Current issue
Archive
Manuscripts accepted
About the Journal
Editorial office
Editorial board
Section Editors
Abstracting and indexing
Subscription
Contact
Ethical standards and procedures
Most read articles
Instructions for authors
Article Processing Charge (APC)
Regulations of paying article processing charge (APC)
RHEUMATOLOGY / BASIC RESEARCH
Exosomes derived from bone marrow mesenchymal stem cells pre-treated with curcumin alleviate osteoporosis by promoting osteogenic differentiation via regulating the METTL3/microRNA-320/RUNX2 signaling pathway
1
Department of Orthopedics, Baoshan Hospital, Shanghai, China
Submission date: 2020-05-24
Final revision date: 2020-07-16
Acceptance date: 2020-07-28
Online publication date: 2021-04-18
Publication date: 2026-07-07
Corresponding author
Arch Med Sci 2026;22(3):1822-1837
KEYWORDS
osteoporosiscurcuminexosomebone marrow stem cellsmethyltransferase-like 3miRNA-320runt-related transcription factor 2
TOPICS
ABSTRACT
Introduction:
Curcumin (CUR) has been reported to stimulate the expression of methyltransferase-like 3 (METTL3), a potential therapeutic target for osteoporosis. Also, bone marrow mesenchymal stem cell (BMSC)-derived exosomes (EXO) have been demonstrated to improve osteoporosis by pro-moting the proliferation of osteoblasts. In this study, we aimed to study the effect of CUR and BMSC-derived exosomes in the treatment of osteoporosis.
Material and methods:
Microscopy was used to characterize exosomes de-rived from BMSCs. MicroCT was carried out to analyze the parameters of bone formation. Western blot was carried out to analyze the expression of surface markers on BMSC-derived exosomes and METTL3/Runt-related transcription factor 2 (RUNX2) proteins under different conditions. Realtime PCR was used to assess the gene expression under different circumstances.
Results:
The exosomes derived from CUR-treated BMSCs showed an en-hanced therapeutic effect on osteoporotic mice compared with exosomes derived from untreated BMSCs. Mechanistically, CUR pretreatment of BMMSCs significantly enhanced the ability of BM-MSCderived exosomes to restore the dysregulated expression of METTL3, miR-320, and RUNX2. Addi-tionally, CUR treatment of BMSCs markedly enhanced the stimulatory effect of BMSC-derived exosomes on the expression of METTL3, miR-320, RUNX2, BGLAP, and LAP in BMSCs. Furthermore, luciferase assay demonstrated that miR-320 was capable of suppressing the expression of RUNX2 through bind-ing to the 3’ UTR of RUNX2.
Conclusions:
Our study demonstrated that BMSC-derived exosomes could modulate the METTL3/miRNA-320/RUNX2 axis to attenuate osteoporosis by promoting osteogenic differentiation of BMSCs. Moreover, the CUR treat-ment of BMSCs promoted the therapeutic effect of BMSC-derived exosomes.
Curcumin (CUR) has been reported to stimulate the expression of methyltransferase-like 3 (METTL3), a potential therapeutic target for osteoporosis. Also, bone marrow mesenchymal stem cell (BMSC)-derived exosomes (EXO) have been demonstrated to improve osteoporosis by pro-moting the proliferation of osteoblasts. In this study, we aimed to study the effect of CUR and BMSC-derived exosomes in the treatment of osteoporosis.
Material and methods:
Microscopy was used to characterize exosomes de-rived from BMSCs. MicroCT was carried out to analyze the parameters of bone formation. Western blot was carried out to analyze the expression of surface markers on BMSC-derived exosomes and METTL3/Runt-related transcription factor 2 (RUNX2) proteins under different conditions. Realtime PCR was used to assess the gene expression under different circumstances.
Results:
The exosomes derived from CUR-treated BMSCs showed an en-hanced therapeutic effect on osteoporotic mice compared with exosomes derived from untreated BMSCs. Mechanistically, CUR pretreatment of BMMSCs significantly enhanced the ability of BM-MSCderived exosomes to restore the dysregulated expression of METTL3, miR-320, and RUNX2. Addi-tionally, CUR treatment of BMSCs markedly enhanced the stimulatory effect of BMSC-derived exosomes on the expression of METTL3, miR-320, RUNX2, BGLAP, and LAP in BMSCs. Furthermore, luciferase assay demonstrated that miR-320 was capable of suppressing the expression of RUNX2 through bind-ing to the 3’ UTR of RUNX2.
Conclusions:
Our study demonstrated that BMSC-derived exosomes could modulate the METTL3/miRNA-320/RUNX2 axis to attenuate osteoporosis by promoting osteogenic differentiation of BMSCs. Moreover, the CUR treat-ment of BMSCs promoted the therapeutic effect of BMSC-derived exosomes.
REFERENCES (46)
1.
Pietschmann P, Rauner M, Sipos W, Kerschan-Schindl K. Osteoporosis: an age-related and gender-specific disease--a mini-review. Gerontology 2009; 55: 3-12.
2.
Mulder JE, Kolatkar NS, LeBoff MS. Drug insight: Existing and emerging therapies for osteoporosis. Nat Clin Pract Endocrinol Metab 2006; 2: 670-80.
3.
Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res 2007; 22: 465-75.
4.
Toden S, Theiss AL, Wang X, Goel A. Essential turmeric oils enhance anti-inflammatory efficacy of curcumin in dextran sulfate sodium-induced colitis. Sci Rep 2017; 7: 814.
5.
Shlar I, Droby S, Rodov V. Modes of antibacterial action of curcumin under dark and light conditions: a toxicoproteomics approach. J Proteomics 2017; 160: 8-20.
6.
Mollazadeh H, Cicero AFG, Blesso CN, Pirro M, Majeed M, Sahebkar A. Immune modulation by curcumin: the role of interleukin-10. Crit Rev Food Sci Nutr 2019; 59: 89-101.
7.
Pan CJ, Tang JJ, Shao ZY, Wang J, Huang N. Improved blood compatibility of rapamycin-eluting stent by incorporating curcumin. Colloids Surf B Biointerfaces 2007; 59: 105-11.
8.
Mawani Y, Orvig C. Improved separation of the curcuminoids, syntheses of their rare earth complexes, and studies of potential antiosteoporotic activity. J Inorg Biochem 2014; 132: 52-8.
9.
Khanizadeh F, Rahmani A, Asadollahi K, Ahmadi MRH. Combination therapy of curcumin and alendronate modulates bone turnover markers and enhances bone mineral density in postmenopausal women with osteoporosis. Arch Endocrinol Metab 2018; 62: 438-45.
10.
Ahmed MF, El-Sayed AK, Chen H, et al. Comparison between curcumin and all-trans retinoic acid in the osteogenic differentiation of mouse bone marrow mesenchymal stem cells. Exp Ther Med 2019; 17: 4154-66.
11.
Wang H, Zhang Y, Yang Y, et al. Curcumin pretreatment protects against hypoxia/reoxgenation injury via improvement of mitochondrial function, destabilization of HIF-1 and activation of Epac1-Akt pathway in rat bone marrow mesenchymal stem cells. Biomed Pharmacother 2019; 109: 1268-75.
12.
Sahebkar A, Cicero AFG, Simental-Mendía LE, Aggarwal BB, Gupta SC. Curcumin downregulates human tumor necrosis factor- levels: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res 2016; 107: 234-42.
13.
Lu N, Li X, Yu J, et al. Curcumin attenuates lipopolysaccharide-induced hepatic lipid metabolism disorder by modification of m(6) A RNA methylation in piglets. Lipids 2018; 53: 53-63.
14.
Xie Y, Zhao X, Jia H, Ma B. Derivation and characterization of goat fetal fibroblast cells induced with human telomerase reverse transcriptase. In Vitro Cell Dev Biol Anim 2013; 49: 8-14.
15.
Timmers L, Lim SK, Arslan F, et al. Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res 2007; 1: 129-37.
16.
Ebrahim N, Ahmed IA, Hussien NI, et al. Mesenchymal stem cell-derived exosomes ameliorated diabetic nephropathy by autophagy induction through the mTOR signaling pathway. Cells 2018; 7: 226.
17.
Furuta T, Miyaki S, Ishitobi H, et al. Mesenchymal stem cell-derived exosomes promote fracture healing in a mouse model. Stem Cells Transl Med 2016; 5: 1620-30.
18.
Katsuda T, Ochiya T. Molecular signatures of mesenchymal stem cell-derived extracellular vesicle-mediated tissue repair. Stem Cell Res Ther 2015; 6: 212.
19.
Zhao P, Xiao L, Peng J, Qian YQ, Huang CC. Exosomes derived from bone marrow mesenchymal stem cells improve osteoporosis through promoting osteoblast proliferation via MAPK pathway. Eur Rev Med Pharmacol Sci 2018; 22: 3962-70.
20.
Visvanathan A, Patil V, Arora A, et al. Essential role of METTL3-mediated m(6)A modification in glioma stem-like cells maintenance and radioresistance. Oncogene 2018; 37: 522-33.
21.
Wen J, Lv R, Ma H, et al. Zc3h13 Regulates nuclear RNA m(6)A methylation and mouse embryonic stem cell self-renewal. Mol Cell 2018; 69: 1028-38e6.
22.
Wu Y, Xie L, Wang M, et al. Mettl3-mediated m(6)A RNA methylation regulates the fate of bone marrow mesenchymal stem cells and osteoporosis. Nat Commun 2018; 9: 4772.
23.
Yan G, Yuan Y, He M, et al. m(6)A methylation of precursor-miR-320/RUNX2 controls osteogenic potential of bone marrow-derived mesenchymal stem cells. Mol Ther Nucleic Acids 2020; 19: 421-36.
24.
Komori T. Regulation of osteoblast differentiation by Runx2. Adv Exp Med Biol 2010; 658: 43-9.
25.
Pratap J, Wixted JJ, Gaur T, et al. Runx2 transcriptional activation of Indian Hedgehog and a downstream bone metastatic pathway in breast cancer cells. Cancer Res 2008; 68: 7795-802.
26.
Vashisht M, Rani P, Onteru SK, Singh D. Curcumin encapsulated in milk exosomes resists human digestion and possesses enhanced intestinal permeability in vitro. Appl Biochem Biotechnol 2017; 183: 993-1007.
27.
Oskouie MN, Moghaddam NSA, Butler AE, Zamani P, Sahebkar A. Therapeutic use of curcumin-encapsulated and curcumin-primed exosomes. J Cell Physiol 2019; 234: 8182-91.
28.
Aggarwal BB, Sundaram C, Malani N, Ichikawa H. Curcumin: the Indian solid gold. Adv Exp Med Biol 2007; 595: 1-75.
29.
Bharti AC, Takada Y, Aggarwal BB. Curcumin (diferuloylmethane) inhibits receptor activator of NF-kappa B ligand-induced NF-kappa B activation in osteoclast precursors and suppresses osteoclastogenesis. J Immunol 2004; 172: 5940-7.
30.
Ozaki K, Kawata Y, Amano S, Hanazawa S. Stimulatory effect of curcumin on osteoclast apoptosis. Biochem Pharmacol 2000; 59: 1577-81.
31.
Chen Z, Xue J, Shen T, Mu S, Fu Q. Curcumin alleviates glucocorticoid-induced osteoporosis through the regulation of the Wnt signaling pathway. Int J Mol Med 2016; 37: 329-38.
32.
Böhrnsen F, Krier M, Grohmann S, et al. MSC differentiation on two-photon polymerized, stiffness and BMP2 modified biological copolymers. Biomed Mater 2019; 14: 035001.
33.
Chen T, Hao YJ, Zhang Y, et al. m(6)A RNA methylation is regulated by microRNAs and promotes reprogramming to pluripotency. Cell Stem Cell 2015; 16: 289-301.
34.
Liao Y, Du X, Li J, Lönnerdal B. Human milk exosomes and their microRNAs survive digestion in vitro and are taken up by human intestinal cells. Mol Nutr Food Res 2017; 61: doi: 10.1002/mnfr.201700082.
35.
Ma H, Xu Y, Zhang R, Guo B, Zhang S, Zhang X. Differential expression study of circular RNAs in exosomes from serum and urine in patients with idiopathic membranous nephropathy. Arch Med Sci 2019; 15: 738-53.
36.
Agrawal AK, Aqil F, Jeyabalan J, et al. Milk-derived exosomes for oral delivery of paclitaxel. Nanomedicine 2017; 13: 1627-36.
37.
Yang X, Yang J, lei P, Wen T. LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis. Aging 2019; 11: 8777-91.
38.
Liu J, Dou X, Chen C, et al. N (6)-methyladenosine of chromosome-associated regulatory RNA regulates chromatin state and transcription. Science 2020; 367: 580-6.
39.
Hamam D, Ali D, Vishnubalaji R, et al. microRNA-320/RUNX2 axis regulates adipocytic differentiation of human mesenchymal (skeletal) stem cells. Cell Death Dis 2014; 5: e1499.
40.
Sancisi V, Manzotti G, Gugnoni M, et al. RUNX2 expression in thyroid and breast cancer requires the cooperation of three non-redundant enhancers under the control of BRD4 and c-JUN. Nucleic Acids Res 2017; 45: 11249-67.
41.
Yu S, Geng Q, Sun F, Yu Y, Pan Q, Hong A. Osteogenic differentiation of C2C12 myogenic progenitor cells requires the Fos-related antigen Fra-1 – a novel target of Runx2. Biochem Biophys Res Commun 2013; 430: 173-8.
42.
Li H, Xie H, Liu W, et al. A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 2009; 119: 3666-77.
43.
Kobayashi H, Gao YH, Ueta C, Yamaguchi A, Komori T. Multilineage differentiation of Cbfa1-deficient calvarial cells in vitro. Biochem Biophys Res Commun 2000; 273: 630-6.
44.
Otto F, Thornell AP, Crompton T, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 1997; 89: 765-71.
45.
Hesse E, Saito H, Kiviranta R, et al. Zfp521 controls bone mass by HDAC3-dependent attenuation of Runx2 activity. J Cell Biol 2010; 191: 1271-83.
46.
James AW. Review of signaling pathways governing msc osteogenic and adipogenic differentiation. Scientifica 2013; 2013: 684736.
Share
RELATED ARTICLE
| eISSN: | 1896-9151 |
| ISSN: | 1734-1922 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
