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研究生:李柏輝
研究生(外文):Po-Hui Lee
論文名稱:應用基因治療給予副甲狀腺素或人類β-防禦素第二型以治療顱顏骨缺損之研究
論文名稱(外文):Delivery of Parathyroid Hormone or Human β-defensin 2 via Gene Therapy Strategy for Treatment of Craniofacial Bone Defects
指導教授:陳恆理陳恆理引用關係
指導教授(外文):Hen-Li Chen
學位類別:博士
校院名稱:國立陽明大學
系所名稱:口腔生物研究所
學門:醫藥衛生學門
學類:牙醫學類
論文種類:學術論文
論文出版年:2018
畢業學年度:106
語文別:中文
論文頁數:103
中文關鍵詞:同種異體移植體骨塑型蛋白骨再生基因治療腹甲狀腺素人類β-防禦素第二型骨髓間葉幹細胞金黃色葡萄球菌細菌污染
外文關鍵詞:allograftsbone morphogenetic proteinsbone regenerationgene therapyparathyroid hormonehuman β-defensin 2bone marrow-derived mesenchymal stem cellStaphylococcus aureusbacterial contamination
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顱顏骨缺損(craniofacial osseous defect)是牙科常見情況,大尺寸或有細菌污染的骨缺損在臨床上目前仍難以確保獲良好的療效。本論文研究目的在探討組織工程及基因治療等新興再生性治療策略在難以治療的顱顏骨缺損上的療效。第一部分研究針對大尺寸顱顏骨缺損的治療。GAM為符合組織工程原理的非病毒性基因療法,由攜帶生長因子基因的質體DNA (pDNA)包埋在可吸收的基質(matrix)內組合而成。過去使用含副甲狀腺素(PTH)基因pDNA及膠原蛋白基質的GAM,已被證實可有效促進長骨(long bone)骨缺損再生。脫鈣冷凍乾燥異體移植骨(DFDBA)為牙科廣為應用的骨移植(bone graft)。我們探討探討副甲狀腺素活化基因基質(PTH-GAM)在含膠原蛋白(collagen)或DFDBA/collagen基質情況下,在大鼠臨界尺寸顱頂 (calvarial) 骨缺損的療效。研究中製備DFDBA/collagen複合支架(D/C)、以collagen為基質之PTH-GAM (PTH-C-GAM)及以D/C為基質之PTH-GAM (PTH-D/C-GAM),分別植入大鼠顱頂骨缺損中,在對照組(Sham)則在骨缺損中未植入材料。利用X光片、雙能量骨質密度儀(DEXA)、微電腦斷層掃描儀(μCT)及組織切片染色觀測骨再生情形,結果顯示新骨生成從多到少之排序為PTH-D/C-GAM > PTH-C-GAM > D/C > Sham(對照組)。此部分結論是以膠原蛋白為基質的PTH-GAM可促進大鼠大尺寸顱顏骨缺損之骨再生,將PTH-GAM的基質由膠原蛋白改成DFDBA/膠原蛋白可更加促進其骨生成效果。本論文第二部分的研究針對大尺寸且有細菌污染顱顏骨缺損的治療。人類防禦素第二型(hBD2)為人體先天性免疫系統中的抗菌胜肽(antimicrobial peptide),具良好抗菌能力且不易產生抗藥性,目前尚未有應用在骨再生治療的研究。我們探討hBD2基因改質骨髓間葉幹細胞(BMSC)在大鼠有金黃色葡萄球菌(S.a.)污染顱頂骨缺損的療效。研究結果顯示以腺病毒感染方式過度表達hBD2之BMSC在體外及體內實驗均可降低S.a.的活菌數。利用本研究所建立的細菌污染大鼠顱頂骨缺損模型,證實細菌污染會明顯抑制使用BMSC細胞的骨再生療效。進一步發現以hBD2基因改質的BMSC可在缺損部位大幅降低骨缺損內S.a.的活菌數,改善細菌污染所造成的負面影響,有效促進骨頭癒合。期待未來在如本研究所使用的新興再生性治療技術進步之下,牙科臨床上目前難以再生之骨缺損情形得以獲得有效治療。
Craniofacial bone defects are common dental conditions. It is still challenging clinically to obtain predictable bone regeneration in large or bacteria-contaminated bone defects. The purpose of this study was to explore the effect of novel regenerative strategies, such as tissue engineering and gene therapy, in difficult-to-treat craniofacial bone defects. The first part of the study was focus on treating large size craniofacial bone defects. Gene activated matrix (GAM) is a nonviral gene therapy technique based on the principles of tissue engineering. A GAM is formed by plasmid DNA (pDNA), encoding gene of growth factor, entrapped in resorbable matrix. GAM composed of pDNA containing gene of parathyroid hormone (PTH) and collagen matrix can effectively promote bone regeneration in bone defects of long bones. Demineralized freeze-dried bone allograft (DFDBA) is one of the bone grafts widely used in dentistry. We aimed to explore the bone regenerative effects of PTH-GAM, with collagen matrix or DFDBA/collagen matrix, in the treatment of rat critical-sized calvarial bone defect. Rat calvarial bone defected were implanted with DFDBA/collagen composite scaffold (D/C), PTH-GAM with collagen matrix (PTH-C-GAM), or PTH-GAM with D/C matrix (PTH-D/C-GAM). The defects without implantation were used as control (Sham). New bone formation was evaluated by performing radiography, dual energy X-ray absorptiometry (DEXA), microcomputed tomography (μCT), and histological examination. The results indicated that the new bone formation in the calvarial bone defects, from more to less, was in the order of PTH-D/C-GAM, PTH-C-GAM, D/C, and Sham groups. We concluded that PTH-GAM with collagen matrix can promote bone regeneration in large craniofacial bone defects in rats. Moreover, the change of the collagen matrix with the D/C matrix improves the osteogenic effects of PTH-GAM. The second part of the study was focus on treating bacteria-contaminated large size craniofacial bone defects. Human β-defensin 2 (hBD2), an antimicrobial peptide of innate immune system, possesses excellent antimicrobial activities and rare drug resistance. The application of hBD2 in bone regenerative therapies is still unexplored. We aimed to determine the effects of hBD2 gene-modified bone marrow mesenchymal stem cell (BMSC) in the treatment of Staphylococcus aureus (S.a.)-contaminated calvarial bone defect in rats. The results indicated that BMSC overexpressing hBD2, generated via adenoviral infection method, can reduce the viable S.a. numbers both in vitro and in vivo. We established a bacteria-contaminated rat calvarial bone defect model and found that bacterial contamination severely compromises the bone regenerative effects of BMSCs. Furthermore, the hBD2 gene-modified BMSCs can dramatically reduce the viable S.a. numbers in the bone defects, mitigate the negative effects of bacterial contamination, and effectively promote bone healing. We hope that with advancement of the novel regenerative techniques, as we used in this study, the current difficult-to-treated bone defects in dental clinical practice can be effectively treated in the future.
中文摘要 i
英文摘要 iii
目錄 vi
表目錄 x
圖目錄 xi
第一章 研究動機 1
第二章 研究背景回顧 3
2.1 顱顏骨缺損臨床治療方式-脫鈣冷凍乾燥異體移植骨(DFDBA) 3
2.2 細菌污染/感染在牙科治療造成的問題 4
2.3 組織工程與再生醫學 5
2.4 基因治療 8
2.5 活化基因基質技術 9
2.6 副甲狀腺素 11
2.7 副甲狀腺素在骨骼上扮演的角色 12
2.8 副甲狀腺素PTH 1-34─骨質疏鬆症治療藥及強效促骨生成因子 13
2.9 副甲狀腺素的訊息傳遞 14
2.10 金黃色葡萄球菌與抗藥性 15
2.11 先天性免疫系統中之防禦素 16
2.12 人類防禦素之來源 18
2.13 人類β-防禦素第二型之抗菌能力及抗菌機制 19
2.14 人類β-防禦素在骨頭細胞之發現與影響 21
2.15 人類β-防禦素之基因治療應用 22
第三章 研究目的 25
3.1 目標一:探討副甲狀腺素的活化基因基質(PTH-GAM)基因治療在顱頂骨缺損修復的療效 25
3.2 目標二:探討人類β-防禦素第二型基因改質骨髓間葉幹細胞治療,用於細菌污染骨缺損的效果 26
第四章 研究方法與材料 27
4.1 實驗設計與流程 27
4.2 副甲狀腺素的活化基因基質(PTH-GAM)基因治療應用於顱頂骨缺損再生實驗 28
4.3 人類β-防禦素第二型基因改質骨髓間葉幹細胞用於細菌污染顱頂骨缺損再生實驗 35
4.4 統計方法 42
第五章 研究結果 43
5.1 建立pUMVC1/hPTH質體並確認PTH 1-34具有生物活性 43
5.2 確認DFDBA具有異位骨形成功效 43
5.3 觀察PTH-GAM膠原蛋白支架之結構 44
5.4 PTH-GAM可在大鼠顱頂骨缺損中表達PTH 1-34 44
5.5 PTH-GAM在顱頂骨缺損癒合中提升骨密度、骨礦物質含量、新骨生成面積及骨體積 44
5.6 組織形態顯示PTH-GAM增加新骨生成效果 46
5.7 建立過度表現hBD2或LacZ之基因轉殖BMSC 46
5.8 BMSC/hBD2可表現具有抗菌能力之hBD2胜肽 47
5.9 BMSC/hBD2在體內皮下擴散盒抑制金黃色葡萄球菌之生長 48
5.10 金黃色葡萄球菌污染對大鼠顱頂骨缺損之癒合有負面的影響 48
5.11 hBD2基因改質之BMSC可有效降低大鼠細菌污染顱頂骨缺損之細菌增長 49
5.12 hBD2基因改質之BMSC促進細菌污染骨缺損癒合之狀況 50
5.13 組織形態顯示hBD2基因改質之BMSC增加骨缺損再生效果 51
第六章 討論 52
6.1 探討副甲狀腺素的活化基因基質(PTH-GAM)基因治療用於顱頂骨缺損再生 52
6.2 探討β-防禦素第二型基因改質骨髓間葉幹細胞治療,用於細菌污染骨缺損再生 54
第七章 結論 60
參考文獻 61
附 表 80
附 圖 81
1. Lane JM. Bone graft substitutes. West J Med 1995;163:565-6
2. Misch CE, Dietsh F. Bone-grafting materials in implant dentistry. Implant Dent 1993;2:158-67
3. Pinholt EM, Solheim E, Bang G, Sudmann E. Bone induction by composite of bioerodible polyorthoester and demineralized bone matrix in rats. Acta Orthop Scand 1991;62:476-80
4. Pinholt EM, Bang G, Haanaes HR. Alveolar ridge augmentation in rats by Bio-Oss. Scand J Dent Res 1991;99:154-61
5. Heise U, Osborn JF, Duwe F. Hydroxyapatite ceramic as a bone substitute. Int Orthop 1990;14:329-38
6. Urist MR. Bone: formation by autoinduction. Science 1965;150:893-9
7. Urist MR, Nilsson O, Rasmussen J, Hirota W, Lovell T, Schmalzreid T, et al. Bone regeneration under the influence of a bone morphogenetic protein (BMP) beta tricalcium phosphate (TCP) composite in skull trephine defects in dogs. Clin Orthop Relat Res 1987:295-304
8. Wang EA, Israel DI, Kelly S, Luxenberg DP. Bone morphogenetic protein-2 causes commitment and differentiation in C3H10T1/2 and 3T3 cells. Growth Factors 1993;9:57-71
9. Polson AM, Heijl LC. Osseous repair in infrabony periodontal defects. J Clin Periodontol 1978;5:13-23
10. Pye AD, Lockhart DE, Dawson MP, Murray CA, Smith AJ. A review of dental implants and infection. J Hosp Infect 2009;72:104-10
11. Souza SL, Novaes Jr AB, Pontes CC, Taba Jr M, Grisi MF, e Souza AMS. Guided bone regeneration with intentionally exposed membranes and its implications for implant d. Journal of osseointegration 2010;2:45-51
12. Ferry T, Uckay I, Vaudaux P, Francois P, Schrenzel J, Harbarth S, et al. Risk factors for treatment failure in orthopedic device-related methicillin-resistant Staphylococcus aureus infection. Eur J Clin Microbiol Infect Dis 2010;29:171-80
13. DeCesare GE, Cooper GM, Smith DM, Cray JJ, Jr., Durham EL, Kinsella CR, Jr., et al. Novel animal model of calvarial defect in an infected unfavorable wound: reconstruction with rhBMP-2. Plast Reconstr Surg 2011;127:588-94
14. Zheng Z, Yin W, Zara JN, Li W, Kwak J, Mamidi R, et al. The use of BMP-2 coupled - Nanosilver-PLGA composite grafts to induce bone repair in grossly infected segmental defects. Biomaterials 2010;31:9293-300
15. Cowin SC. Tissue growth and remodeling. Annu Rev Biomed Eng 2004;6:77-107
16. Levenberg S, Langer R. Advances in tissue engineering. Curr Top Dev Biol 2004;61:113-34
17. Yaszemski MJ, Payne RG, Hayes WC, Langer R, Mikos AG. Evolution of bone transplantation: molecular, cellular and tissue strategies to engineer human bone. Biomaterials 1996;17:175-85
18. Amini AR, Laurencin CT, Nukavarapu SP. Bone tissue engineering: recent advances and challenges. Crit Rev Biomed Eng 2012;40:363-408
19. Brown KL, Cruess RL. Bone and cartilage transplantation in orthopaedic surgery. A review. J Bone Joint Surg Am 1982;64:270-9
20. Mulligan RC. The basic science of gene therapy. Science 1993;260:926-32
21. Kukowska-Latallo JF, Raczka E, Quintana A, Chen C, Rymaszewski M, Baker JR, Jr. Intravascular and endobronchial DNA delivery to murine lung tissue using a novel, nonviral vector. Hum Gene Ther 2000;11:1385-95
22. Li S, Huang L. Nonviral gene therapy: promises and challenges. Gene Ther 2000;7:31-4
23. Fang J, Zhu YY, Smiley E, Bonadio J, Rouleau JP, Goldstein SA, et al. Stimulation of new bone formation by direct transfer of osteogenic plasmid genes. Proc Natl Acad Sci U S A 1996;93:5753-8
24. Goldstein SA, Bonadio J. Potential role for direct gene transfer in the enhancement of fracture healing. Clin Orthop Relat Res 1998:S154-62
25. Bonadio J, Smiley E, Patil P, Goldstein S. Localized, direct plasmid gene delivery in vivo: prolonged therapy results in reproducible tissue regeneration. Nat Med 1999;5:753-9
26. Levy RJ, Goldstein SA, Bonadio J. Gene therapy for tissue repair and regeneration. Adv Drug Deliv Rev 1998;33:53-69
27. Geiger F, Bertram H, Berger I, Lorenz H, Wall O, Eckhardt C, et al. Vascular endothelial growth factor gene-activated matrix (VEGF165-GAM) enhances osteogenesis and angiogenesis in large segmental bone defects. J Bone Miner Res 2005;20:2028-35
28. Bonadio J. Tissue engineering via local gene delivery. J Mol Med 2000;78:303-11
29. Goldstein SA. In vivo nonviral delivery factors to enhance bone repair. Clin Orthop Relat Res 2000:S113-9
30. Winn SR, Chen JC, Gong X, Bartholomew SV, Shreenivas S, Ozaki W. Non-viral-mediated gene therapy approaches for bone repair. Orthod Craniofac Res 2005;8:183-90
31. Huang YC, Simmons C, Kaigler D, Rice KG, Mooney DJ. Bone regeneration in a rat cranial defect with delivery of PEI-condensed plasmid DNA encoding for bone morphogenetic protein-4 (BMP-4). Gene Ther 2005;12:418-26
32. Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev 2008;29:441-64
33. Kronenberg HM, McDevitt BE, Majzoub JA, Nathans J, Sharp PA, Potts JT, Jr., et al. Cloning and nucleotide sequence of DNA coding for bovine preproparathyroid hormone. Proc Natl Acad Sci U S A 1979;76:4981-5
34. Hendy GN, Kronenberg HM, Potts JT, Jr., Rich A. Nucleotide sequence of cloned cDNAs encoding human preproparathyroid hormone. Proc Natl Acad Sci U S A 1981;78:7365-9
35. Selye H. On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol. Endocrinology 1932;16 547–58
36. Dobnig H. A review of teriparatide and its clinical efficacy in the treatment of osteoporosis. Expert Opin Pharmacother 2004;5:1153-62
37. Lotinun S, Sibonga JD, Turner RT. Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression. Endocrine 2002;17:29-36
38. Hock JM, Gera I. Effects of continuous and intermittent administration and inhibition of resorption on the anabolic response of bone to parathyroid hormone. J Bone Miner Res 1992;7:65-72
39. Kimmel DB, Bozzato RP, Kronis KA, Coble T, Sindrey D, Kwong P, et al. The effect of recombinant human (1-84) or synthetic human (1-34) parathyroid hormone on the skeleton of adult osteopenic ovariectomized rats. Endocrinology 1993;132:1577-84
40. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocr Rev 1993;14:690-709
41. Reeve J, Hesp R, Williams D, Hulme P, Klenerman L, Zanelli JM, et al. Anabolic effect of low doses of a fragment of human parathyroid hormone on the skeleton in postmenopausal osteoporosis. Lancet 1976;1:1035-8
42. Reeve J, Arlot ME, Bradbeer JN, Hesp R, McAlly E, Meunier PJ, et al. Human parathyroid peptide treatment of vertebral osteoporosis. Osteoporos Int 1993;3 Suppl 1:199-203
43. Sone T, Fukunaga M, Ono S, Nishiyama T. A small dose of human parathyroid hormone(1-34) increased bone mass in the lumbar vertebrae in patients with senile osteoporosis. Miner Electrolyte Metab 1995;21:232-5
44. Lane NE, Sanchez S, Modin GW, Genant HK, Pierini E, Arnaud CD. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. Results of a randomized controlled clinical trial. J Clin Invest 1998;102:1627-33
45. Plotkin H, Gundberg C, Mitnick M, Stewart AF. Dissociation of bone formation from resorption during 2-week treatment with human parathyroid hormone-related peptide-(1-36) in humans: potential as an anabolic therapy for osteoporosis. J Clin Endocrinol Metab 1998;83:2786-91
46. Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen V, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997;350:550-5
47. Mosekilde L, Sogaard CH, Danielsen CC, Torring O. The anabolic effects of human parathyroid hormone (hPTH) on rat vertebral body mass are also reflected in the quality of bone, assessed by biomechanical testing: a comparison study between hPTH-(1-34) and hPTH-(1-84). Endocrinology 1991;129:421-8
48. Ejersted C, Andreassen TT, Hauge EM, Melsen F, Oxlund H. Parathyroid hormone (1-34) increases vertebral bone mass, compressive strength, and quality in old rats. Bone 1995;17:507-11
49. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41
50. Andreassen TT, Cacciafesta V. Intermittent parathyroid hormone treatment enhances guided bone regeneration in rat calvarial bone defects. J Craniofac Surg 2004;15:424-7; discussion 28-9
51. Andreassen TT, Ejersted C, Oxlund H. Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 1999;14:960-8
52. Chen H, Frankenburg EP, Goldstein SA, McCauley LK. Combination of local and systemic parathyroid hormone enhances bone regeneration. Clin Orthop Relat Res 2003:291-302
53. Miller SC, Hunziker J, Mecham M, Wronski TJ. Intermittent parathyroid hormone administration stimulates bone formation in the mandibles of aged ovariectomized rats. J Dent Res 1997;76:1471-6
54. Barros SP, Silva MA, Somerman MJ, Nociti FH, Jr. Parathyroid hormone protects against periodontitis-associated bone loss. J Dent Res 2003;82:791-5
55. Liu B, Tang J, Ji J, Gu J. The expression of functional human parathyroid hormone in a gene therapy model for osteoporosis. Cell Tissue Res 2004;317:57-63
56. Abou-Samra AB, Juppner H, Force T, Freeman MW, Kong XF, Schipani E, et al. Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci U S A 1992;89:2732-6
57. Rubin DA, Hellman P, Zon LI, Lobb CJ, Bergwitz C, Juppner H. A G protein-coupled receptor from zebrafish is activated by human parathyroid hormone and not by human or teleost parathyroid hormone-related peptide. Implications for the evolutionary conservation of calcium-regulating peptide hormones. J Biol Chem 1999;274:23035-42
58. Rubin DA, Juppner H. Zebrafish express the common parathyroid hormone/parathyroid hormone-related peptide receptor (PTH1R) and a novel receptor (PTH3R) that is preferentially activated by mammalian and fugufish parathyroid hormone-related peptide. J Biol Chem 1999;274:28185-90
59. Fujimori A, Cheng SL, Avioli LV, Civitelli R. Dissociation of second messenger activation by parathyroid hormone fragments in osteosarcoma cells. Endocrinology 1991;128:3032-9
60. Morgan EF, Mason ZD, Bishop G, Davis AD, Wigner NA, Gerstenfeld LC, et al. Combined effects of recombinant human BMP-7 (rhBMP-7) and parathyroid hormone (1-34) in metaphyseal bone healing. Bone 2008;43:1031-8
61. Jevon M, Guo C, Ma B, Mordan N, Nair SP, Harris M, et al. Mechanisms of internalization of Staphylococcus aureus by cultured human osteoblasts. Infect Immun 1999;67:2677-81
62. Nair SP, Meghji S, Wilson M, Reddi K, White P, Henderson B. Bacterially induced bone destruction: mechanisms and misconceptions. Infect Immun 1996;64:2371-80
63. Tarbox BB, Conroy BP, Malicky ES, Moussa FW, Hockman DE, Anglen JO, et al. Benzalkonium chloride. A potential disinfecting irrigation solution for orthopaedic wounds. Clin Orthop Relat Res 1998:255-61
64. Claro T, Widaa A, O'Seaghdha M, Miajlovic H, Foster TJ, O'Brien FJ, et al. Staphylococcus aureus protein A binds to osteoblasts and triggers signals that weaken bone in osteomyelitis. PLoS One 2011;6:e18748
65. Waness A. Revisiting Methicillin-Resistant Staphylococcus aureus Infections. J Glob Infect Dis 2010;2:49-56
66. Zilberberg MD, Shorr AF, Kollef MH. Growth and geographic variation in hospitalizations with resistant infections, United States, 2000-2005. Emerg Infect Dis 2008;14:1756-8
67. Zasloff M. Antimicrobial peptides of multicellular organisms. Nature 2002;415:389-95
68. Ganz T, Selsted ME, Szklarek D, Harwig SS, Daher K, Bainton DF, et al. Defensins. Natural peptide antibiotics of human neutrophils. J Clin Invest 1985;76:1427-35
69. Selsted ME, Harwig SS, Ganz T, Schilling JW, Lehrer RI. Primary structures of three human neutrophil defensins. J Clin Invest 1985;76:1436-9
70. Ganz T. Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 2003;3:710-20
71. Selsted ME, Ouellette AJ. Mammalian defensins in the antimicrobial immune response. Nat Immunol 2005;6:551-7
72. Pazgier M, Li X, Lu W, Lubkowski J. Human defensins: synthesis and structural properties. Curr Pharm Des 2007;13:3096-118
73. Cowland JB, Borregaard N. The individual regulation of granule protein mRNA levels during neutrophil maturation explains the heterogeneity of neutrophil granules. J Leukoc Biol 1999;66:989-95
74. Ayabe T, Satchell DP, Wilson CL, Parks WC, Selsted ME, Ouellette AJ. Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat Immunol 2000;1:113-8
75. Liu L, Roberts AA, Ganz T. By IL-1 signaling, monocyte-derived cells dramatically enhance the epidermal antimicrobial response to lipopolysaccharide. J Immunol 2003;170:575-80
76. Klotman ME, Chang TL. Defensins in innate antiviral immunity. Nat Rev Immunol 2006;6:447-56
77. Selsted ME, Brown DM, DeLange RJ, Lehrer RI. Primary structures of MCP-1 and MCP-2, natural peptide antibiotics of rabbit lung macrophages. J Biol Chem 1983;258:14485-9
78. Selsted ME, Szklarek D, Ganz T, Lehrer RI. Activity of rabbit leukocyte peptides against Candida albicans. Infect Immun 1985;49:202-6
79. Lehrer RI, Ganz T, Szklarek D, Selsted ME. Modulation of the in vitro candidacidal activity of human neutrophil defensins by target cell metabolism and divalent cations. J Clin Invest 1988;81:1829-35
80. Joly S, Maze C, McCray PB, Jr., Guthmiller JM. Human beta-defensins 2 and 3 demonstrate strain-selective activity against oral microorganisms. J Clin Microbiol 2004;42:1024-9
81. Feng Z, Dubyak GR, Lederman MM, Weinberg A. Cutting edge: human beta defensin 3--a novel antagonist of the HIV-1 coreceptor CXCR4. J Immunol 2006;177:782-6
82. Hazrati E, Galen B, Lu W, Wang W, Ouyang Y, Keller MJ, et al. Human alpha- and beta-defensins block multiple steps in herpes simplex virus infection. J Immunol 2006;177:8658-66
83. Scott MG, Hancock RE. Cationic antimicrobial peptides and their multifunctional role in the immune system. Crit Rev Immunol 2000;20:407-31
84. Harder J, Glaser R, Schroder JM. The role and potential therapeutical applications of antimicrobial proteins in infectious and inflammatory diseases. Endocr Metab Immune Disord Drug Targets 2007;7:75-82
85. Midorikawa K, Ouhara K, Komatsuzawa H, Kawai T, Yamada S, Fujiwara T, et al. Staphylococcus aureus susceptibility to innate antimicrobial peptides, beta-defensins and CAP18, expressed by human keratinocytes. Infect Immun 2003;71:3730-9
86. Huang HW. Action of antimicrobial peptides: two-state model. Biochemistry 2000;39:8347-52
87. Lohner K, Latal A, Lehrer RI, Ganz T. Differential scanning microcalorimetry indicates that human defensin, HNP-2, interacts specifically with biomembrane mimetic systems. Biochemistry 1997;36:1525-31
88. Matsuzaki K. Why and how are peptide-lipid interactions utilized for self-defense? Magainins and tachyplesins as archetypes. Biochim Biophys Acta 1999;1462:1-10
89. Shai Y. Mechanism of the binding, insertion and destabilization of phospholipid bilayer membranes by alpha-helical antimicrobial and cell non-selective membrane-lytic peptides. Biochim Biophys Acta 1999;1462:55-70
90. Dale BA, Krisanaprakornkit S. Defensin antimicrobial peptides in the oral cavity. J Oral Pathol Med 2001;30:321-7
91. Warnke PH, Springer IN, Russo PA, Wiltfang J, Essig H, Kosmahl M, et al. Innate immunity in human bone. Bone 2006;38:400-8
92. Varoga D, Tohidnezhad M, Paulsen F, Wruck CJ, Brandenburg L, Mentlein R, et al. The role of human beta-defensin-2 in bone. J Anat 2008;213:749-57
93. Varoga D, Wruck CJ, Tohidnezhad M, Brandenburg L, Paulsen F, Mentlein R, et al. Osteoblasts participate in the innate immunity of the bone by producing human beta defensin-3. Histochem Cell Biol 2009;131:207-18
94. Abiko Y, Nishimura M, Kaku T. Defensins in saliva and the salivary glands. Med Electron Microsc 2003;36:247-52
95. Kraus D, Deschner J, Jager A, Wenghoefer M, Bayer S, Jepsen S, et al. Human beta-defensins differently affect proliferation, differentiation, and mineralization of osteoblast-like MG63 cells. J Cell Physiol 2012;227:994-1003
96. Baroni A, Donnarumma G, Paoletti I, Longanesi-Cattani I, Bifulco K, Tufano MA, et al. Antimicrobial human beta-defensin-2 stimulates migration, proliferation and tube formation of human umbilical vein endothelial cells. Peptides 2009;30:267-72
97. Huang GT, Zhang HB, Kim D, Liu L, Ganz T. A model for antimicrobial gene therapy: demonstration of human beta-defensin 2 antimicrobial activities in vivo. Hum Gene Ther 2002;13:2017-25
98. Sawamura D, Goto M, Shibaki A, Akiyama M, McMillan JR, Abiko Y, et al. Beta defensin-3 engineered epidermis shows highly protective effect for bacterial infection. Gene Ther 2005;12:857-61
99. Yin C, Dang HN, Gazor F, Huang GT. Mouse salivary glands and human beta-defensin-2 as a study model for antimicrobial gene therapy: technical considerations. Int J Antimicrob Agents 2006;28:352-60
100. Yin C, Dang HN, Zhang HB, Gazor F, Kim D, Sorensen OE, et al. Capacity of human beta-defensin expression in gene-transduced and cytokine-induced cells. Biochem Biophys Res Commun 2006;339:344-54
101. Hirsch T, Spielmann M, Zuhaili B, Fossum M, Metzig M, Koehler T, et al. Human beta-defensin-3 promotes wound healing in infected diabetic wounds. J Gene Med 2009;11:220-8
102. Hao L, Wang J, Zou Z, Yan G, Dong S, Deng J, et al. Transplantation of BMSCs expressing hPDGF-A/hBD2 promotes wound healing in rats with combined radiation-wound injury. Gene Ther 2009;16:34-42
103. Gibson AL, Thomas-Virnig CL, Centanni JM, Schlosser SJ, Johnston CE, Van Winkle KF, et al. Nonviral human beta defensin-3 expression in a bioengineered human skin tissue: a therapeutic alternative for infected wounds. Wound Repair Regen 2012;20:414-24
104. D'Mello S, Atluri K, Geary SM, Hong L, Elangovan S, Salem AK. Bone regeneration using gene-activated matrices. AAPS J 2017;19:43-53
105. Chen DC, Lai YL, Lee SY, Hung SL, Chen HL. Osteoblastic response to collagen scaffolds varied in freezing temperature and glutaraldehyde crosslinking. J Biomed Mater Res A 2007;80:399-409
106. Takagi K, Urist MR. The reaction of the dura to bone morphogenetic protein (BMP) in repair of skull defects. Ann Surg 1982;196:100-9
107. Bilezikian JP, Raisz LG, Rodan GA. Principles of Bone Biology, Two-Volume Set. Academic Press, 2002.
108. Tsai CH, Chou MY, Jonas M, Tien YT, Chi EY. A composite graft material containing bone particles and collagen in osteoinduction in mouse. J Biomed Mater Res 2002;63:65-70
109. Schwartz Z, Somers A, Mellonig JT, Carnes DL, Jr., Dean DD, Cochran DL, et al. Ability of commercial demineralized freeze-dried bone allograft to induce new bone formation is dependent on donor age but not gender. J Periodontol 1998;69:470-8
110. Elangovan S, D'Mello SR, Hong L, Ross RD, Allamargot C, Dawson DV, et al. The enhancement of bone regeneration by gene activated matrix encoding for platelet derived growth factor. Biomaterials 2014;35:737-47
111. Kohles SS, Vernino AR, Clagett JA, Yang JC, Severson S, Holt RA. A morphometric evaluation of allograft matrix combinations in the treatment of osseous defects in a baboon model. Calcif Tissue Int 2000;67:156-62
112. Kempen DH, Lu L, Hefferan TE, Creemers LB, Heijink A, Maran A, et al. Enhanced bone morphogenetic protein-2-induced ectopic and orthotopic bone formation by intermittent parathyroid hormone (1-34) administration. Tissue Eng Part A 2010;16:3769-77
113. Kaito T, Morimoto T, Kanayama S, Otsuru S, Kashii M, Makino T, et al. Modeling and remodeling effects of intermittent administration of teriparatide (parathyroid hormone 1-34) on bone morphogenetic protein-induced bone in a rat spinal fusion model. Bone Rep 2016;5:173-80
114. Sheyn D, Cohn Yakubovich D, Kallai I, Su S, Da X, Pelled G, et al. PTH promotes allograft integration in a calvarial bone defect. Mol Pharm 2013;10:4462-71
115. Silva ED, Vasconcelos DF, Marques MR, Silva MA, Manzi FR, Barros SP. Intermittent administration of parathyroid hormone improves the repairing process of rat calvaria defects: A histomorphometric and radiodensitometric study. Med Oral Patol Oral Cir Bucal 2015;20:e489-93
116. Uzawa T, Hori M, Ejiri S, Ozawa H. Comparison of the effects of intermittent and continuous administration of human parathyroid hormone(1-34) on rat bone. Bone 1995;16:477-84
117. Shen V, Birchman R, Wu DD, Lindsay R. Skeletal effects of parathyroid hormone infusion in ovariectomized rats with or without estrogen repletion. J Bone Miner Res 2000;15:740-6
118. Poole KE, Reeve J. Parathyroid hormone - a bone anabolic and catabolic agent. Curr Opin Pharmacol 2005;5:612-7
119. Khan SN, Lane JM. The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in orthopaedic applications. Expert Opin Biol Ther 2004;4:741-8
120. Nevins M, Giannobile WV, McGuire MK, Kao RT, Mellonig JT, Hinrichs JE, et al. Platelet-derived growth factor stimulates bone fill and rate of attachment level gain: results of a large multicenter randomized controlled trial. J Periodontol 2005;76:2205-15
121. Evans CH. Gene delivery to bone. Adv Drug Deliv Rev 2012;64:1331-40
122. Lu CH, Chang YH, Lin SY, Li KC, Hu YC. Recent progresses in gene delivery-based bone tissue engineering. Biotechnol Adv 2013;31:1695-706
123. Feeley BT, Conduah AH, Sugiyama O, Krenek L, Chen IS, Lieberman JR. In vivo molecular imaging of adenoviral versus lentiviral gene therapy in two bone formation models. J Orthop Res 2006;24:1709-21
124. Tsai CC, Chen YJ, Yew TL, Chen LL, Wang JY, Chiu CH, et al. Hypoxia inhibits senescence and maintains mesenchymal stem cell properties through down-regulation of E2A-p21 by HIF-TWIST. Blood 2011;117:459-69
125. Yew TL, Huang TF, Ma HL, Hsu YT, Tsai CC, Chiang CC, et al. Scale-up of MSC under hypoxic conditions for allogeneic transplantation and enhancing bony regeneration in a rabbit calvarial defect model. J Orthop Res 2012;30:1213-20
126. Yang D, Chertov O, Bykovskaia SN, Chen Q, Buffo MJ, Shogan J, et al. Beta-defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 1999;286:525-8
127. Rohrl J, Yang D, Oppenheim JJ, Hehlgans T. Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2. J Immunol 2010;184:6688-94
128. Funderburg N, Lederman MM, Feng Z, Drage MG, Jadlowsky J, Harding CV, et al. Human β-defensin-3 activates professional antigen-presenting cells via Toll-like receptors 1 and 2. Proc Natl Acad Sci U S A 2007;104:18631-5
129. Seebach E, Holschbach J, Buchta N, Bitsch RG, Kleinschmidt K, Richter W. Mesenchymal stromal cell implantation for stimulation of long bone healing aggravates Staphylococcus aureus induced osteomyelitis. Acta Biomater 2015;21:165-77
130. Ward CL, Sanchez CJ, Jr., Pollot BE, Romano DR, Hardy SK, Becerra SC, et al. Soluble factors from biofilms of wound pathogens modulate human bone marrow-derived stromal cell differentiation, migration, angiogenesis, and cytokine secretion. BMC Microbiol 2015;15:75
131. Pietila M, Lahteenmaki K, Lehtonen S, Leskela HV, Narhi M, Lonnroth M, et al. Monitoring mitochondrial inner membrane potential for detecting early changes in viability of bacterium-infected human bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther 2012;3:53
132. Warnke PH, Voss E, Russo PA, Stephens S, Kleine M, Terheyden H, et al. Antimicrobial peptide coating of dental implants: biocompatibility assessment of recombinant human beta defensin-2 for human cells. Int J Oral Maxillofac Implants 2013;28:982-8
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