Calcium 24:75–83. Taiani, J. T., H. R. Buie, G. M. Campbell, S. L. Manske, R. J. Krawetz, D. E. Rancourt, S. K. Boyd, and J. R. Matyas. 2014. Embryonic stem cell therapy improves bone quality in a model of impaired fracture healing in the mouse; tracked temporally using in vivo micro-CT. Bone 64:263–272. Takahashi, K., and S. Yamanaka. 2006. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676. Takahashi, K., K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda, and S. Yamanaka. 2007. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872. Tang, Y., X. Wu, W. Lei, L. Pang, C. Wan, Z. Shi, L. Zhao, T. R. Nagy, X. Peng, J. Hu, X. Feng, W. Van Hul, M. Wan, and X. Cao. 2009. TGF-beta1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med. 15:757–765. Teitelbaum, S. L. 2010. Stem cells and osteoporosis therapy. Cell Stem Cell 7:553–554. Thompson, D. D., and G. A. Rodan. 1988. Indomethacin inhibition of tenotomy- induced bone resorption in rats. J. Bone Miner. Res. 3:409–414. Thomson, J. A., J. Itskovitz-Eldor, S. S. Shapiro, M. A. Waknitz, J. J. Swiergiel, V. S. Marshall, and J. M. Jones. 1998. Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147. Toquet, J., R. Rohanizadeh, J. Guicheux, S. Couillaud, N. Passuti, G. Daculsi, and D. Heymann. 1999. Osteogenic potential in vitro of human bone marrow cells cultured on macroporous biphasic calcium phosphate ceramic. J. Biomed. Mater. Res. 44:98–108. Trounson, A., R. G. Thakar, G. Lomax, and D. Gibbons. 2011. Clinical trials for stem cell therapies. BMC Med. 9:52. Tsutsumi, H., S. Ikeda, and T. Nakamura. 2011. Osteoporosis model in minipigs. Page 517–524 in The Minipig in Biomedical Research. McAnulty, P. A., A. D. Dayan, N. C. Ganderup, K. L. Hastings, eds. CRC Press, Boca Raton, FL, USA. Turner, A. S. 2001. Animal models of osteoporosis--necessity and limitations. Eur. Cell Mater. 1:66–81. Turner, R. T., J. J. Vandersteenhooven, and N. H. Bell. 1987. The effects of ovariectomy and 17β estradiol on cortical bone histomorphometry in growing rats. J. Bone Miner. Res. 2:115–122. Turner, R. T., S. Lotinun, T. Hefferan, G. L. Evans, M. Zhang, and J. D. Sibonga. 2001. Animal models for osteoporosis. Rev. Endocr. Metab. Disord. 2:117–127. Valverde, P. 2008. Pharmacotherapies to manage bone loss-associated diseases: a quest for the perfect benefit-to-risk ratio. Curr. Med. Chem. 15:284–304. Wakayama, T., V. Tabar, I. Rodriguez, A. C. Perry, L. Studer, and P. Mombaerts. 2001. Differentiation of embryonic stem cell lines generated from adult somatic cells by nuclear transfer. Science 292:740–743. Wanderman, N. R., C. Mallet, H. Giambini, N. Bao, C. Zhao, K. N. An, B. A. Freedman, and A. Nassr. 2018. An ovariectomy-induced rabbit osteoporotic model: a new perspective. Asian Spine J. 12:12–17. Wang, Z., J. Goh, S. Das De, Z. Ge, H. Ouyang, J. S. Chong, S. L. Low, and E. H. Lee. 2006. Efficacy of bone marrow-derived stem cells in strengthening osteoporotic bone in a rabbit model. Tissue Eng. 12:1753–1761. Warren, L., P. D. Manos, T. Ahfeldt, Y. H. Loh, H. Li, F. Lau, W. Ebina, P. K. Mandal, Z. D. Smith, A. Meissner, G. Q. Daley, A. S. Brack, J. J. Collins, C. Cowan, T. M. Schlaeger, and D. J. Rossi. 2010. Highly efficient reprogramming to pluripotency and directed differentiation of human cells with synthetic modified mRNA. Cell Stem Cell 7:618–630. Wilmut, I., A. E. Schnieke, J. McWhir, A. J. Kind, and K. H. Campbell. 1997. Viable offspring derived from fetal and adult mammalian cells. Nature 385:810–813. Wobus, A. M., G. Kaomei, J. Shan, M. C. Wellner, J. Rohwedel, G. Ji, B. Fleischmann, H. A. Katus, J. Hescheler, and W. M. Franz. 1997. Retinoic acid accelerates embryonic stem cell-derived cardiac differentiation and enhances development of ventricular cardiomyocytes. J. Mol. Cell Cardiol. 29:1525–1539 Wolthers, O. C., and S. Pedersen. 1991. Growth of asthmatic children during treatment with budesonide: a bouble blind trial. Br. Med. J. 303:163–165. Woltjen, K., I. P. Michael, P. Mohseni, R. Desai, M. Mileikovsky, R. Hämäläinen, R. Cowling, W. Wang, P. Liu, M. Gertsenstein, K. Kaji, H. K. Sung, and A. Nagy. 2009. piggyBac transposition reprograms fibroblasts to induced pluripotent stem cells. Nature 458:766–770. World Health Organization. 1998. Preclinical studies. Page 7–20 in Guideline for Preclinical Evaluation and Clinical Trials in Osteoporosis. Geneva: WHO Library Cataloguing in Publication Data. Wronski, T. J., L. M. Dann, and S. L. Horner. 1990. Time course of vertebral osteopenia in ovariectomized rats. Bone 10:295–301. Wronski, T. J., L. M. Dann, K. S. Scott, and L. M. Cintron. 1989. Long-term effects of ovariectomy and aging on the rat skeleton. Calcif. Tissue Int. 45:360–366. Wronski, T. J., M. Cintron, and L. M. Dann. 1988. Temporal relationship between bone loss and increased bone turnover in ovariectomized rats. Calcif. Tissue Int. 43:179–183. Wu, C. Y., Y. N. Jiang, H. P. Chu, S. H. Li, Y. Wang, Y. H. Li, Y. Chang, and Y. T. Ju. 2007. The type I Lanyu pig has a maternal genetic lineage distinct from Asian and European pigs. Anim. Genet. 38:499–505. Wu, W. T., R. P. Lee, C. H. Wang, T. C. Fang, N. T. Lin, I. H. Chen, and B. G. Hsu. 2010a. The association of serum osteoprotegerin and osteoporosis in postmenopausal hemodialysis patients: a pilot study. J. Womens Health (Larchmt) 19:785–790. Wu, X., L. Pang, W. Lei, W. Lu, J. Li, Z. Li, F. J. Frassica, X. Chen, M. Wan, and X. Cao. Cell Stem Cell. 2010b. Inhibition of Sca-1-positive skeletal stem cell recruitment by alendronate blunts the anabolic effects of parathyroid hormone on bone remodeling. Cell Stem Cell 7:571–580. Wu, Z., J. Chen, J. Ren, L. Bao, J. Liao, C. Cui, L. Rao, H. Li, Y. Gu, H. Dai, H. Zhu, X. Teng, L. Cheng, and L. Xiao. 2009. Generation of pig-induced pluripotent stem cells with a drug-inducible system. J. Mol. Cell Biol. 1:46–54. Yamanaka, S. 2012. Induced pluripotent stem cells: past, present, and future. Cell Stem Cell 10:678–684. Yamane, T., T. Kunisada, H. Yamazaki, T. Era, T. Nakano, and S. I. Hayashi. 1997. Development of osteoclasts from embryonic stem cells through a pathway that is c-fms but not c-kit dependent. Blood 90:3516–3523. Yamashita, A., T. Takada, J. Narita, G. Yamamoto, and R. Torii. 2005. Osteoblastic differentiation of monkey embryonic stem cells in vitro. Cloning Stem Cells 7:232–237. Yang, J. R., C. H. Liao, C. Y. Pang, L. L. H. Huang, Y. L. Chen, Y. L. Shiue, and L. R. Chen. 2013a. Transplantation of porcine embryonic stem cells and their derived neuronal progenitors in a spinal cord injury rat model. Cytotherapy 15:201-208. Yang, J. R., C. H. Liao, C. Y. Pang, L. L. H. Huang, Y. T. Lin, Y. L. Chen, Y. L. Shiue, and L. R. Chen. 2010. Directed differentiation into neural lineages and therapeutic potential of porcine embryonic stem cells in rat Parkinson's disease model. Cell. Reprogram. 12:447–461. Yang, J. R., C. W. Hsu, S. C. Liao, Y. T. Lin, L. R. Chen, and K. Yuan. 2013b. Transplantation of embryonic stem cells improves the regeneration of periodontal furcation defects in a porcine model. J. Clin. Periodontol. 40:364–731. Yang, J. R., Y. L. Shiue, C. H. Liao, S. Z. Lin, and L. R. Chen. 2009. Establishment and characterization of novel porcine embryonic stem cell lines expressing hrGFP. Cloning Stem Cells 11:235–244. Yao, W., Z. Cheng, A. Pham, C. Busse, E. A. Zimmermann, R. O. Ritchie, and N. E. Lane. 2008. Glucocorticoid-induced bone loss in mice can be reversed by the actions of parathyroid hormone and risedronate on different pathways for bone formation and mineralization. Arthritis Rheum. 58:3485–3497. Yu, J., K. Hu, K. Smuga-Otto, S. Tian, R. Stewart, I. I. Slukvin, and J. A. Thomson. 2009. Human induced pluripotent stem cells free of vector and transgene sequences. Science 324:797–801. Yu, J., M. A. Vodyanik, K. Smuga-Otto, J. Antosiewicz-Bourget, J. L. Frane, S. Tian, J. Nie, G. A. Jonsdottir, V. Ruotti, R. Stewart, I. I. Slukvin, and J. A. Thomson. 2007. Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920. Zeng, Q. Q., W. S. S. Jee, A. E. Bigornia, J. G. King, S. M. D'Souza, X. J. Li, Y. F. Ma, and W. J. Wechter. 1996. Time responses of cancellous and cortical bones to schiatic neurectomy in growing female rats. Bone 19:13–21. zur Nieden, N. I., G. Kempka, and H. J. Ahr. 2003. In vitro differentiation of embryonic stem cells into mineralized osteoblasts. Differentiation 71:18–27 zur Nieden, N. I., G. Kempka, D. E. Rancourt, and H. J. Ahr. 2005. Induction of chondro-, osteo- and adipogenesis in embryonic stem cells by bone morphogenetic protein-2: effect of cofactors on differentiating lineages. BMC Dev. Biol. 5:1.||摘要:||
骨質疏鬆症（osteoporosis）發生原因為破骨細胞（osteclasts）與成骨細胞（osteblasts）活性的動態平衡失衡所致，以致骨質重吸收（bone resoprtion）遠大於骨質形成（bone formation），最終導致骨質流失（bone loss）。目前已有利用藥物或細胞移植治療的方式，來改善骨質流失。誘導多能性幹細胞（induced pluripotent stem cells, iPSCs）之特性與胚幹細胞（embryonic stem cells, ESCs）相似，於特定環境下可分化為各種組織。本試驗即利用豬耳朵纖維母細胞建立豬誘導多能性幹細胞（porcine iPSCs, piPSCs），以人類hOct4、hSox2、hKlf4與hc-Myc基因以慢病毒載體（lentivirus vector）轉染入表現綠色螢光蛋白質的豬耳朵纖維母細胞內。結果顯示，轉染後的細胞擁有體外形成類胚體（embryoid body, EB）與分化為三胚層（three germ layers），以及體內分化為畸胎瘤（teratomas）等胚幹細胞特性。此細胞稱為表現綠色螢光蛋白質之豬誘導多能性幹細胞（green fluorescent protein expressing porcine induced pluripotent stem cells, piPSCs/GFP+）。接著，再將其誘導分化為成骨細胞，探討其治療骨質疏鬆症大鼠與蘭嶼豬（Lanyu pigs）之效果。piPSCs/GFP+經骨生成培養液培養4週後，細胞有鈣鹽沉積現象，並表現骨連接素（osteonectin）、骨鈣素（osteocalcin）與膠原蛋白I型（collagen type I）等成骨細胞特異性蛋白質。此分化之細胞稱為豬誘導多能性幹細胞衍生之成骨細胞（piPSCs/GFP+-derived osteoblast-like cells）。大鼠經卵巢移除、鈣含量0.1%之飼糧餵飼與3 mg/kg的prednisolone處理3個月後，股骨（femurs）有較低的骨小樑體積百分比（percent bone volume）、骨表面積/體積比（bone surface/volume ratio）、骨小樑厚度（trabecular thickness）與骨小樑數目（trabecular number），而有較高的骨小樑分離度（trabecular separation）與總孔隙率（total porosity）。將豬誘導多能性幹細胞衍生之成骨細胞移植於股骨骨髓腔3個月後，可修復骨小樑缺陷，且移植處有骨質新生現象。蘭嶼豬經卵巢移除、鈣含量0.5%之飼糧餵飼與1 mg/kg的prednisolone處理12個月後，其脛骨（tibiae）骨小樑體積百分比、骨表面積/體積比、骨小樑厚度、骨小樑數目，以及總孔隙率等指標，皆與控制組有顯著差異。將豬誘導多能性幹細胞衍生之成骨細胞移植於脛骨骨髓腔6個月後，於細胞移植處同樣可修復骨小樑缺陷，且有骨質再生現象。研就結果顯示，豬誘導多能性幹細胞衍生之成骨細胞可改善骨質流失現象。這些結果可強化piPSCs於再生醫學上之應用。
The main cause of osteoporosis is due to the imbalance of osteoclast and osteoblast activity, and bone resoprtion surpasses bone formation. This phenomenon results in bone loss. Nowadays, drug treatments and cell therapy have been used to ameliorate bone loss. The properties of induced pluripotent stem cells (iPSCs) are similar to those of embryonic stem cells (ESCs), and the cells can differentiate into different types of cells under certain culture conditions. In the present study, we established porcine iPSCs (piPSCs) from porcine ear fibroblasts and investigated the therapeutic effects of piPSCs on rat and Lanyu pig model of osteoporosis. The green fluorescent protein expressing ear fibroblasts were infected with human hOct4, hSox2, hKlf4, and hc-Myc cloned into lentivirus vectors. After transfection, the infected cells expressed the properties of ESCs, such as in vitro embryoid body formation, in vitro three germ layer differentiation, and in vivo teratoma formation. The established cells were named as green fluorescent protein expressing porcine induced pluripotent stem cells (piPSCs/GFP+). After culturing in osteogenic medium for four weeks, piPSCs/GFP+ showed calcium deposition and expressed specific protein markers of osteoblasts, such as osteonectin, osteocalcin, and collagen type I. The differentiated cells were named as piPSCs/GFP+-derived osteoblast-like cells. After three months of ovariectomy, 0.1% calcium diet feeding, and 3 mg/kg of prednisolone treatment, the rat femurs exhibited low level of percent bone volume, bone surface/volume ratio, trabecular thickness, and trabecular number but showed high level of trabecular separation and total porosity. After transplanting piPSCs/GFP+-derived osteoblast-like cells into the medullary cavity of the femurs for three months, the trabecular bone defects were restored to the level as the control group, and trabecular bone regeneration was evident at the transplanted sites. Furthermore, after twelve months of ovariectomy, 0.5% calcium diet feeding, and 1 mg/kg of prednisolone treatment, the level of percent bone volume, bone surface/volume ratio, trabecular thickness, trabecular number, and total porosity in the tibiae of Lanyu pigs were significantly different from the control group. After transplanting piPSCs/GFP+-derived osteoblast-like cells into the medullary cavity of the tibiae for six months, the trabecular bone defects at the transplanted sites were also recovered to the level as the control group, and bone regeneration was evident at the transplanted site. These results revealed that piPSCs/GFP+-derived osteoblast-like cells can ameliorate bone loss, and the results can enhance the application of piPSCs on regenerative medicine.
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