Top

Journal of Orthopaedic Surgery and Research

Published in:

Open Access 01-12-2024 | Osteonecrosis of the Femoral Head | Research article

Exosomes derived from M2 macrophages prevent steroid-induced osteonecrosis of the femoral head by modulating inflammation, promoting bone formation and inhibiting bone resorption

Authors: Na Yuan, Weiying Zhang, Weizhou Yang, Wenchen Ji, Jia Li

Published in: Journal of Orthopaedic Surgery and Research | Issue 1/2024

Abstract

Inflammatory reactions are involved in the development of steroid-induced osteonecrosis of the femoral head(ONFH). Studies have explored the therapeutic efficacy of inhibiting inflammatory reactions in steroid-induced ONFH and revealed that inhibiting inflammation may be a new strategy for preventing the development of steroid-induced ONFH. Exosomes derived from M2 macrophages(M2-Exos) display anti-inflammatory properties. This study aimed to examine the preventive effect of M2-Exos on early-stage steroid-induced ONFH and explore the underlying mechanisms involved. In vitro, we explored the effect of M2-Exos on the proliferation and osteogenic differentiation of bone marrow-derived mesenchymal stem cells(BMMSCs). In vivo, we investigated the role of M2-Exos on inflammation, osteoclastogenesis, osteogenesis and angiogenesis in an early-stage rat model of steroid-induced ONFH. We found that M2-Exos promoted the proliferation and osteogenic differentiation of BMMSCs. Additionally, M2-Exos effectively attenuated the osteonecrotic changes, inhibited the expression of proinflammatory mediators, promoted osteogenesis and angiogenesis, reduced osteoclastogenesis, and regulated the polarization of M1/M2 macrophages in steroid-induced ONFH. Taken together, our data suggest that M2-Exos are effective at preventing steroid-induced ONFH. These findings may be helpful for providing a potential strategy to prevent the development of steroid-induced ONFH.

Quaranta M, Miranda L, Oliva F, Aletto C, Maffulli N. Osteotomies for avascular necrosis of the femoral head. Br Med Bull. 2021;137(1):98–111.PubMedCrossRef

Migliorini F, Maffulli N, Eschweiler J, Tingart M, Baroncini A. Core decompression isolated or combined with bone marrow-derived cell therapies for femoral head osteonecrosis. Expert Opin Biol Ther. 2021;21(3):423–30.PubMedCrossRef

Sadile F, Bernasconi A, Russo S, Maffulli N. Core decompression versus other joint preserving treatments for osteonecrosis of the femoral head: a meta-analysis. Br Med Bull. 2016;118(1):33–49.PubMedPubMedCentralCrossRef

Okazaki S, Nishitani Y, Nagoya S, Kaya M, Yamashita T, Matsumoto H. Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway. Rheumatology (Oxford). 2009;48(3):227–32.PubMedCrossRef

Pei J, Fan L, Nan K, Li J, Shi Z, Dang X, et al. Excessive activation of TLR4/NF-κB interactively suppresses the canonical Wnt/β-catenin pathway and induces SANFH in SD rats. Sci Rep. 2017;7(1):11928.PubMedPubMedCentralCrossRef

Kuroyanagi G, Adapala NS, Yamaguchi R, Kamiya N, Deng Z, Aruwajoye O, et al. Interleukin-6 deletion stimulates revascularization and new bone formation following ischemic osteonecrosis in a murine model. Bone. 2018;116:221–31.PubMedCrossRef

Ren Y, Deng Z, Gokani V, Kutschke M, Mitchell TW, Aruwajoye O, et al. Anti-interleukin-6 therapy decreases hip synovitis and bone resorption and increases bone formation following ischemic osteonecrosis of the femoral head. J Bone Min Res. 2021;36(2):357–68.CrossRef

Wu X, Xu W, Feng X, He Y, Liu X, Gao Y, et al. TNF-a mediated inflammatory macrophage polarization contributes to the pathogenesis of steroid-induced osteonecrosis in mice. Int J Immunopathol Pharmacol. 2015;28(3):351–61.PubMedCrossRef

Fang B, Wang D, Zheng J, Wei Q, Zhan D, Liu Y, et al. Involvement of tumor necrosis factor alpha in steroid-associated osteonecrosis of the femoral head: friend or foe? Stem Cell Res Ther. 2019;10(1):5.PubMedPubMedCentralCrossRef

10.

Wu X, Feng X, He Y, Gao Y, Yang S, Shao Z, et al. IL-4 administration exerts preventive effects via suppression of underlying inflammation and TNF-α-induced apoptosis in steroid-induced osteonecrosis. Osteoporos Int. 2016;27(5):1827–37.PubMedCrossRef

11.

Shin KO, Ha DH, Kim JO, Crumrine DA, Meyer JM, Wakefield JS et al. Exosomes from human adipose tissue-derived mesenchymal stem cells promote epidermal barrier repair by Inducing De Novo Synthesis of ceramides in atopic dermatitis. Cells. 2020;9(3).

12.

Gupta A, Cady C, Fauser AM, Rodriguez HC, Mistovich RJ, Potty AGR et al. Cell-free stem cell-derived Extract Formulation for Regenerative Medicine Applications. Int J Mol Sci. 2020;21(24).

13.

Qiu G, Zheng G, Ge M, Wang J, Huang R, Shu Q, et al. Functional proteins of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther. 2019;10(1):359.PubMedPubMedCentralCrossRef

14.

Gupta A, Shivaji K, Kadam S, Gupta M, Rodriguez HC, Potty AG, et al. Immunomodulatory extracellular vesicles: an alternative to cell therapy for COVID-19. Expert Opin Biol Ther. 2021;21(12):1551–60.PubMedCrossRef

15.

Li M, Li S, Du C, Zhang Y, Li Y, Chu L, et al. Exosomes from different cells: characteristics, modifications, and therapeutic applications. Eur J Med Chem. 2020;207:112784.PubMedCrossRef

16.

Wang Y, Zhao M, Liu S, Guo J, Lu Y, Cheng J, et al. Macrophage-derived extracellular vesicles: diverse mediators of pathology and therapeutics in multiple diseases. Cell Death Dis. 2020;11(10):924.PubMedPubMedCentralCrossRef

17.

Fang S, Li Y, Chen P. Osteogenic effect of bone marrow mesenchymal stem cell-derived exosomes on steroid-induced osteonecrosis of the femoral head. Drug Des Devel Ther. 2019;13:45–55.PubMedCrossRef

18.

Guo SC, Tao SC, Yin WJ, Qi X, Sheng JG, Zhang CQ. Exosomes from human synovial-derived mesenchymal stem cells prevent glucocorticoid-Induced osteonecrosis of the femoral head in the rat. Int J Biol Sci. 2016;12(10):1262–72.PubMedPubMedCentralCrossRef

19.

Liu X, Li Q, Niu X, Hu B, Chen S, Song W, et al. Exosomes secreted from Human-Induced pluripotent stem cell-derived mesenchymal stem cells prevent osteonecrosis of the femoral head by promoting angiogenesis. Int J Biol Sci. 2017;13(2):232–44.PubMedPubMedCentralCrossRef

20.

Hou Y, Liu Y, Liang S, Ding R, Mo S, Yan D, et al. The novel target: exosoms derived from M2 macrophage. Int Rev Immunol. 2021;40(3):183–96.PubMedCrossRef

21.

Yang R, Liao Y, Wang L, He P, Hu Y, Yuan D, et al. Exosomes Derived from M2b macrophages Attenuate DSS-Induced Colitis. Front Immunol. 2019;10:2346.PubMedPubMedCentralCrossRef

22.

Dai Y, Wang S, Chang S, Ren D, Shali S, Li C, et al. M2 macrophage-derived exosomes carry microRNA-148a to alleviate myocardial ischemia/reperfusion injury via inhibiting TXNIP and the TLR4/NF-κB/NLRP3 inflammasome signaling pathway. J Mol Cell Cardiol. 2020;142:65–79.PubMedCrossRef

23.

Long R, Gao L, Li Y, Li G, Qin P, Wei Z, et al. M2 macrophage-derived exosomes carry mir-1271-5p to alleviate cardiac injury in acute myocardial infarction through down-regulating SOX6. Mol Immunol. 2021;136:26–35.PubMedCrossRef

24.

Barrett JP, Costello DA, O’Sullivan J, Cowley TR, Lynch MA. Bone marrow-derived macrophages from aged rats are more responsive to inflammatory stimuli. J Neuroinflammation. 2015;12:67.PubMedPubMedCentralCrossRef

25.

Fridman E, Ginini L, Gil Z, Milman N. The purification and characterization of Exosomes from macrophages. Methods Mol Biol. 2020;2184:77–90.PubMedCrossRef

26.

Yuan N, Ge Z, Ji W, Li J. Exosomes secreted from Hypoxia-preconditioned mesenchymal stem cells prevent Steroid-Induced osteonecrosis of the femoral head by promoting angiogenesis in rats. Biomed Res Int. 2021;2021:6655225.PubMedPubMedCentralCrossRef

27.

Li J, Ge Z, Ji W, Yuan N, Wang K. The Proosteogenic and Proangiogenic effects of small extracellular vesicles derived from bone marrow mesenchymal stem cells are attenuated in Steroid-Induced osteonecrosis of the femoral head. Biomed Res Int. 2020;2020:4176926.PubMedPubMedCentral

28.

Yu Z, Fan L, Li J, Ge Z, Dang X, Wang K. Lithium prevents rat steroid-related osteonecrosis of the femoral head by β-catenin activation. Endocrine. 2016;52(2):380–90.PubMedCrossRef

29.

Fang S, Liu Z, Wu S, Chen X, You M, Li Y, et al. Pro-angiognetic and pro-osteogenic effects of human umbilical cord mesenchymal stem cell-derived exosomal mir-21-5p in osteonecrosis of the femoral head. Cell Death Discov. 2022;8(1):226.PubMedPubMedCentralCrossRef

30.

Nan K, Zhang Y, Zhang X, Li D, Zhao Y, Jing Z, et al. Exosomes from miRNA-378-modified adipose-derived stem cells prevent glucocorticoid-induced osteonecrosis of the femoral head by enhancing angiogenesis and osteogenesis via targeting miR-378 negatively regulated suppressor of fused (Sufu). Stem Cell Res Ther. 2021;12(1):331.PubMedPubMedCentralCrossRef

31.

Yamamoto T, Irisa T, Sugioka Y, Sueishi K. Effects of pulse methylprednisolone on bone and marrow tissues: corticosteroid-induced osteonecrosis in rabbits. Arthritis Rheum. 1997;40(11):2055–64.PubMedCrossRef

32.

Nan K, Pei JP, Fan LH, Zhang YK, Zhang X, Liu K, et al. Resveratrol prevents steroid-induced osteonecrosis of the femoral head via miR-146a modulation. Ann N Y Acad Sci. 2021;1503(1):23–37.PubMedCrossRef

33.

Schlundt C, El Khassawna T, Serra A, Dienelt A, Wendler S, Schell H, et al. Macrophages in bone fracture healing: their essential role in endochondral ossification. Bone. 2018;106:78–89.PubMedCrossRef

34.

Jin SS, He DQ, Luo D, Wang Y, Yu M, Guan B, et al. A biomimetic hierarchical Nanointerface orchestrates macrophage polarization and mesenchymal stem cell recruitment to promote endogenous bone regeneration. ACS Nano. 2019;13(6):6581–95.PubMedCrossRef

35.

Zhu K, Yang C, Dai H, Li J, Liu W, Luo Y, et al. Crocin inhibits titanium particle-induced inflammation and promotes osteogenesis by regulating macrophage polarization. Int Immunopharmacol. 2019;76:105865.PubMedCrossRef

36.

He XT, Li X, Yin Y, Wu RX, Xu XY, Chen FM. The effects of conditioned media generated by polarized macrophages on the cellular behaviours of bone marrow mesenchymal stem cells. J Cell Mol Med. 2018;22(2):1302–15.PubMedCrossRef

37.

Xia Y, He XT, Xu XY, Tian BM, An Y, Chen FM. Exosomes derived from M0, M1 and M2 macrophages exert distinct influences on the proliferation and differentiation of mesenchymal stem cells. PeerJ. 2020;8:e8970.PubMedPubMedCentralCrossRef

38.

Zhou YK, Han CS, Zhu ZL, Chen P, Wang YM, Lin S, et al. M2 exosomes modified by hydrogen sulfide promoted bone regeneration by moesin mediated endocytosis. Bioact Mater. 2024;31:192–205.PubMed

39.

Chen B, Liu Y, Cheng L. IL-21 enhances the degradation of cartilage through the JAK-STAT signaling pathway during osteonecrosis of femoral Head Cartilage. Inflammation. 2018;41(2):595–605.PubMedCrossRef

40.

Tanaka Y, Nakayamada S, Okada Y. Osteoblasts and osteoclasts in bone remodeling and inflammation. Curr Drug Targets Inflamm Allergy. 2005;4(3):325–8.PubMedCrossRef

41.

Vergadi E, Ieronymaki E, Lyroni K, Vaporidi K, Tsatsanis C. Akt signaling pathway in macrophage activation and M1/M2 polarization. J Immunol. 2017;198(3):1006–14.PubMedCrossRef

42.

Murray PJ. Macrophage polarization. Annu Rev Physiol. 2017;79:541–66.PubMedCrossRef

43.

Horwood NJ. Macrophage polarization and bone formation: a review. Clin Rev Allergy Immunol. 2016;51(1):79–86.PubMedCrossRef

44.

Lassus J, Salo J, Jiranek WA, Santavirta S, Nevalainen J, Matucci-Cerinic M et al. Macrophage activation results in bone resorption. Clin Orthop Relat Res. 1998(352):7–15.

45.

Tan Z, Wang Y, Chen Y, Liu Y, Ma M, Ma Z, et al. The dynamic feature of macrophage M1/M2 imbalance facilitates the progression of non-traumatic osteonecrosis of the femoral head. Front Bioeng Biotechnol. 2022;10:912133.PubMedPubMedCentralCrossRef

46.

Jin S, Meng C, He Y, Wang X, Zhang Q, Wang Z, et al. Curcumin prevents osteocyte apoptosis by inhibiting M1-type macrophage polarization in mice model of glucocorticoid-associated osteonecrosis of the femoral head. J Orthop Res. 2020;38(9):2020–30.PubMedPubMedCentralCrossRef

Title: Exosomes derived from M2 macrophages prevent steroid-induced osteonecrosis of the femoral head by modulating inflammation, promoting bone formation and inhibiting bone resorption
Authors: Na Yuan
Weiying Zhang
Weizhou Yang
Wenchen Ji
Jia Li
Publication date: 01-12-2024
Publisher: BioMed Central
Keyword: Osteonecrosis of the Femoral Head
Published in: Journal of Orthopaedic Surgery and Research / Issue 1/2024
Electronic ISSN: 1749-799X
DOI: https://doi.org/10.1186/s13018-024-04711-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Exosomes derived from M2 macrophages prevent steroid-induced osteonecrosis of the femoral head by modulating inflammation, promoting bone formation and inhibiting bone resorption

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

Correlation between vascular endothelial growth factor A gene polymorphisms and tendon and ligament injury risk: a systematic review and meta-analysis

The effect of long-term alendronic acid treatment on Modic changes in the lumbar spine: a gender and age-matched study

Translation, reliability and validity of the Turkish versions of Norwich Patellar Instability score and The Banff Patellar Instability Instrument 2.0

Incorporation of black phosphorus nanosheets into poly(propylene fumarate) biodegradable bone cement to enhance bioactivity and osteogenesis

Risk of low bone mineral density in patients with haemophilia: a systematic review and meta-analysis

Development and validation of multiple linear regression models for predicting total hip arthroplasty acetabular prosthesis