Journal of Shandong University (Health Sciences) ›› 2024, Vol. 62 ›› Issue (10): 76-86.doi: 10.6040/j.issn.1671-7554.0.2024.0169

• Preclinical Medicine • Previous Articles    

Mechanism of curcumin regulating bone formation via the Wnt/β-catenin signaling pathway

YAN Xiaolong1, QIN Ying2, SHAO Jiang3, CHEN Dongfeng3, GUAN Donghui3, ZHAO Canbin4   

  1. 1. Emergency Intensive Care Medical Center, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China;
    2. Department of Orthopedics, Jinan Changqing District Traditional Chinese Medicine Hospital, Jinan 250300, Shandong, China;
    3. Department of Orthopedics, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong, China;
    4. First Clinical Medical College, Guangxi University of Chinese Medicine, Nanning 530200, Guangxi, China
  • Published:2024-10-12

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Abstract: Objective To explore the potential regulatory mechanism of curcumin on osteogenic differentiation of bone marrow-derived mesenchymal stem cells(BMSCs). Methods The target genes of curcumin regulating osteogenic differentiation were obtained through network pharmacology, and a protein-protein interaction network(PPI)was constructed. Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis and molecular docking were performed. CCK-8 and cell cloning were used to screen the concentration of curcumin. ALP staining and activity assay, AR staining and quantitative analysis were used to evaluate the macro-regulatory effect of curcumin on osteogenic differentiation. RT-qPCR and Western blotting were used to detect the micro-expression differences of mRNA and protein related to the Wnt/β-catenin gignaling pathway. Results A total of 92 target genes for curcumin regulation of osteogenic differentiation were screened, mainly involving biological processes such as the intracellular response to chemical stimuli and the response to oxidative compounds. Three target genes acted on the Wnt/β-catenin signaling pathway and could be effectively docked with curcumin. In addition, low concentrations of curcumin(5, 10 μmol)showed no obvious toxicity to rat bone marrow-derived mesenchymal stem cells(rBMSCs), enhanced alkaline phosphatase activity, increased calcium deposition(P<0.05), up-regulated the expression of osteogenic-related genes and proteins(P<0.05), and promoted osteogenic differentiation of rBMSCs. However, high concentration of curcumin(15 μmol)had a potential inhibitory effect on the osteogenic differentiation of rBMSCs. Conclusion Curcumin can regulate the expression of osteogenic-related genes by modulating the Wnt/β-catenin signaling pathway, thereby regulating the osteogenic differentiation of BMSCs.

Key words: Curcumin, Bone marrow-derived mesenchymal stem cells, Osteogenic differentiation, Network pharmacology, Wnt/β-catenin signaling pathway

CLC Number: 

  • R274
[1] Fuggle NR, Curtis B, Clynes M, et al. The treatment gap: the missed opportunities for osteoporosis therapy[J]. Bone, 2021, 144: 115833. doi: 10.1016/j.bone.2020.115833.
[2] Hu M, Xing L, Zhang L, et al. NAP1L2 drives mesenchymal stem cell senescence and suppresses osteogenic differentiation[J]. Aging Cell, 2022, 21(2): e13551.
[3] Yang W, Li HY, Wu YF, et al. ac4C acetylation of RUNX2 catalyzed by NAT10 spurs osteogenesis of BMSCs and prevents ovariectomy-induced bone loss[J]. Mol Ther Nucleic Acids, 2021, 26: 135-147. doi: 10.1016/j.omtn.2021.06.022.
[4] Liu F, Yuan Y, Bai L, et al. LRRc17 controls BMSC senescence via mitophagy and inhibits the therapeutic effect of BMSCs on ovariectomy-induced bone loss[J]. Redox Biol, 2021, 43: 101963. doi: 10.1016/j.redox.2021.101963.
[5] Lu J, Hu D, Ma C, et al. Advances in our understanding of the mechanism of action of drugs(including traditional Chinese medicines)for the intervention and treatment of osteoporosis[J]. Front Pharmacol, 2022, 13: 938447. doi: 10.3389/fphar.2022.938447.
[6] Freires IA, Santaella GM, de Cássia Orlandi Sardi J, et al. The alveolar bone protective effects of natural products: a systematic review[J]. Arch Oral Biol, 2018, 87: 196-203. doi: 10.1016/j.archoralbio.2017.12.019.
[7] 吴彧,夏彦清,伍玥,等.炎性细胞模型中姜黄素对胆固醇逆转运蛋白ABCA1和ABCG1基因的影响[J].山东大学学报(医学版), 2016, 54(11): 24-26. WU Yu, XIA Yanqing, WU Yue, et al. The effect of curcumin on the expression of ABCA1 and ABCG1 genes in an inflammatory cell model of reverse cholesterol transport [J]. Journal of Shandong University(Medical Edition), 2016, 54(11): 24-26.
[8] 丁菲,姜洁.姜黄素对子宫内膜癌孕激素抵抗的影响[J].山东大学学报(医学版), 2021, 59(4): 35-41. DING Fei, JIANG Jie. The impact of curcumin on hormone resistance in endometrial cancer[J]. Journal of Shandong University(Medical Edition), 2021, 59(4): 35-41.
[9] Sahebkar A, Cicero AFG, Simental-Mendía LE, et al. Curcumin downregulates human tumor necrosis factor-α levels: a systematic review and meta-analysis ofrandomized controlled trials[J]. Pharmacol Res, 2016, 107: 234-242. doi: 10.1016/j.phrs.2016.03.026.
[10] Son HE, Kim EJ, Jang WG. Curcumin induces osteoblast differentiation through mild-endoplasmic reticulum stress-mediated such as BMP2 on osteoblast cells[J]. Life Sci, 2018, 193: 34-39. doi: 10.1016/j.lfs.2017.12.008.
[11] Chen Z, Xue J, Shen T, et al. Curcumin alleviates glucocorticoid-induced osteoporosis through the regulation of the Wnt signaling pathway[J]. Int J Mol Med, 2016, 37(2): 329-338.
[12] Riva A, Togni S, Giacomelli L, et al. Effects of a curcumin-based supplementation in asymptomatic subjects with low bone density: a preliminary 24-week supplement study[J]. Eur Rev Med Pharmacol Sci, 2017, 21(7): 1684-1689.
[13] Molagoda IMN, Kang CH, Lee MH, et al. Fisetin promotes osteoblast differentiation and osteogenesis through GSK-3β phosphorylation at Ser9 and consequent β-catenin activation, inhibiting osteoporosis[J]. Biochem Pharmacol, 2021, 192: 114676. doi: 10.1016/j.bcp.2021.114676.
[14] Hsin KY, Ghosh S, Kitano H. Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology[J]. PLoS One, 2013, 8(12): e83922.
[15] Kim KT, Lee YS, Han I. The role of epigenomics in osteoporosis and osteoporotic vertebral fracture[J]. Int J Mol Sci, 2020, 21(24): E9455.
[16] Zhao H, Zhao N, Zheng P, et al. Prevention and treatment of osteoporosis using Chinese medicinal plants: special emphasis on mechanisms of immune modulation[J]. J Immunol Res, 2018, 2018: 6345857. doi: 10.1155/2018/6345857.
[17] Li Y, Zhang T. Targeting cancer stem cells by curcumin and clinical applications[J]. Cancer Lett, 2014, 346(2): 197-205.
[18] Peddada KV, Peddada KV, Shukla SK, et al. Role of curcumin in common musculoskeletal disorders: a review of current laboratory, translational, and clinical data[J]. Orthop Surg, 2015, 7(3): 222-231.
[19] 熊艺璇,赵斌,贾凌璐,等.姜黄素通过Nrf2信号通路促进炎症状态下牙周膜干细胞的成骨分化[J].山东大学学报(医学版), 2020, 58(5): 19-26. XIONG Yixuan, ZHAO Bin, JIA Linglu, et al. Curcumin promotes osteogenic differentiation of periodontal ligament stem cells under inflammatory conditions through the Nrf2 signaling pathway [J]. Journal of Shandong University(Medical Edition), 2020, 58(5): 19-26.
[20] Saito K, Shinozuka T, Nakao A, et al. Synthesis and structure-activity relationship of 4-alkoxy-thieno[2,3-b] pyridine derivatives as potent alkaline phosphatase enhancers for osteoporosis treatment[J]. Bioorg Med Chem Lett, 2019, 29(14): 1769-1773.
[21] Opdebeeck B, DHaese PC, Verhulst A. Inhibition of tissue non-specific alkaline phosphatase; a novel therapy against arterial media calcification? [J]. J Pathol, 2020, 250(3): 248-250.
[22] Khorsand B, Elangovan S, Hong L, et al. A Comparative Study of the Bone Regenerative Effect of Chemically Modified RNA Encoding BMP-2 or BMP-9[J]. AAPS J, 2017, 19(2): 438-446.
[23] Rim EY, Clevers H, Nusse R. The wnt pathway: from signaling mechanisms to synthetic modulators[J]. Annu Rev Biochem, 2022, 91: 571-598. doi: 10.1146/annurev-biochem-040320-103615.
[24] Molagoda IMN, Kang CH, Lee MH, et al. Fisetin promotes osteoblast differentiation and osteogenesis through GSK-3β phosphorylation at Ser9 and consequent β-catenin activation, inhibiting osteoporosis[J]. Biochem Pharmacol, 2021, 192: 114676. doi: 10.1016/j.bcp.2021.114676.
[25] Turnham RE, Scott JD. Protein kinase a catalytic subunit isoform PRKACA; History, function and physiology[J]. Gene, 2016, 577(2): 101-108.
[26] Dutta R, Tiu B, Sakamoto KM. CBP/p300 acetyltransferase activity in hematologic malignancies[J]. Mol Genet Metab, 2016, 119(1/2): 37-43.
[27] Syrovatkina V, Alegre KO, Dey R, et al. Regulation, signaling, and physiological functions of G-proteins[J]. J Mol Biol, 2016, 428(19): 3850-3868.
[28] Cheng X, Liu D, Ren X, et al. The β-catenin/CBP signaling axis participates in sepsis-induced inflammatory lung injury[J]. Exp Biol Med(Maywood), 2022, 247(17): 1548-1557.
[29] Ge L, Cui Y, Liu B, et al. ERα and Wnt/β catenin signaling pathways are involved in angelicin-dependent promotion of osteogenesis[J]. Mol Med Rep, 2019, 19(5): 3469-3476.
[30] Morgan RG, Ridsdale J, Payne M, et al. LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells[J]. Haematologica, 2019, 104(7): 1365-1377.
[31] Ni F, Zhang T, Xiao W, et al. IL-18-mediated SLC7A5 overexpression enhances osteogenic differentiation of human bone marrow mesenchymal stem cells via the c-MYC pathway[J]. Front Cell Dev Biol, 2021, 9: 748831. doi: 10.3389/fcell.2021.748831.
[32] Liu Z, Wu Y. Arctiin elevates osteogenic differentiation of MC3T3-E1 cells by modulating cyclin D1[J]. Bioengineered, 2022, 13(4): 10866-10874.
[33] Jeong JH, Choi JY. Interrelationship of Runx2 and estrogen pathway in skeletal tissues[J]. BMB Rep, 2011, 44(10): 613-618.
[34] Zhang X, Yang M, Lin L, et al. Runx2 overexpression enhances osteoblastic differentiation and mineralization in adipose - derived stem cells in vitro and in vivo[J]. Calcif Tissue Int, 2006,79(3): 169-178.
[35] Qiu WX, Ma XL, Lin X, et al. Deficiency of Macf1 in osterix expressing cells decreases bone formation by Bmp2/Smad/Runx2 pathway[J]. J Cell Mol Med, 2020, 24(1): 317-327.
[36] Ao Q, Wang SL, He Q, et al. Fibrin glue/fibronectin/heparin-based delivery system of BMP2 induces osteogenesis in MC3T3-E1 cells and bone formation in rat calvarial critical-sized defects[J]. ACS Appl Mater Interfaces, 2020, 12(11): 13400-13410.
[37] Aghali A. Craniofacial bone tissue engineering: current approaches and potential therapy[J]. Cells, 2021, 10(11): 2993.
[38] Kan T, He Z, Du J, et al. Irisin promotes fracture healing by improving osteogenesis and angiogenesis[J]. Orthop Translat, 2022, 37: 37-45. doi: 10.1016/j.jot.2022.07.006
[39] Hou ZY, Wang Z, Tao YX, et al. KLF2 regulates osteoblast differentiation by targeting of Runx2[J]. Lab Investig, 2019, 99(2): 271-280.
[40] Martin V, Ribeiro IA, Alves MM, et al. Engineering a multifunctional 3D-printed PLA-collagen-minocycline-nanoHydroxyapatite scaffold with combined antimicrobial and osteogenic effects for bone regeneration[J]. Mater Sci Eng C Mater Biol Appl, 2019, 101: 15-26. doi: 10.1016/j.msec.2019.03.056.
[41] Lee WB, Wang CF, Lee JH, et al. Whitlockite granules on bone regeneration in defect of rat Calvaria[J]. ACS Appl Bio Mater, 2020, 3(11): 7762-7768.
[42] Mohamad N, Nabih ES, Zakaria ZM, et al. Insight into the possible role of miR-214 in primary osteoporosis via osterix[J]. J Cell Biochem, 2019, 120(9): 15518-15526.
[43] Ghorbaninejad M, Khademi-Shirvan M, Hosseini S, et al. Effective role of Curcumin on expression regulation of EZH2 histone methyltransferase as a dynamic epigenetic factor in osteogenic differentiation of human mesenchymal stem cells[J]. Biochim Biophys Acta Gene Regul Mech, 2023, 1866(1): 194903.
[44] Hu S, Huang Y, Chen Y, et al. Diosmetin reduces bone loss and osteoclastogenesis by regulating the expression of TRPV1 in osteoporosis rats[J]. Ann Transl Med, 2020, 8(20): 1312.
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