Skip to main content

Exosomes from Adipose Tissues Derived Mesenchymal Stem Cells Overexpressing MicroRNA-146a Alleviate Diabetic Osteoporosis in Rats

Cellular and Molecular Bioengineering volume 15, pages 87–97 (2022)Cite this article

Abstract

Background

Inflammation is one of major contributors of diabetic osteoporosis. Here, we combined adipose tissues derived mesenchymal stem cells (AD-MSCs)-derived exosomes and microRNA-146a (miR-146a) to develop more effective anti-inflammation strategy in osteoclasts.

Methods

miR-146a was overexpressed in AD-MSCs and miR-146a exosomes (miR-146a-Exo) were isolated and characterized. Cellular and animal diabetic osteoporosis models were created to evaluate the anti-inflammation effect of miR-146a-Exo by using ELISA, qRT-PCR, MTT, bone resorption assay, Western blot, and bone mineral content and density analysis in vitro and in vivo.

Results

miR-146a-Exo administration presented the most potent effect on inhibition of pro-inflammatory cytokines production in high glucose-treated osteoclasts, restraint bone resorption, and restoration of the bone loss in streptozotocin-induced diabetic osteoporosis rats. Mechanistically, miR-146a-Exo suppressed the expression of TNF-α, IL-18, and IL-1β, induced the inactivation of inflammasome, and finally reduced bone resorption and recovered bone loss.

Conclusion

Combination of AD-MSCs-Exo and miR-146a more effectively exert the anti-inflammation effect in osteoclasts, providing a potential drug for the treatment of diabetic osteoporosis.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price includes VAT (USA)
Tax calculation will be finalised during checkout.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

References

  1. Hamann, C., S. Kirschner, K. P. Gunther, and L. C. Hofbauer. Bone, sweet bone–osteoporotic fractures in diabetes mellitus. Nat. Rev. Endocrinol. 8(5):297–305, 2012.

    Article  Google Scholar 

  2. Saito, M., and K. Marumo. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 21(2):195–214, 2010.

    Article  Google Scholar 

  3. Cheloni, R., S. A. Gandolfi, C. Signorelli, and A. Odone. Global prevalence of diabetic retinopathy: protocol for a systematic review and meta-analysis. BMJ Open. 9(3):e022188, 2019.

    Article  Google Scholar 

  4. Reilly, J. J., A. El-Hamdouchi, A. Diouf, A. Monyeki, and S. A. Somda. Determining the worldwide prevalence of obesity. Lancet. 391(10132):1773–1774, 2018.

    Article  Google Scholar 

  5. Harding, J. L., M. E. Pavkov, D. J. Magliano, J. E. Shaw, and E. W. Gregg. Global trends in diabetes complications: a review of current evidence. Diabetologia. 62(1):3–16, 2019.

    Article  Google Scholar 

  6. Vlassara, H., and J. Uribarri. Advanced glycation end products (AGE) and diabetes: cause, effect, or both? Curr. Diabetes Rep. 14(1):453, 2014.

    Article  Google Scholar 

  7. Asadipooya, K., and E. M. Uy. Advanced glycation end products (AGEs), receptor for AGEs, diabetes, and bone: review of the literature. J. Endocr. Soc. 3(10):1799–1818, 2019.

    Article  Google Scholar 

  8. Agidigbi, T. S., and C. Kim. Reactive oxygen species in osteoclast differentiation and possible pharmaceutical targets of ROS-mediated osteoclast diseases. Int. J. Mol. Sci. 20(14):3576, 2019.

    Article  Google Scholar 

  9. Domazetovic, V., G. Marcucci, T. Iantomasi, M. L. Brandi, and M. T. Vincenzini. Oxidative stress in bone remodeling: role of antioxidants. Clin. Cases Miner. Bone Metab. 14(2):209–216, 2017.

    Article  Google Scholar 

  10. Kanazawa, I. Interaction between bone and glucose metabolism [Review]. Endocr. J. 64(11):1043–1053, 2017.

    Article  Google Scholar 

  11. De Martinis, M., M. M. Sirufo, C. Nocelli, L. Fontanella, and L. Ginaldi. Hyperhomocysteinemia is associated with inflammation, bone resorption, Vitamin B12 and folate deficiency and MTHFR C677T polymorphism in postmenopausal women with decreased bone mineral density. Int. J. Environ. Res. Public Health. 17(12):4260, 2020.

    Article  Google Scholar 

  12. Rao, S. S., Y. Hu, P. L. Xie, J. Cao, Z. X. Wang, J. H. Liu, H. Yin, J. Huang, Y. J. Tan, J. Luo, M. J. Luo, S. Y. Tang, T. H. Chen, L. Q. Yuan, E. Y. Liao, R. Xu, Z. Z. Liu, C. Y. Chen, and H. Xie. Omentin-1 prevents inflammation-induced osteoporosis by downregulating the pro-inflammatory cytokines. Bone Res. 6:9, 2018.

    Article  Google Scholar 

  13. Tofino-Vian, M., M. I. Guillen, M. D. Perez Del Caz, A. Silvestre, and M. J. Alcaraz. Microvesicles from human adipose tissue-derived mesenchymal stem cells as a new protective strategy in osteoarthritic chondrocytes. Cell Physiol. Biochem. 47(1):11–25, 2018.

    Article  Google Scholar 

  14. Yun, B., B. E. Maburutse, M. Kang, M. R. Park, D. J. Park, Y. Kim, and S. Oh. Short communication: dietary bovine milk-derived exosomes improve bone health in an osteoporosis-induced mouse model. J. Dairy Sci. 103(9):7752–7760, 2020.

    Article  Google Scholar 

  15. Yang, C., W. Lim, J. Park, S. Park, S. You, and G. Song. Anti-inflammatory effects of mesenchymal stem cell-derived exosomal microRNA-146a-5p and microRNA-548e-5p on human trophoblast cells. Mol. Hum. Reprod. 25(11):755–771, 2019.

    Article  Google Scholar 

  16. Lo, W. Y., C. T. Peng, and H. J. Wang. MicroRNA-146a-5p mediates high glucose-induced endothelial inflammation via targeting interleukin-1 receptor-associated kinase 1 expression. Front. Physiol. 8:551, 2017.

    Article  Google Scholar 

  17. Boldin, M. P., K. D. Taganov, D. S. Rao, L. Yang, J. L. Zhao, M. Kalwani, Y. Garcia-Flores, M. Luong, A. Devrekanli, J. Xu, G. Sun, J. Tay, P. S. Linsley, and D. Baltimore. miR-146a is a significant brake on autoimmunity, myeloproliferation, and cancer in mice. J. Exp. Med. 208(6):1189–1201, 2011.

    Article  Google Scholar 

  18. Chang, C. L., P. H. Sung, K. H. Chen, P. L. Shao, C. C. Yang, B. C. Cheng, K. C. Lin, C. H. Chen, H. T. Chai, H. W. Chang, H. K. Yip, and H. H. Chen. Adipose-derived mesenchymal stem cell-derived exosomes alleviate overwhelming systemic inflammatory reaction and organ damage and improve outcome in rat sepsis syndrome. Am. J. Transl. Res. 10(4):1053–1070, 2018.

    Google Scholar 

  19. Vestergaard, P. Bone metabolism in type 2 diabetes and role of thiazolidinediones. Curr. Opin. Endocrinol. Diabetes Obes. 16(2):125–131, 2009.

    Article  Google Scholar 

  20. Li, B., A. Hock, R. Y. Wu, A. Minich, S. R. Botts, C. Lee, L. Antounians, H. Miyake, Y. Koike, Y. Chen, A. Zani, P. M. Sherman, and A. Pierro. Bovine milk-derived exosomes enhance goblet cell activity and prevent the development of experimental necrotizing enterocolitis. PLoS ONE. 14(1):e0211431, 2019.

    Article  Google Scholar 

  21. Georgess, D., M. Mazzorana, J. Terrado, C. Delprat, C. Chamot, R. M. Guasch, I. Perez-Roger, P. Jurdic, and I. Machuca-Gayet. Comparative transcriptomics reveals RhoE as a novel regulator of actin dynamics in bone-resorbing osteoclasts. Mol. Biol. Cell. 25(3):380–396, 2014.

    Article  Google Scholar 

  22. Ren, Z. Y., I. Machuca-Gayet, C. Domenget, R. Buchet, Y. Wu, P. Jurdic, and S. Mebarek. Azanitrile cathepsin K inhibitors: effects on cell toxicity, osteoblast-induced mineralization and osteoclast-mediated bone resorption. PLoS ONE. 10(7):e0132513, 2015.

    Article  Google Scholar 

  23. Wei, M., L. Ong, M. T. Smith, F. B. Ross, K. Schmid, A. J. Hoey, D. Burstow, and L. Brown. The streptozotocin-diabetic rat as a model of the chronic complications of human diabetes. Heart Lung Circ. 12(1):44–50, 2003.

    Article  Google Scholar 

  24. An, Y., H. Zhang, C. Wang, F. Jiao, H. Xu, X. Wang, W. Luan, F. Ma, L. Ni, X. Tang, M. Liu, W. Guo, and L. Yu. Activation of ROS/MAPKs/NF-kappaB/NLRP3 and inhibition of efferocytosis in osteoclast-mediated diabetic osteoporosis. FASEB J. 33(11):12515–12527, 2019.

    Article  Google Scholar 

  25. Baek, D., J. Villen, C. Shin, F. D. Camargo, S. P. Gygi, and D. P. Bartel. The impact of microRNAs on protein output. Nature. 455(7209):64–71, 2008.

    Article  Google Scholar 

  26. Baltimore, D., M. P. Boldin, R. M. O’Connell, D. S. Rao, and K. D. Taganov. MicroRNAs: new regulators of immune cell development and function. Nat. Immunol. 9(8):839–845, 2008.

    Article  Google Scholar 

  27. Sheedy, F. J., E. Palsson-McDermott, E. J. Hennessy, C. Martin, J. J. O’Leary, Q. Ruan, D. S. Johnson, Y. Chen, and L. A. O’Neill. Negative regulation of TLR4 via targeting of the proinflammatory tumor suppressor PDCD4 by the microRNA miR-21. Nat. Immunol. 11(2):141–147, 2010.

    Article  Google Scholar 

  28. Tokuhiro, S., R. Yamada, X. Chang, A. Suzuki, Y. Kochi, T. Sawada, M. Suzuki, M. Nagasaki, M. Ohtsuki, M. Ono, H. Furukawa, M. Nagashima, S. Yoshino, A. Mabuchi, A. Sekine, S. Saito, A. Takahashi, T. Tsunoda, Y. Nakamura, and K. Yamamoto. An intronic SNP in a RUNX1 binding site of SLC22A4, encoding an organic cation transporter, is associated with rheumatoid arthritis. Nat. Genet. 35(4):341–348, 2003.

    Article  Google Scholar 

  29. Taganov, K. D., M. P. Boldin, K. J. Chang, and D. Baltimore. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl. Acad. Sci. U.S.A. 103(33):12481–12486, 2006.

    Article  Google Scholar 

  30. Baraban, J. M., A. Shah, and X. Fu. Multiple pathways mediate microRNA degradation: focus on the translin/Trax RNase complex. Adv. Pharmacol. 82:1–20, 2018.

    Article  Google Scholar 

  31. Zhang, Z., Y. W. Qin, G. Brewer, and Q. Jing. MicroRNA degradation and turnover: regulating the regulators. Wiley Interdiscip. Rev. RNA. 3(4):593–600, 2012.

    Article  Google Scholar 

  32. Pers, Y. M., M. Ruiz, D. Noel, and C. Jorgensen. Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives. Osteoarthritis Cartilage. 23(11):2027–2035, 2015.

    Article  Google Scholar 

  33. Singer, N. G., and A. I. Caplan. Mesenchymal stem cells: mechanisms of inflammation. Annu. Rev. Pathol. 6:457–478, 2011.

    Article  Google Scholar 

  34. Bouffi, C., C. Bony, C. Jorgensen, and D. Noel. Skin fibroblasts are potent suppressors of inflammation in experimental arthritis. Ann. Rheum. Dis. 70(9):1671–1676, 2011.

    Article  Google Scholar 

  35. Luz-Crawford, P., D. Noel, X. Fernandez, M. Khoury, F. Figueroa, F. Carrion, C. Jorgensen, and F. Djouad. Mesenchymal stem cells repress Th17 molecular program through the PD-1 pathway. PLoS ONE. 7(9):e45272, 2012.

    Article  Google Scholar 

  36. Picke, A. K., G. Campbell, N. Napoli, L. C. Hofbauer, and M. Rauner. Update on the impact of type 2 diabetes mellitus on bone metabolism and material properties. Endocr. Connect. 8(3):R55–R70, 2019.

    Article  Google Scholar 

  37. Wu, H., H. Fan, Z. Shou, M. Xu, Q. Chen, C. Ai, Y. Dong, Y. Liu, Z. Nan, Y. Wang, T. Yu, and X. Liu. Extracellular vesicles containing miR-146a attenuate experimental colitis by targeting TRAF6 and IRAK1. Int. Immunopharmacol. 68:204–212, 2019.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Cangzhou Central Hospital, No. 16 Xinhuaxi Road, Cangzhou, 061000, Hebei, China

    Lei Zhang, Qinghai Wang, Hang Su & Jiaxiang Cheng

Authors
  1. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qinghai Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hang Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiaxiang Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lei Zhang.

Ethics declarations

Conflict of interest

Lei Zhang, Qinghai Wang, Hang Su, and Jiaxiang Cheng declare that they have no conflict of interest.

Ethical Approval

No human studies were carried out by the authors for this article. All animal studies were carried out in accordance with the Guide for the Care and Use of Laboratory Animals (8th edition, NIH), and were approved by the ethical committee of Cangzhou Central Hospital.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Associate Editor Michael R. King oversaw the review of this article.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Wang, Q., Su, H. et al. Exosomes from Adipose Tissues Derived Mesenchymal Stem Cells Overexpressing MicroRNA-146a Alleviate Diabetic Osteoporosis in Rats. Cel. Mol. Bioeng. 15, 87–97 (2022). https://doi.org/10.1007/s12195-021-00699-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12195-021-00699-4

Keywords

  • Diabetic osteoporosis
  • miR-146a
  • MSCs
  • Exosomes
  • Inflammasome