Icariin: Does it have an osteoinductive potential for bone tissue engineering?

Phytotherapy Research

Volumn 28, Issue 4, 2014, Pages 498-509

  Zhang, Xin ^a   Liu, Tie ^b   Huang, Yuanliang ^c   Wismeijer, Daniel ^b   Liu, Yuelian ^b  

^a TONGJI UNIVERSITY   (China)

^b UNIVERSITY OF AMSTERDAM   (Netherlands)

^c Key Laboratory of Arrhythmias of Ministry of Education   (China)

Author keywords

BMPs; bone regeneration; bone tissue engineering; icariin; osteoinductive

Indexed keywords

3,5,7 TRIHYDROXY 4' METHOXY 8 (3 HYDROXY 3 METHYLBUTYL) FLAVONE; BIOMATERIAL; BONE MORPHOGENETIC PROTEIN; BU ZHONG YI QI TANG; BUSHEN NINGXIN; CALCIUM PHOSPHATE CERAMIC; CHITOSAN; DANG GUI JI HWANG YEUM; DRYNARIAE RHIZOMA; FLAVONE DERIVATIVE; FLAVONOID GLYCOSIDE; HACHIMIJIOGAN; HERBACEOUS AGENT; HYDROXYAPATITE; ICARIIN; JIAN GU; KAMI KIHI TO; LIPOSOME; PROPYLENE GLYCOL; PUERARIAE RADIX; SAMBUCUS WILLIAMSI; SHEN GU; SHU DI SHAN ZHA; UNCLASSIFIED DRUG; XIAN LING GU BAO; YANG HUO GU BAO;

ABELMOSCHUS; ABELMOSCHUS MANIHOT; ACTAEA RACEMOSA; ANGIOGENESIS; ASTRAGALUS MEMBRANACEUS; BONE DEVELOPMENT; BONE REGENERATION; BONE REMODELING; BONE TISSUE; CHINESE MEDICINE; CHONDROGENESIS; CISTANCHE SALSA; DRUG COST; DRUG DELIVERY SYSTEM; DRUG FORMULATION; DRUG STRUCTURE; EXTRACTION; HERB; HERBA EPIMEDII; HUMAN; MUSCULOSKELETAL SYSTEM; NONHUMAN; OSTEOCLASTOGENESIS; OSTEOPOROSIS; REVIEW; SIGNAL TRANSDUCTION; TISSUE ENGINEERING; WEDELIA; WEDELIA CALENDULACEA;

BMPS; BONE REGENERATION; BONE TISSUE ENGINEERING; ICARIIN; OSTEOINDUCTIVE;

ANIMALS; BONE AND BONES; BONE REGENERATION; DRUGS, CHINESE HERBAL; FLAVONOIDS; HUMANS; MEDICINE, CHINESE TRADITIONAL; OSTEOGENESIS; OSTEOPOROSIS; SIGNAL TRANSDUCTION; TISSUE ENGINEERING;

EID: 84898733886     PISSN: 0951418X     EISSN: 10991573     Source Type: Journal    
DOI: 10.1002/ptr.5027     Document Type: Review

References (132)

1. Ahlmann E, Patzakis M, Roidis N, Shepherd L, Holtom P,. 2002. Comparison of anterior and posterior iliac crest bone grafts in terms of harvest-site morbidity and functional outcomes. J Bone Joint Surg Am 84: 716-720.
2. Alt V, Bitschnau A, Schnettler R,. 2006. Cost-benefit analysis of the use of rhBMP-2 in open tibial fractures. Savings from a health insurer's perspective. Unfallchirurg 109: 463-470
3. Annie S, Prabhu RG, Malini S,. 2006. Activity of Wedelia calendulacea Less. in post-menopausal osteoporosis. Phytomedicine 13: 43-48.
4. Bauer TW, Muschler GF,. 2000. Bone graft materials. An overview of the basic science. Clin Orthop Relat Res 371: 10-27.
5. Bi W, Deng JM, Zhang Z, Behringer RR, De Crombrugghe B,. 1999. Sox9 is required for cartilage formation. Nat Genet 22: 85-89.
6. Bian Q, Huang JH, Liu SF, et al,. 2012. Different molecular targets of Icariin on bMSCs in CORT and OVX -rats. Front Biosci (Elite Ed) 4: 1224-1236.
7. Bridwell KH, Anderson PA, Boden SD, Vaccaro AR, Zigler JE,. 2004. What's new in spine surgery. J Bone Joint Surg Am 86: 1587-1594.
8. Byers BA, Guldberg RE, Garcia AJ,. 2004. Synergy between genetic and tissue engineering: Runx2 overexpression and in vitro construct development enhance in vivo mineralization. Tissue Eng 10: 1757-1766.
9. Cao H, Ke Y, Zhang Y, Zhang CJ, Qian W, Zhang GL,. 2012. Icariin stimulates MC3T3-E1 cell proliferation and differentiation through up-regulation of bone morphogenetic protein-2. Int J Mol Med 29: 435-439.
10. Casado PL, Duarte MEL, Carvalho W, da Silva LE, Barboza EP,. 2010. Ridge bone maintenance in human after extraction. Implant Dent 19: 314-322.
11. Chae HJ, Yun DH, Chin HY, et al,. 2004. Effect of dang-gui-ji-hwang-yeum on osteoporosis in ovariectomized rats. Am J Chin Med 32: 351-360.
12. Chen KM, Ge BF, Ma HP, Liu XY, Bai MH, Wang Y,. 2005. Icariin, a flavonoid from the herb Epimedium enhances the osteogenic differentiation of rat primary bone marrow stromal cells. Pharmazie 60 (12): 939-942.
13. Chen KM, Ge BF, Liu XY, et al,. 2007a. Icariin inhibits the osteoclast formation induced by RANKL and macrophage-colony stimulating factor in mouse bone marrow culture. Pharmazie 62: 388-391.
14. Chen KM, Ma HP, Ge BF, et al,. 2007b. Icariin enhances the osteogenic differentiation of bone marrow stromal cells but has no effects on the differentiation of newborn calvarial osteoblasts of rats. Pharmazie 62: 785-789.
15. Chen SR, Xu XZ, Wang YH, et al,. 2010. Icariin derivative inhibits inflammation through suppression of p38 mitogen-activated protein kinase and nuclear factor-kappaB pathways. Biol Pharm Bull 33: 1307-1313.
16. Chung BH, Kim JD, Kim CK, et al,. 2008. Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells. Biochem Biophys Res Commun 376: 404-408.
17. Cowan CM, Shi YY, Aalami OO, et al,. 2004. Adipose-derived adult stromal cells heal critical-size mouse calvarial defects. Nat Biotechnol 22: 560-567.
18. Dai Y, Liu H, Xia L, Zhou Z,. 2011. Preparation and characterization of icariin/PHBV drug delivery coatings on anodic oxidized titanium. Trans Nonferrous Met Soc China 21 (11): 2448-2453.
19. Dickerman RD, Reynolds AS, Morgan BC, Tompkins J, Cattorini J, Bennett M,. 2007. rh-BMP-2 can be used safely in the cervical spine: dose and containment are the keys! Spine J 7: 508-509.
20. Donos N, Lang NP, Karoussis IK, Bosshardt D, Tonetti M, Kostopoulos L,. 2004. Effect of GBR in combination with deproteinized bovine bone mineral and/or enamel matrix proteins on the healing of critical-size defects. Clin Oral Implants Res 15: 101-111.
21. Dorozhkin SV,. 2010. Bioceramics of calcium orthophosphates. Biomaterials 31: 1465-1485.
22. Einhorn TA,. 1998. The cell and molecular biology of fracture healing. Clin Orthop Relat Res 355: S7-21.
23. Fan J, Bi L, Wu T, et al,. 2012. A combined chitosan/nano-size hydroxyapatite system for the controlled release of icariin. J Mater Sci Mater Med 23: 399-407.
24. Fan JJ, Cao LG, Wu T, et al,. 2011. The dose-effect of icariin on the proliferation and osteogenic differentiation of human bone mesenchymal stem cells. Molecules 16: 10123-10133.
25. Franceschi RT, Yang S, Rutherford RB, Krebsbach PH, Zhao M, Wang D,. 2004. Gene therapy approaches for bone regeneration. Cells Tissues Organs 176: 95-108.
26. Garrison KR, Shemilt I, Donell S, et al,. 2010. Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev 6: 1-51.
27. Geesink RGT, Hoefnagels NHM, Bulstra SK,. 1999. Osteogenic activity of OP-1 bone morphogenetic protein (BMP-7) in a human fibular defect. J Bone Joint Surg Br 81: 710-718.
28. Guan XY, Li HF, Yang WZ, et al,. 2011. HPLC-DAD-MS(n) analysis and HPLC quantitation of chemical constituents in Xian-ling-gu-bao capsules. J Pharm Biomed Anal 55: 923-933.
29. Guo HL, Zhao YF, Wang X, Xu Y, Zhan HS,. 2011. Experimental study on the mechanism of icariin improving human osteoblasts proliferation and the expression of OPG protein. Beijing Da Xue Xue Bao 24: 585-588.
30. He W, Li ZL, Cui YL, et al,. 2009. Effect of icariin on the mRNA expressions of Cbfalpha1, BMP2, BMP4 in rat osteoblasts. Beijing Da Xue Xue Bao 41: 669-673.
31. Hidaka S, Okamoto Y, Nakajima K, Suekawa M, Liu SY,. 1997. Preventive effects of traditional Chinese (Kampo) medicines on experimental osteoporosis induced by ovariectomy in rats. Calcif Tissue Int 61: 239-246.
32. Hsieh TP, Sheu SY, Sun JS, Chen MH,. 2011. Icariin inhibits osteoclast differentiation and bone resorption by suppression of MAPKs/NF-kappaB regulated HIF-1alpha and PGE(2) synthesis. Phytomedicine 18: 176-185.
33. Hsieh TP, Sheu SY, Sun JS, Chen MH, Liu MH,. 2010. Icariin isolated from Epimedium pubescens regulates osteoblasts anabolism through BMP-2, SMAD4, and Cbfa1 expression. Phytomedicine 17: 414-423.
34. Huang J, Yuan L, Wang X, Zhang TL, Wang K,. 2007a. Icaritin and its glycosides enhance osteoblastic, but suppress osteoclastic, differentiation and activity in vitro. Life Sci 81: 832-840.
35. Huang J, Zhang J, Zhang TL, Wang K,. 2007b. Icariin suppresses bone resorption activity of rabbit osteoclasts in vitro. Chin Sci Bull 52 (7): 890-895.
36. Islam NM, Yoo HH, Lee MW, et al,. 2008. Simultaneous quantitation of five flavonoid glycosides in Herba Epimedii by high-performance liquid chromatography-tandem mass spectrometry. Phytoche Anal 19: 71-77.
37. Jeong JC, Lee BT, Yoon CH, Kim HM, Kim CH,. 2005. Effects of Drynariae rhizoma on the proliferation of human bone cells and the immunomodulatory activity. Pharmacol Res 51: 125-136.
38. Jeong JC, Yoon CH, Jeong CW, Lee YC, Chang YC, Kim CH,. 2004. Inhibitory activity of Drynariae rhizoma extracts on cathepsin having bone resorption activity. Immunopharmacol Immunotoxicol 26: 373-385.
39. Ji RR, Li FY, Zhang XJ,. 2005. Effect of icariin on hypoxia induced vascular endothelial cells injury. Chin J Integ Tradit Western Med 25: 525-530.
40. Jia HH, Gao JL, Zeng W, et al,. 2011. Study on extraction process for the icariin of hugu capsule with ultrasonic technology. J Chin Med Mater 34: 1604-1607.
41. Joo SS, Won TJ, Kang HC, Lee DI,. 2004. Isoflavones extracted from Sophorae fructus upregulate IGF-I and TGF-beta and inhibit osteoclastogenesis in rat bone marrow cells. Arch Pharm Res 27: 99-105.
42. Kanai S, Taniguchi N, Higashino H,. 2005. Effect of kami-kihi-to (jia-wei-gui-pi-tang) for experimental osteopenia. Am J Chin Med 33: 41-48.
43. Kang Q, Sun MH, Cheng H, et al,. 2004. Characterization of the distinct orthotopic bone-forming activity of 14 BMPs using recombinant adenovirus-mediated gene delivery. Gene Ther 11: 1312-1320.
44. Kao DW, Kubota A, Nevins M, Fiorellini JP,. 2012. The Negative Effect of Combining rhBMP-2 and Bio-Oss on Bone Formation for Maxillary Sinus Augmentation. Int J Periodontics Restorative Dent 32: 61-67.
45. Kim C, Ha H, Lee JH, Kim JS, Song K, Park SW,. 2003. Herbal extract prevents bone loss in ovariectomized rats. Arch Pharm Res 26: 917-924.
46. Koizumi H, Yu J, Hashimoto R, Ouchi Y, Okabe T,. 2010. Involvement of androgen receptor in nitric oxide production induced by icariin in human umbilical vein endothelial cells. FEBS Lett 584: 2440-2444.
47. Langer R,. 2009. Perspectives and challenges in tissue engineering and regenerative medicine. Adv Mater 21: 3235-3236.
48. Lee SY, Choi DY, Woo ER,. 2005. Inhibition of osteoclast differentiation by tanshinones from the root of Salvia miltiorrhiza bunge. Arch Pharm Res 28: 909-9013.
49. Li D, Yuan T, Zhang X, Xiao Y, Wang R, Fan Y,. 2012. Icariin: a potential promoting compound for cartilage tissue engineering. Osteoarthritis Cartilage 20: 1647-1656.
50. Li HB, Chen F,. 2009. Separation and Purification of Epimedin A, B, C, and Icariin from the Medicinal Herb Epimedium brevicornum Maxim by Dual-Mode HSCCC. J Chromatogr Sci 47: 337-340.
51. Li L, Peng L, Miao J, et al,. 2011. Icariin induces the expression of toll-like receptor 9 in ana-1 murine macrophages. Phytother Res 25: 1732-1735.
52. Liang W, Lin M, Li X, et al,. 2012. Icariin promotes bone formation via the BMP-2/Smad4 signal transduction pathway in the hFOB 1.19 human osteoblastic cell line. Int J Mol Med 30: 889-895.
53. Liao S, Kao YH, Hiipakka RA,. 2001. Green tea: biochemical and biological basis for health benefits. Vitam Horm 62: 1-94.
54. Lieberman JR, Daluiski A, Einhorn TA,. 2002. The role of growth factors in the repair of bone-Biology and clinical applications. J Bone Joint Surg Am 84: 1032-1044.
55. Lin YP, Zhou RX, Guo SM,. 2004. Effect of jiangu granule on quality of bone in model rats with osteoporosis induced by ovariectomy. Chin J Integ Tradit Western Med 24: 431-434.
56. Liu M, Zhong C, He RX, Chen LF,. 2012. Icariin associated with exercise therapy is an effective treatment for postmenopausal osteoporosis. Chin Med J 125: 1784-1789.
57. Liu MH, Sun JS, Tsai SW, Sheu SY, Chen MH,. 2010a. Icariin protects murine chondrocytes from lipopolysaccharide-induced inflammatory responses and extracellular matrix degradation. Nutr Res 30: 57-65.
58. Liu T, Qin XC, Li WR, et al,. 2011. Effects of icariin and icariside II on eNOS expression and NOS activity in porcine aorta endothelial cells. Beijing Da Xue Xue Bao 43: 500-504.
59. Liu Y, Wu G, De Groot K,. 2010b. Biomimetic coatings for bone tissue engineering of critical-sized defects. J R Soc Interface 7: S631-647.
60. Liu Y, Zang H, Zhang H, Chen J,. 2005. Effect of Herba Epimedii Flavone on expression of OPG and RANKL in rat osteoblasts. J Chin Med Mater 28: 1076-1078.
61. Liu YH, Zhang HY, Zang HM, Cheng JC,. 2006. Effect of Herba Epimedii flavone on the osteoblasts metabolism in vitro. China J Chin Mater Med 31: 487-490.
62. Luo Y, Nie J, Gong QH, Lu YF, Wu Q, Shi JS,. 2007. Protective effects of icariin against learning and memory deficits induced by aluminium in rats. Clin Exp Pharmacol Physiol 34: 792-795.
63. Ma HP, Ming LG, Ge BF, et al,. 2011. Icariin is more potent than genistein in promoting osteoblast differentiation and mineralization in vitro. J Cell Biochem 112: 916-923.
64. Magin MN, Delling G,. 2001. Improved lumbar vertebral interbody fusion using rhOP-1: a comparison of autogenous bone graft, bovine hydroxylapatite (Bio-Oss), and BMP-7 (rhOP-1) in sheep. Spine 26: 469-478.
65. Meng FH, Li YB, Xiong ZL, Jiang ZM, Li FM,. 2005a. Osteoblastic proliferative activity of Epimedium brevicornum Maxim. Phytomedicine 12: 189-193.
66. Meng FH, Xiong ZL, Jiang ZM, Li FM,. 2005b. Osteoblastic proliferation stimulating activity of Epimedium koreanum Nakai extracts and its flavonol glycosides. Pharm Biol 43 (1): 92-95.
67. Ming L, Chen K, Ge B, Ma H, Zhou J,. 2011. Comparative study on effect of icariin and genistein on proliferation and mineralization of osteoblasts in vitro. China J Chin Mater Med 36: 2240-2245.
68. Mingyue W, Ling G, Bei X, Junqing C, Peiqing Z, Jie H,. 2005. Clinical observation on 96 cases of primary osteoporosis treated with kidney-tonifying and bone-strengthening mixture. J Tradit Chin Med 25: 132-136.
69. Mok SK, Chen WF, Lai WP, et al,. 2010. Icariin protects against bone loss induced by oestrogen deficiency and activates oestrogen receptor-dependent osteoblastic functions in UMR 106 cells. Br J Pharmacol 159: 939-949.
70. Mordenfeld A, Hallman M, Johansson CB, Albrektsson T,. 2010. Histological and histomorphometrical analyses of biopsies harvested 11 years after maxillary sinus floor augmentation with deproteinized bovine and autogenous bone. Clin Oral Implants Res 21: 961-970.
71. Nian H, Ma MH, Nian SS, Xu LL,. 2009. Antiosteoporotic activity of icariin in ovariectomized rats. Phytomedicine 16: 320-326.
72. Nisslein T, Freudenstein J,. 2003. Effects of an isopropanolic extract of Cimicifuga racemosa on urinary crosslinks and other parameters of bone quality in an ovariectomized rat model of osteoporosis. J Bone Miner Metab 21: 370-376.
73. Otto WR, Rao J,. 2004. Tomorrow's skeleton staff: mesenchymal stem cells and the repair of bone and cartilage. Cell Prolif 37: 97-110.
74. Ozkan Y, Akoglu B, Kulak-Ozkan Y,. 2011. Maxillary sinus floor augmentation using bovine bone grafts with simultaneous implant placement: a 5-year prospective follow-up study. Implant Dent 20: 455-459.
75. Park JB,. 2011. Treatment of peri-implantitis with deproteinised bovine bone and tetracycline: a case report. Gerodontology 29: 145-149.
76. Pei LK, Guo BL,. 2007. A review on research of raw material and cut crude drug of Herba epimedii in last ten years. China J Chin Mater Med 32: 466-471.
77. Puel C, Mathey J, Kati-Coulibaly S, et al,. 2005. Preventive effect of Abelmoschus manihot (L.) Medik. on bone loss in the ovariectomised rats. J Ethnopharmacol 99: 55-60.
78. Putnam SE, Scutt AM, Bicknell K, Priestley CM, Williamson EM,. 2007. Natural products as alternative treatments for metabolic bone disorders and for maintenance of bone health. Phytother Res 21: 99-112.
79. Qian G, Zhang X, Lu L, Wu X, Li S, Meng J,. 2006. Regulation of Cbfa1 expression by total flavonoids of Herba epimedii. Endocr J 53: 87-94.
80. Qian Q, Li SL, Sun E, et al,. 2012. Metabolite profiles of icariin in rat plasma by ultra-fast liquid chromatography coupled to triple-quadrupole/time- of-flight mass spectrometry. J Pharm Biomed Anal 66: 392-398.
81. Qin L, Han T, Zhang Q, et al,. 2008. Antiosteoporotic chemical constituents from Er-Xian Decoction, a traditional Chinese herbal formula. J Ethnopharmacol 118 (2): 271-279.
82. Qin L, Zhang G, Hung WY, et al,. 2005. Phytoestrogen-rich herb formula XLGB prevents OVX-induced deterioration of musculoskeletal tissues at the hip in old rats. J Bone Miner Metab 23: 55-61.
83. Ruhe PQ, Boerman OC, Russel FG, Spauwen PH, Mikos AG, Jansen JA,. 2005. Controlled release of rhBMP-2 loaded poly(dl-lactic-co-glycolic acid)/calcium phosphate cement composites in vivo. J Control Release 106: 162-171.
84. Rustemeyer J, Bremerich A,. 2007. Patients ' knowledge and expectations regarding dental implants: assessment by questionnaire. Int J Oral Maxillofac Surg 36: 814-817.
85. Sakamoto S, Sassa S, Kudo H, Suzuki S, Mitamura T, Shinoda H,. 2000. Preventive effects of a herbal medicine on bone loss in rats treated with a GnRH agonist. Eur J Endocrinol 143: 139-142.
86. Schmidmaier G, Capanna R, Wildemann B, Beque T, Lowenberg D,. 2009. Bone morphogenetic proteins in critical-size bone defects: what are the options? Injury 40: S39-43.
87. Seeherman H, Azari K, Bidic S, et al,. 2006. rhBMP-2 delivered in a calcium phosphate cement accelerates bridging of critical-sized defects in rabbit radii. J Bone Joint Surg Am 88: 1553-1565.
88. Shang TY, Gu YW, Dong FH,. 1987. Treatment of forearm bone fractures by an integrated method of traditional Chinese and Western medicine. Clin Orthop Relat Res 215: 56-64.
89. Shimer AL, Oner FC, Vaccaro AR,. 2009. Spinal reconstruction and bone morphogenetic proteins: open questions. Injury 40: S32-38.
90. Shirwaikar A, Khan S, Malini S,. 2003. Antiosteoporotic effect of ethanol extract of Cissus quadrangularis Linn. on ovariectomized rat. J Ethnopharmacol 89: 245-250.
91. Stevenson S,. 1998. Enhancement of fracture healing with autogenous and allogeneic bone grafts. Clin Orthop Relat Res 355: S239-246.
92. Tonetti MS, Haemmerle CH,. 2008. Advances in bone augmentation to enable dental implant placement: Consensus Report of the Sixth European Workshop on Periodontology. J Clin Periodontol 35: 168-172.
93. Urist MR,. 1965. Bone-Formation by Autoinduction. Science 150: 893-899.
94. Wang D, Li F, Jiang Z,. 2001. Osteoblastic proliferation stimulating activity of Psoralea corylifolia extracts and two of its flavonoids. Planta Med 67: 748-749.
95. Wang F, Liu Z, Lin S, Lu H, Xu J,. 2012. Icariin enhances the healing of rapid palatal expansion induced root resorption in rats. Phytomedicine 19: 1035-1041.
96. Wang J, Zheng Y, Zhao J, et al,. 2011. Low-dose rhBMP2/7 heterodimer to reconstruct peri-implant bone defects: a micro-CT evaluation. J Clin Periodontol 39: 98-105.
97. Wang YK, Huang ZQ,. 2005. Protective effects of icariin on human umbilical vein endothelial cell injury induced by H2O2 in vitro. Pharmacol Res 52: 174-182.
98. Wei H, Zili L, Yuanlu C, et al,. 2011. Effect of icariin on bone formation during distraction osteogenesis in the rabbit mandible. Int J Oral Maxillofac Surg 40: 413-418.
99. Wernike E, Montjovent MO, Liu Y, et al,. 2010. VEGF incorporated into calcium phosphate ceramics promotes vascularisation and bone formation in vivo. Eur Cell Mater 19: 30-40.
100. Wu J, Du J, Xu C, et al,. 2011. In vivo and in vitro anti-inflammatory effects of a novel derivative of icariin. Immunopharmacol Immunotoxicol 33: 49-54.
101. Wu J, Zhou J, Chen X, et al,. 2012. Attenuation of LPS-induced inflammation by ICT, a derivate of icariin, via inhibition of the CD14/TLR4 signaling pathway in human monocytes. Int Immunopharmacol 12: 74-79.
102. Wu JF, Dong JC, Xu CQ,. 2009a. Effects of icariin on inflammation model stimulated by lipopolysaccharide in vitro and in vivo. Chin J Integ Tradit Western Med 29: 330-334.
103. Wu T, Nan KH, Chen JD, et al,. 2009b. A new bone repair scaffold combined with chitosan/hydroxyapatite and sustained releasing icariin. Chin Sci Bull 54: 2953-2961.
104. Xiao Q, Chen A, Guo F,. 2005. Effects of Icariin on expression of OPN mRNA and type I collagen in rat osteoblasts in vitro. J Huazhong Univ Sci Technolog Med Sci 25: 690-692.
105. Xie F, Wu CF, Lai WP, et al,. 2005a. The osteoprotective effect of Herba epimedii (HEP) extract in vivo and in vitro. Evid Based Complement Alternat Med 2: 353-361.
106. Xie F, Wu CF, Zhang Y, et al,. 2005b. Increase in bone mass and bone strength by Sambucus williamsii HANCE in ovariectomized rats. Biol Pharm Bull 28: 1879-1885.
107. Xu CQ, Liu BJ, Wu JF, et al,. 2010. Icariin attenuates LPS-induced acute inflammatory responses: involvement of PI3K/Akt and NF-kappaB signaling pathway. Eur J Pharmacol 642: 146-153.
108. Xu H, Lawson D,. 2004. Effects of Chinese herbal medicine on bone structure and function. J Tradit Chin Med 24: 224-232.
109. Xu HB, Huang ZQ,. 2007. Icariin enhances endothelial nitric-oxide synthase expression on human endothelial cells in vitro. Vascul Pharmacol 47: 18-24.
110. Xue L, Jiao L, Wang Y, et al,. 2012a. Effects and interaction of icariin, curculigoside, and berberine in er-xian decoction, a traditional chinese medicinal formula, on osteoclastic bone resorption. Evid Based Complement Alternat Med. doi: 10.1155/2012/490843
111. Xue L, Wang Y, Jiang Y, et al,. 2012b. Comparative effects of er-xian decoction, epimedium herbs, and icariin with estrogen on bone and reproductive tissue in ovariectomized rats. Evid Based Complement Alternat Med. doi: 10.1155/2012/241416
112. Yamaguchi K, Shinohara C, Kojima S, Sodeoka M, Tsuji T,. 1999. (2E,6R)-8-hydroxy-2,6-dimethyl-2-octenoic acid, a novel anti-osteoporotic monoterpene, isolated from Cistanche salsa. Biosci Biotechnol Biochem 63: 731-735. doi: 10.1155/2012/241416
113. Yamamoto M, Tabata Y, Hong L, Miyamoto S, Hashimoto N, Ikada Y,. 2000. Bone regeneration by transforming growth factor beta 1 released from a biodegradable hydrogel. J Control Release 64: 133-142.
114. Yang L, Lu D, Guo J, Meng X, Zhang G, Wang F,. 2013. Icariin from Epimedium brevicornum Maxim promotes the biosynthesis of estrogen by aromatase (CYP19). J Ethnopharmacol 145 (3): 715-721.
115. Yang W, Yu XC, Chen XY, Zhang L, Lu CT, Zhao YZ,. 2012. Pharmacokinetics and tissue distribution profile of icariin propylene glycol-liposome intraperitoneal injection in mice. J Pharm Pharmacol 64: 190-198.
116. Yin XX, Chen ZQ, Dang GT, Ma QJ, Liu ZJ,. 2005. Effects of Epimedium pubescens epimedium on proliferation and differentiation of human osteoblasts. China J Chin Mat Med (in Chinese) 30: 289-291.
117. Yin XX, Chen ZQ, Liu ZJ, Ma QJ, Dang GT,. 2007. Icariine stimulates proliferation and differentiation of human osteoblasts by increasing production of bone morphogenetic protein 2. Chin Med J 120 (3): 204-210.
118. Zhai YK, Li ZZ, Chen KM, Zhang N, Cheng GZ, Zhu RQ,. 2011. Effects of icariin on the proliferation, differentiation and maturation of rat calvarial osteoblasts in vitro. J Chin Med Mater 34: 917-922.
119. Zhang D, Zhang J, Fong C, Yao X, Yang M,. 2012a. Herba epimedii flavonoids suppress osteoclastic differentiation and bone resorption by inducing G2/M arrest and apoptosis. Biochimie 94 (12): 2514-2522.
120. Zhang DW, Cheng Y, Wang NL, Zhang JC, Yang MS, Yao XS,. 2008a. Effects of total flavonoids and flavonol glycosides from Epimedium koreanum Nakai on the proliferation and differentiation of primary osteoblasts. Phytomedicine 15: 55-61.
121. Zhang DW, Cheng Y, Zhang JC, et al,. 2008b. Synergistic effect of trace elements and flavonoids from Epimedium koreanum Nakai on primary osteoblasts. Chin Sci Bull 53 (3): 347-356.
122. Zhang G, Qin L, Shi Y,. 2007. Epimedium-derived phytoestrogen flavonoids exert beneficial effect on preventing bone loss in late postmenopausal women: a 24-month randomized, double-blind and placebo-controlled trial. J Bone Miner Res 22: 1072-1079.
123. Zhang HF, Yang TS, Li ZZ, Wang Y,. 2008c. Simultaneous extraction of epimedin A, B, C and icariin from Herba Epimedii by ultrasonic technique. Ultrason Sonochem 15: 376-385.
124. Zhang J, Li Y, Sun J, Liu C, Zhang D,. 2011a. Synergistic or Antagonistic Effect of MTE plus TF or Icariin from Epimedium koreanum on the Proliferation and Differentiation of Primary Osteoblasts In Vitro. Biol Trace Elem Res 143 (3): 1746-1757.
125. Zhang L, Zhang X, Li KF, et al,. 2012b. Icariin promotes extracellular matrix synthesis and gene expression of chondrocytes in vitro. Phytother Res 26: 1385-1392.
126. Zhang X, Guo Y, Li DX, et al,. 2011b. The effect of loading icariin on biocompatibility and bioactivity of porous beta-TCP ceramic. J Mater Sci Mater Med 22: 371-379.
127. Zhao BH, Katagiri T, Toyoda H, et al,. 2006. Heparin potentiates the in vivo ectopic bone formation induced by bone morphogenetic protein-2. J Biol Chem 281: 23246-23253.
128. Zhao J, Ohba S, Komiyama Y, Shinkai M, Chung UI, Nagamune T,. 2010. Icariin: a potential osteoinductive compound for bone tissue engineering. Tissue Eng Part A 16: 233-243.
129. Zhao J, Ohba S, Shinkai M, Chung UI, Nagamune T,. 2008. Icariin induces osteogenic differentiation in vitro in a BMP- and Runx2-dependent manner. Biochem Biophys Res Commun 369: 444-448.
130. Zheng D, Peng S, Yang SH, et al,. 2012. The beneficial effect of Icariin on bone is diminished in osteoprotegerin-deficient mice. Bone 51: 85-92.
131. Zhou J, Wu J, Chen X, et al,. 2011. Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions. Int Immunopharmacol 11: 890-898.
132. Zhu HM, Qin L, Garnero P, et al,. 2012. The first multicenter and randomized clinical trial of herbal Fufang for treatment of postmenopausal osteoporosis. Osteoporos Int 23: 1317-1327.