Research progress of icariin in the treatment of periodontitis and bone defect repairing_West China Medical Journal

Authors：

ZHOU Ziqi ¹ , YANG Sen ² ,  GUO Lijuan ²

1. Oral and Maxillofacial Surgery, People’s Hospital of Anshun City Guizhou Province, Anshun, Guizhou 561000, P. R. China;
2. Stomatology, Suining Central Hospital, Suining, Sichuan 629000, P. R. China;

Corresponding author：

GUO Lijuan, Email: 663418587@qq.com

Keywords：

Icariin; periodontitis treatment; bone defect repairing

DOI：

10.7507/1002-0179.202006226

Video：

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Abstract Full text Figures/Tables Video References Cited by

Icariin（ICA） is one of the main active ingredients in the Berberidaceae family Epimedium. It makes a variety of biological activities, such as promoting bone formation, antibacterial and anti-inflammatory, and regulating immunity. Periodontitis is a chronic inflammatory disease that is present in the soft and hard tissues of the periodontium. The ultimate goals of its treatment are the reconstruction of periodontal tissues and bone defect repairing. At present, conventional treatment of periodontitis fails to achieve the ideal periodontal tissue regeneration. In recent years, the rapid development of tissue engineering technology has brought new ideas for the treatment of periodontal disease and bone defect repairing. Because of its anti-inflammatory and osteogenic effects, ICA has great potential for the treatments of periodontitis and bone defect repairing. This paper summarizes the effect and the molecular mechanism of ICA in the treatment of periodontitis and bone defect repairing, and discusses its application prospect as a drug for periodontal adjuvant therapy. This paper aims to provide a theoretical basis for the research and application of ICA in periodontitis treatment and bone defect repairing.

Citation： ZHOU Ziqi, YANG Sen, GUO Lijuan. Research progress of icariin in the treatment of periodontitis and bone defect repairing. West China Medical Journal, 2022, 37(1): 140-145. doi: 10.7507/1002-0179.202006226 Copy

1.	Xu H, Zhou S, Qu R, et al. Icariin prevents oestrogen deficiency-induced alveolar bone loss through promoting osteogenesis via STAT3. Cell Prolif, 2020, 53(2): e12743.
2.	Wu J, Zhou J, Chen X, et al. Attenuation of LPS-induced inflammation by ICT, a derivate of icariin, via inhibition of the CD14/TLR4 signaling pathway in human monocytes. Int Immunopharmacol, 2012, 12(1): 74-79.
3.	Sun S, Liu L, Tian X, et al. Icariin attenuates high glucose-induced apoptosis, oxidative stress, and inflammation in human umbilical venous endothelial cells. Planta Med, 2019, 85(6): 473-482.
4.	Tonetti MS, Greenwell H, Kornman KS. Staging and grading of periodontitis: framework and proposal of a new classiﬁcation and case deﬁnition. J Periodontol, 2018, 89(Suppl 1): S159-S172.
5.	Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Primers, 2017, 3(1): 17038.
6.	Hernández-Monjaraz B, Santiago-Osorio E, Monroy-García A, et al. Mesenchymal stem cells of dental origin for inducing tissue regeneration in periodontitis: a mini-review. Int J Mol Sci, 2018, 19(4): 944.
7.	项国梁, 陈跃平, 卓映宏. 淫羊藿苷调控骨髓间充质干细胞相关分化机制及应用研究进展. 中国中西医结合杂志, 2020, 40(8): 1019-1024.
8.	Liu M, Zhong C, He RX, et al. Icariin associated with exercise therapy is an effective treatment for postmenopausal osteoporosis. Chin Med J (Engl), 2012, 125(10): 1784-1789.
9.	Liu H, Xiong Y, Zhu X, et al. Icariin improves osteoporosis, inhibits the expression of PPARγ, C/EBPα, FABP4 mRNA, N1ICD and jagged1 proteins, and increases Notch2 mRNA in ovariectomized rats. Exp Ther Med, 2017, 13(4): 1360-1368.
10.	Liu Y, Zuo H, Liu X, et al. The antiosteoporosis effect of icariin in ovariectomized rats: a systematic review and meta-analysis. Cell Mol Biol (Noisy-le-grand), 2017, 63(11): 124-131.
11.	Zeng R, Wang X, Zhou Q, et al. Icariin protects rotenone-induced neurotoxicity through induction of SIRT3. Toxicol Appl Pharmacol, 2019, 379: 114639.
12.	Zhao SY, Liao LX, Tu PF, et al. Icariin inhibits AGE-induced injury in PC12 cells by directly targeting apoptosis regulator bax. Oxid Med Cell Longev, 2019: 7940808.
13.	Kim JY, Shim SH. Epimedium koreanum extract and its flavonoids reduced atherosclerotic risk via suppressing modification of human HDL. Nutrients, 2019, 11(5): 1110.
14.	Wu T, Wang S, Wu J, et al. Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma. J Exp Clin Cancer Res, 2015, 34(1): 17.
15.	Xie RF, Liu S, Yang M, et al. Effects and possible mechanism of ruyiping formula application to breast cancer based on network prediction. Sci Rep, 2019, 9(1): 5249.
16.	Wu T, Shu T, Kang L, et al. Icaritin, a novel plant-derived osteoinductive agent, enhances the osteogenic differentiation of human bone marrow-and human adipose tissue-derived mesenchymal stem cells. Int J Mol Med, 2017, 39(4): 984-992.
17.	秦子顺, 殷丽华, 王开娟, 等. 淫羊藿苷促进人牙周膜干细胞增殖及骨向分化的作用. 华西口腔医学杂志, 2015, 33(4): 370-376.
18.	Liu HJ, Liu XY, Jing DB. Icariin induces the growth, migration and osteoblastic differentiation of human periodontal ligament fibroblasts by inhibiting toll-like receptor 4 and NF-κB p65 phosphorylation. Mol Med Rep, 2018, 18(3): 3325-3331.
19.	李雪, 朱勇, 王丹杨, 等. 淫羊藿苷对体外牙周膜细胞增殖、成骨分化以及成骨和破骨因子表达的影响. 生物技术通讯, 2019, 30(3): 403-408.
20.	廖丹. 淫羊藿苷与补肾固齿丸对大鼠慢性牙周炎牙槽骨重建的比较研究. 遵义: 遵义医学院, 2018.
21.	Zhang X, Han N, Li G, et al. Local icariin application enhanced periodontal tissue regeneration and relieved local inflammation in a minipig model of periodontitis. Int J Oral Sci, 2018, 10(2): 19.
22.	杨卫, 赵品, 陶美玲, 等. 淫羊藿苷口服给药对骨质疏松牙周炎小鼠牙槽骨吸收的影响. 上海口腔医学, 2019, 28(1): 30-35.
23.	Lephart ED. Modulation of aromatase by phytoestrogens. Enzyme Res, 2015: 594656.
24.	Gao J, Lv S, Li C, et al. Bioactivity-based antioxidative components screening and evaluation in grape seed proanthocyanidin extract. J Food Sci Technol, 2017, 54(9): 2645-2652.
25.	Xiong W, Zhang W, Yuan W, et al. Phosphorylation of icariin can alleviate the oxidative stress caused by the duck hepatitis virus a through mitogen-activated protein kinases signaling pathways. Front Microbiol, 2017, 8: 1850.
26.	Parks WC, Wilson CL, López-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol, 2004, 4(8): 617-629.
27.	Xu Q, Chen G, Liu X, et al. Icariin inhibits RANKL-induced osteoclastogenesis via modulation of the NF-κB and MAPK signaling pathways. Biochem Biophys Res Commun, 2019, 508(3): 902-906.
28.	李伟娟, 谢保平, 石丽颖, 等. 从 ERα/RANK 通路探讨淫羊藿苷抑制破骨细胞分化作用. 中国实验方剂学杂志, 2017, 23(7): 121-126.
29.	Sun LJ, Li C, Wen XH, et al. Icariin stimulates hFOB 1. 19 osteoblast proliferation and differentiation via OPG/RANKL mediated by the estrogen receptor. Curr Pharm Biotechnol, 2021, 22(1): 168-175.
30.	Liu J, Li D, Sun X, et al. Icariine restores LPS-induced bone loss by downregulating mir-34c level. Inflammation, 2016, 39(5): 1764-1770.
31.	Wang LM, Zhao N, Zhang J, et al. Tumor necrosis factor-alpha inhibits osteogenic differentiation of pre-osteoblasts by downregulation of EphB4 signaling via activated nuclear factor-kappaB signaling pathway. J Periodontal Res, 2018, 53(1): 66-72.
32.	Wang YJ, Zhang HQ, Han HL, et al. Taxifolin enhances osteogenic differentiation of human bone marrow mesenchymal stem cells partially via NF-κB pathway. Biochem Biophys Res Commun, 2017, 490(1): 36-43.
33.	Zhang M, Hu X, Li S, et al. Hepatoprotective effects of ethyl pyruvate against CCl4-induced hepatic fibrosis via inhibition of TLR4/NF-κB signaling and up-regulation of MMPs/TIMPs ratio. Clin Res Hepatol Gastroenterol, 2018, 42(1): 72-81.
34.	Hsieh TP, Sheu SY, Sun JS, et al. Icariin inhibits osteoclast differentiation and bone resorption by suppression of MAPKs/NF-κB regulated HIF-1α and PGE(2) synthesis. Phytomedicine, 2011, 18(2/3): 176-185.
35.	Xiong D, Deng Y, Huang B, et al. Icariin attenuates cerebral ischemia-reperfusion injury through inhibition of inflammatory response mediated by NF-κB, PPARα and PPARγ in rats. Int Immunopharmacol, 2016, 30: 157-162.
36.	Kong L, Liu J, Wang J, et al. Icariin inhibits TNF-α/IFN-γ induced inflammatory response via inhibition of the substance P and p38-MAPK signaling pathway in human keratinocytes. Int Immunopharmacol, 2015, 29(2): 401-407.
37.	Dutzan N, Gamonal J, Silva A, et al. Over-expression of forkhead box P3 and its association with receptor activator of nuclear factor-kappa B ligand, interleukin (IL) -17, IL-10 and transforming growth factor-beta during the progression of chronic periodontitis. J Clin Periodontol, 2009, 36(5): 396-403.
38.	Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity, 2013, 38(3): 414-423.
39.	Wei Y, Liu B, Sun J, et al. Regulation of Th17/Treg function contributes to the attenuation of chronic airway inflammation by icariin in ovalbumin-induced murine asthma model. Immunobiology, 2015, 220(6): 789-797.
40.	Luo G, Xu B, Wang W, et al. Study of the osteogenesis effect of icarisideⅡ and icaritin on canine bone marrow mesenchymal stem cells. J Bone Miner Metab, 2018, 36(6): 668-678.
41.	Zhang Y, Shen L, Mao Z, et al. Icariin enhances bone repair in rabbits with bone infection during post-infection treatment and prevents inhibition of osteoblasts by vancomycin. Front Pharmacol, 2017, 8: 784.
42.	梁广胜, 陈伟才, 殷嫦嫦, 等. 淫羊藿总黄酮对大鼠骨髓间充质干细胞成骨分化过程 BMP-2/RunX2/OSX 通路的影响. 中国中西医结合杂志, 2016, 36(5): 614-618.
43.	Chen M, Cui Y, Li H, et al. Icariin promotes the osteogenic action of BMP2 by activating the cAMP signaling pathway. Molecules, 2019, 24(21): 3875.
44.	Hu H, Chen M, Dai G, et al. An inhibitory role of osthole in rat MSCs osteogenic differentiation and proliferation via Wnt/β-catenin and Erk1/2-MAPK pathways. Cell Physiol Biochem, 2016, 38(6): 2375-2388.
45.	Ye Y, Jing X, Li N, et al. Icariin promotes proliferation and osteogenic differentiation of rat adipose-derived stem cells by activating the RhoA-TAZ signaling pathway. Biomed Pharmacother, 2017, 88: 384-394.
46.	Wang Y, Wang R, Zhang F. Icariin promotes the proliferation and differentiation of osteoblasts from the rat mandible by the Wnt/β-catenin signalling pathway. Mol Med Rep, 2018, 18(3): 3445-3450.
47.	Fu S, Yang L, Hong H, et al. Wnt/β-catenin signaling is involved in the icariin induced proliferation of bone marrow mesenchymal stem cells. J Tradit Chin Med, 2016, 36(3): 360-368.
48.	Liu Y, Huang L, Hao B, et al. Use of an osteoblast overload damage model to probe the effect of icariin on the proliferation, differentiation and mineralization of MC3T3-E1 cells through the Wnt/β-catenin signalling pathway. Cell Physiol Biochem, 2017, 41(4): 1605-1615.
49.	Huang JM, Bao Y, Xiang W, et al. Icariin regulates the bidirectional differentiation of bone marrow mesenchymal stem cells through canonical wnt signaling pathway. Evid Based Complement Alternat Med, 2017: 8085325.
50.	Zhang S, Feng P, Mo G, et al. Icariin influences adipogenic differentiation of stem cells affected by osteoblast-osteoclast co-culture and clinical research adipogenic. Biomed Pharmacother, 2017, 88: 436-442.
51.	Fan JJ, Cao LG, Wu T, et al. The dose-effect of icariin on the proliferation and osteogenic differentiation of human bone mesenchymal stem cells. Molecules, 2011, 16(12): 10123-10133.
52.	Huang Z, Cheng C, Cao B, et al. Icariin protects against glucocorticoid-induced osteonecrosis of the femoral head in rats. Cell Physiol Biochem, 2018, 47(2): 694-706.
53.	Wei Q, He M, Chen M, et al. Icariin stimulates osteogenic differentiation of rat bone marrow stromal stem cells by increasing TAZ expression. Biomed Pharmacother, 2017, 91: 581-589.
54.	Sagomonyants K, Mina M. Biphasic effects of FGF2 on odontoblast differentiation involve changes in the BMP and Wnt signaling pathways. Connect Tissue Res, 2014, 55(Suppl 1): 53-56.
55.	Hakki SS, Bozkurt B, Hakki EE, et al. Bone morphogenetic protein-2, -6, and -7 differently regulate osteogenic differentiation of human periodontal ligament stem cells. J Biomed Mater Res B Appl Biomater, 2014, 102(1): 119-130.
56.	Zhang Xr, Liu T, Huang Y, et al. Osteogenic potential of icariin compared with recombinant human bone morphogenetic protein 2 in vitro: a preliminary study. J Biomater Tissue Eng, 2015, 5(3): 226-233.
57.	薛鹏, 杜斌, 王礼宁, 等. 可控释淫羊藿苷-β-磷酸三钙复合支架的制备. 中国组织工程研究, 2018, 22(6): 865-870.
58.	Zhang X, Lin X, Liu T, et al. Osteogenic enhancement between icariin and bone morphogenetic protein 2: a potential osteogenic compound for bone tissue engineering. Front Pharmacol, 2019, 10: 201.
59.	Zhang Yl, Chen Lg, Liu Cd, et al. Self assembly chitosan/gelatin composite coating on icariin-modified TiO₂ nanotubes for the regulation of osteoblast bioactivity. Mater Des, 2016, 92: 471-479.
60.	Zhang X, Guo Y, Li DX, et al. The effect of loading icariin on biocompatibility and bioactivity of porous β-TCP ceramic. J Mater Sci Mater Med, 2011, 22(2): 371-379.
61.	Wang Z, Li K, Sun H, et al. Icariin promotes stable chondrogenic differentiation of bone marrow mesenchymal stem cells in self-assembling peptide nanofiber hydrogel scaffolds. Mol Med Rep, 2018, 17(6): 8237-8243.
62.	Xie Y, Sun W, Yan F, et al. Icariin-loaded porous scaffolds for bone regeneration through the regulation of the coupling process of osteogenesis and osteoclastic activity. Int J Nanomedicine, 2019, 14: 6019-6033.

1. Xu H, Zhou S, Qu R, et al. Icariin prevents oestrogen deficiency-induced alveolar bone loss through promoting osteogenesis via STAT3. Cell Prolif, 2020, 53(2): e12743.
2. Wu J, Zhou J, Chen X, et al. Attenuation of LPS-induced inflammation by ICT, a derivate of icariin, via inhibition of the CD14/TLR4 signaling pathway in human monocytes. Int Immunopharmacol, 2012, 12(1): 74-79.
3. Sun S, Liu L, Tian X, et al. Icariin attenuates high glucose-induced apoptosis, oxidative stress, and inflammation in human umbilical venous endothelial cells. Planta Med, 2019, 85(6): 473-482.
4. Tonetti MS, Greenwell H, Kornman KS. Staging and grading of periodontitis: framework and proposal of a new classiﬁcation and case deﬁnition. J Periodontol, 2018, 89(Suppl 1): S159-S172.
5. Kinane DF, Stathopoulou PG, Papapanou PN. Periodontal diseases. Nat Rev Dis Primers, 2017, 3(1): 17038.
6. Hernández-Monjaraz B, Santiago-Osorio E, Monroy-García A, et al. Mesenchymal stem cells of dental origin for inducing tissue regeneration in periodontitis: a mini-review. Int J Mol Sci, 2018, 19(4): 944.
7. 项国梁, 陈跃平, 卓映宏. 淫羊藿苷调控骨髓间充质干细胞相关分化机制及应用研究进展. 中国中西医结合杂志, 2020, 40(8): 1019-1024.
8. Liu M, Zhong C, He RX, et al. Icariin associated with exercise therapy is an effective treatment for postmenopausal osteoporosis. Chin Med J (Engl), 2012, 125(10): 1784-1789.
9. Liu H, Xiong Y, Zhu X, et al. Icariin improves osteoporosis, inhibits the expression of PPARγ, C/EBPα, FABP4 mRNA, N1ICD and jagged1 proteins, and increases Notch2 mRNA in ovariectomized rats. Exp Ther Med, 2017, 13(4): 1360-1368.
10. Liu Y, Zuo H, Liu X, et al. The antiosteoporosis effect of icariin in ovariectomized rats: a systematic review and meta-analysis. Cell Mol Biol (Noisy-le-grand), 2017, 63(11): 124-131.
11. Zeng R, Wang X, Zhou Q, et al. Icariin protects rotenone-induced neurotoxicity through induction of SIRT3. Toxicol Appl Pharmacol, 2019, 379: 114639.
12. Zhao SY, Liao LX, Tu PF, et al. Icariin inhibits AGE-induced injury in PC12 cells by directly targeting apoptosis regulator bax. Oxid Med Cell Longev, 2019: 7940808.
13. Kim JY, Shim SH. Epimedium koreanum extract and its flavonoids reduced atherosclerotic risk via suppressing modification of human HDL. Nutrients, 2019, 11(5): 1110.
14. Wu T, Wang S, Wu J, et al. Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma. J Exp Clin Cancer Res, 2015, 34(1): 17.
15. Xie RF, Liu S, Yang M, et al. Effects and possible mechanism of ruyiping formula application to breast cancer based on network prediction. Sci Rep, 2019, 9(1): 5249.
16. Wu T, Shu T, Kang L, et al. Icaritin, a novel plant-derived osteoinductive agent, enhances the osteogenic differentiation of human bone marrow-and human adipose tissue-derived mesenchymal stem cells. Int J Mol Med, 2017, 39(4): 984-992.
17. 秦子顺, 殷丽华, 王开娟, 等. 淫羊藿苷促进人牙周膜干细胞增殖及骨向分化的作用. 华西口腔医学杂志, 2015, 33(4): 370-376.
18. Liu HJ, Liu XY, Jing DB. Icariin induces the growth, migration and osteoblastic differentiation of human periodontal ligament fibroblasts by inhibiting toll-like receptor 4 and NF-κB p65 phosphorylation. Mol Med Rep, 2018, 18(3): 3325-3331.
19. 李雪, 朱勇, 王丹杨, 等. 淫羊藿苷对体外牙周膜细胞增殖、成骨分化以及成骨和破骨因子表达的影响. 生物技术通讯, 2019, 30(3): 403-408.
20. 廖丹. 淫羊藿苷与补肾固齿丸对大鼠慢性牙周炎牙槽骨重建的比较研究. 遵义: 遵义医学院, 2018.
21. Zhang X, Han N, Li G, et al. Local icariin application enhanced periodontal tissue regeneration and relieved local inflammation in a minipig model of periodontitis. Int J Oral Sci, 2018, 10(2): 19.
22. 杨卫, 赵品, 陶美玲, 等. 淫羊藿苷口服给药对骨质疏松牙周炎小鼠牙槽骨吸收的影响. 上海口腔医学, 2019, 28(1): 30-35.
23. Lephart ED. Modulation of aromatase by phytoestrogens. Enzyme Res, 2015: 594656.
24. Gao J, Lv S, Li C, et al. Bioactivity-based antioxidative components screening and evaluation in grape seed proanthocyanidin extract. J Food Sci Technol, 2017, 54(9): 2645-2652.
25. Xiong W, Zhang W, Yuan W, et al. Phosphorylation of icariin can alleviate the oxidative stress caused by the duck hepatitis virus a through mitogen-activated protein kinases signaling pathways. Front Microbiol, 2017, 8: 1850.
26. Parks WC, Wilson CL, López-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol, 2004, 4(8): 617-629.
27. Xu Q, Chen G, Liu X, et al. Icariin inhibits RANKL-induced osteoclastogenesis via modulation of the NF-κB and MAPK signaling pathways. Biochem Biophys Res Commun, 2019, 508(3): 902-906.
28. 李伟娟, 谢保平, 石丽颖, 等. 从 ERα/RANK 通路探讨淫羊藿苷抑制破骨细胞分化作用. 中国实验方剂学杂志, 2017, 23(7): 121-126.
29. Sun LJ, Li C, Wen XH, et al. Icariin stimulates hFOB 1. 19 osteoblast proliferation and differentiation via OPG/RANKL mediated by the estrogen receptor. Curr Pharm Biotechnol, 2021, 22(1): 168-175.
30. Liu J, Li D, Sun X, et al. Icariine restores LPS-induced bone loss by downregulating mir-34c level. Inflammation, 2016, 39(5): 1764-1770.
31. Wang LM, Zhao N, Zhang J, et al. Tumor necrosis factor-alpha inhibits osteogenic differentiation of pre-osteoblasts by downregulation of EphB4 signaling via activated nuclear factor-kappaB signaling pathway. J Periodontal Res, 2018, 53(1): 66-72.
32. Wang YJ, Zhang HQ, Han HL, et al. Taxifolin enhances osteogenic differentiation of human bone marrow mesenchymal stem cells partially via NF-κB pathway. Biochem Biophys Res Commun, 2017, 490(1): 36-43.
33. Zhang M, Hu X, Li S, et al. Hepatoprotective effects of ethyl pyruvate against CCl4-induced hepatic fibrosis via inhibition of TLR4/NF-κB signaling and up-regulation of MMPs/TIMPs ratio. Clin Res Hepatol Gastroenterol, 2018, 42(1): 72-81.
34. Hsieh TP, Sheu SY, Sun JS, et al. Icariin inhibits osteoclast differentiation and bone resorption by suppression of MAPKs/NF-κB regulated HIF-1α and PGE(2) synthesis. Phytomedicine, 2011, 18(2/3): 176-185.
35. Xiong D, Deng Y, Huang B, et al. Icariin attenuates cerebral ischemia-reperfusion injury through inhibition of inflammatory response mediated by NF-κB, PPARα and PPARγ in rats. Int Immunopharmacol, 2016, 30: 157-162.
36. Kong L, Liu J, Wang J, et al. Icariin inhibits TNF-α/IFN-γ induced inflammatory response via inhibition of the substance P and p38-MAPK signaling pathway in human keratinocytes. Int Immunopharmacol, 2015, 29(2): 401-407.
37. Dutzan N, Gamonal J, Silva A, et al. Over-expression of forkhead box P3 and its association with receptor activator of nuclear factor-kappa B ligand, interleukin (IL) -17, IL-10 and transforming growth factor-beta during the progression of chronic periodontitis. J Clin Periodontol, 2009, 36(5): 396-403.
38. Ohkura N, Kitagawa Y, Sakaguchi S. Development and maintenance of regulatory T cells. Immunity, 2013, 38(3): 414-423.
39. Wei Y, Liu B, Sun J, et al. Regulation of Th17/Treg function contributes to the attenuation of chronic airway inflammation by icariin in ovalbumin-induced murine asthma model. Immunobiology, 2015, 220(6): 789-797.
40. Luo G, Xu B, Wang W, et al. Study of the osteogenesis effect of icarisideⅡ and icaritin on canine bone marrow mesenchymal stem cells. J Bone Miner Metab, 2018, 36(6): 668-678.
41. Zhang Y, Shen L, Mao Z, et al. Icariin enhances bone repair in rabbits with bone infection during post-infection treatment and prevents inhibition of osteoblasts by vancomycin. Front Pharmacol, 2017, 8: 784.
42. 梁广胜, 陈伟才, 殷嫦嫦, 等. 淫羊藿总黄酮对大鼠骨髓间充质干细胞成骨分化过程 BMP-2/RunX2/OSX 通路的影响. 中国中西医结合杂志, 2016, 36(5): 614-618.
43. Chen M, Cui Y, Li H, et al. Icariin promotes the osteogenic action of BMP2 by activating the cAMP signaling pathway. Molecules, 2019, 24(21): 3875.
44. Hu H, Chen M, Dai G, et al. An inhibitory role of osthole in rat MSCs osteogenic differentiation and proliferation via Wnt/β-catenin and Erk1/2-MAPK pathways. Cell Physiol Biochem, 2016, 38(6): 2375-2388.
45. Ye Y, Jing X, Li N, et al. Icariin promotes proliferation and osteogenic differentiation of rat adipose-derived stem cells by activating the RhoA-TAZ signaling pathway. Biomed Pharmacother, 2017, 88: 384-394.
46. Wang Y, Wang R, Zhang F. Icariin promotes the proliferation and differentiation of osteoblasts from the rat mandible by the Wnt/β-catenin signalling pathway. Mol Med Rep, 2018, 18(3): 3445-3450.
47. Fu S, Yang L, Hong H, et al. Wnt/β-catenin signaling is involved in the icariin induced proliferation of bone marrow mesenchymal stem cells. J Tradit Chin Med, 2016, 36(3): 360-368.
48. Liu Y, Huang L, Hao B, et al. Use of an osteoblast overload damage model to probe the effect of icariin on the proliferation, differentiation and mineralization of MC3T3-E1 cells through the Wnt/β-catenin signalling pathway. Cell Physiol Biochem, 2017, 41(4): 1605-1615.
49. Huang JM, Bao Y, Xiang W, et al. Icariin regulates the bidirectional differentiation of bone marrow mesenchymal stem cells through canonical wnt signaling pathway. Evid Based Complement Alternat Med, 2017: 8085325.
50. Zhang S, Feng P, Mo G, et al. Icariin influences adipogenic differentiation of stem cells affected by osteoblast-osteoclast co-culture and clinical research adipogenic. Biomed Pharmacother, 2017, 88: 436-442.
51. Fan JJ, Cao LG, Wu T, et al. The dose-effect of icariin on the proliferation and osteogenic differentiation of human bone mesenchymal stem cells. Molecules, 2011, 16(12): 10123-10133.
52. Huang Z, Cheng C, Cao B, et al. Icariin protects against glucocorticoid-induced osteonecrosis of the femoral head in rats. Cell Physiol Biochem, 2018, 47(2): 694-706.
53. Wei Q, He M, Chen M, et al. Icariin stimulates osteogenic differentiation of rat bone marrow stromal stem cells by increasing TAZ expression. Biomed Pharmacother, 2017, 91: 581-589.
54. Sagomonyants K, Mina M. Biphasic effects of FGF2 on odontoblast differentiation involve changes in the BMP and Wnt signaling pathways. Connect Tissue Res, 2014, 55(Suppl 1): 53-56.
55. Hakki SS, Bozkurt B, Hakki EE, et al. Bone morphogenetic protein-2, -6, and -7 differently regulate osteogenic differentiation of human periodontal ligament stem cells. J Biomed Mater Res B Appl Biomater, 2014, 102(1): 119-130.
56. Zhang Xr, Liu T, Huang Y, et al. Osteogenic potential of icariin compared with recombinant human bone morphogenetic protein 2 in vitro: a preliminary study. J Biomater Tissue Eng, 2015, 5(3): 226-233.
57. 薛鹏, 杜斌, 王礼宁, 等. 可控释淫羊藿苷-β-磷酸三钙复合支架的制备. 中国组织工程研究, 2018, 22(6): 865-870.
58. Zhang X, Lin X, Liu T, et al. Osteogenic enhancement between icariin and bone morphogenetic protein 2: a potential osteogenic compound for bone tissue engineering. Front Pharmacol, 2019, 10: 201.
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