HMGB1 mediates the development of tendinopathy due to mechanical overloading

Autoři: Guangyi Zhao aff001;  Jianying Zhang aff001;  Daibang Nie aff001;  Yiqin Zhou aff001;  Feng Li aff001;  Kentaro Onishi aff004;  Timothy Billiar aff005;  James H-C. Wang aff001
Působiště autorů: MechanoBiology Laboratory, Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America aff001;  Department of Immunology, College of Basic Medicine, Chongqing Medical University, Chongqing, China aff002;  Joint Surgery and Sports Medicine Department, Shanghai Changzheng Hospital, Second Military Medical University, Huangpu, Shanghai, China aff003;  Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America aff004;  Department of Surgery, University of Pittsburgh, Pennsylvania, United States of America aff005;  Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America aff006
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: 10.1371/journal.pone.0222369


Mechanical overloading is a major cause of tendinopathy, but the underlying pathogenesis of tendinopathy is unclear. Here we report that high mobility group box1 (HMGB1) is released to the tendon extracellular matrix and initiates an inflammatory cascade in response to mechanical overloading in a mouse model. Moreover, administration of glycyrrhizin (GL), a naturally occurring triterpene and a specific inhibitor of HMGB1, inhibits the tendon’s inflammatory reactions. Also, while prolonged mechanical overloading in the form of long-term intensive treadmill running induces Achilles tendinopathy in mice, administration of GL completely blocks the tendinopathy development. Additionally, mechanical overloading of tendon cells in vitro induces HMGB1 release to the extracellular milieu, thereby eliciting inflammatory and catabolic responses as marked by increased production of prostaglandin E2 (PGE2) and matrix metalloproteinase-3 (MMP-3) in tendon cells. Application of GL abolishes the cellular inflammatory/catabolic responses. Collectively, these findings point to HMGB1 as a key molecule that is responsible for the induction of tendinopathy due to mechanical overloading placed on the tendon.

Klíčová slova:

Cell staining – Collagens – Extracellular matrix – Inflammation – Inflammatory diseases – Nuclear staining – Tendons – Negative staining


1. Riley G. Chronic tendon pathology: molecular basis and therapeutic implications. Expert reviews in molecular medicine. 2005;7(5):1–25. doi: 10.1017/S1462399405008963 15796783

2. Kaux JF, Forthomme B, Goff CL, Crielaard JM, Croisier JL. Current opinions on tendinopathy. J Sports Sci Med. 2011;10(2):238–53. 24149868

3. Lipman K, Wang C, Ting K, Soo C, Zheng Z. Tendinopathy: injury, repair, and current exploration. Drug Des Devel Ther. 2018;12:591–603. doi: 10.2147/DDDT.S154660 29593382

4. Irwin TA. Current concepts review: insertional achilles tendinopathy. Foot & ankle international. 2010;31(10):933–9.

5. Khan KM, Cook JL, Bonar F, Harcourt P, Astrom M. Histopathology of common tendinopathies. Update and implications for clinical management. Sports Med. 1999;27(6):393–408. doi: 10.2165/00007256-199927060-00004 10418074

6. Magnusson SP, Langberg H, Kjaer M. The pathogenesis of tendinopathy: balancing the response to loading. Nature reviews Rheumatology. 2010;6(5):262–8. doi: 10.1038/nrrheum.2010.43 20308995

7. Scott A, Backman LJ, Speed C. Tendinopathy: Update on Pathophysiology. J Orthop Sports Phys Ther. 2015;45(11):833–41. doi: 10.2519/jospt.2015.5884 26390273

8. Spiesz EM, Thorpe CT, Chaudhry S, Riley GP, Birch HL, Clegg PD, et al. Tendon extracellular matrix damage, degradation and inflammation in response to in vitro overload exercise. Journal of orthopaedic research: official publication of the Orthopaedic Research Society. 2015;33(6):889–97.

9. Thorpe CT, Chaudhry S, Lei II, Varone A, Riley GP, Birch HL, et al. Tendon overload results in alterations in cell shape and increased markers of inflammation and matrix degradation. Scandinavian journal of medicine & science in sports. 2015;25(4):e381–91.

10. Lavagnino M, Wall ME, Little D, Banes AJ, Guilak F, Arnoczky SP. Tendon mechanobiology: Current knowledge and future research opportunities. Journal of orthopaedic research: official publication of the Orthopaedic Research Society. 2015;33(6):813–22.

11. Millar NL, Hueber AJ, Reilly JH, Xu Y, Fazzi UG, Murrell GA, et al. Inflammation is present in early human tendinopathy. The American journal of sports medicine. 2010;38(10):2085–91. doi: 10.1177/0363546510372613 20595553

12. Dakin SG, Martinez FO, Yapp C, Wells G, Oppermann U, Dean BJ, et al. Inflammation activation and resolution in human tendon disease. Sci Transl Med. 2015;7(311):311ra173. doi: 10.1126/scitranslmed.aac4269 26511510

13. Dakin SG, Newton J, Martinez FO, Hedley R, Gwilym S, Jones N, et al. Chronic inflammation is a feature of Achilles tendinopathy and rupture. British journal of sports medicine. 2018;52(6):359–67. doi: 10.1136/bjsports-2017-098161 29118051

14. Riley G. The pathogenesis of tendinopathy. A molecular perspective. Rheumatology (Oxford). 2004;43(2):131–42.

15. Wang JH, Jia F, Yang G, Yang S, Campbell BH, Stone D, et al. Cyclic mechanical stretching of human tendon fibroblasts increases the production of prostaglandin E2 and levels of cyclooxygenase expression: a novel in vitro model study. Connect Tissue Res. 2003;44(3–4):128–33. 14504032

16. Li Z, Yang G, Khan M, Stone D, Woo SL, Wang JH. Inflammatory response of human tendon fibroblasts to cyclic mechanical stretching. The American journal of sports medicine. 2004;32(2):435–40. doi: 10.1177/0095399703258680 14977670

17. Zhang JY, Wang JHC. Production of PGE(2) Increases in Tendons Subjected to Repetitive Mechanical Loading and Induces Differentiation of Tendon Stem Cells into Non-Tenocytes. Journal of Orthopaedic Research. 2010;28(2):198–203. doi: 10.1002/jor.20962 19688869

18. Khan MH, Li ZZ, Wang JHC. Repeated exposure of tendon to prostaglandin-E2 leads to localized tendon degeneration. J Sports Med. 2005;15(1):27–33.

19. Jarvinen TA, Kannus P, Maffulli N, Khan KM. Achilles tendon disorders: etiology and epidemiology. Foot and ankle clinics. 2005;10(2):255–66. doi: 10.1016/j.fcl.2005.01.013 15922917

20. Glazebrook MA, Wright JR Jr., Langman M, Stanish WD, Lee JM. Histological analysis of achilles tendons in an overuse rat model. Journal of orthopaedic research: official publication of the Orthopaedic Research Society. 2008;26(6):840–6.

21. Riley GP, Curry V, DeGroot J, van El B, Verzijl N, Hazleman BL, et al. Matrix metalloproteinase activities and their relationship with collagen remodelling in tendon pathology. Matrix biology: journal of the International Society for Matrix Biology. 2002;21(2):185–95.

22. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285(5425):248–51. doi: 10.1126/science.285.5425.248 10398600

23. Klune JR, Dhupar R, Cardinal J, Billiar TR, Tsung A. HMGB1: endogenous danger signaling. Mol Med. 2008;14(7–8):476–84. doi: 10.2119/2008-00034.Klune 18431461

24. Tang D, Kang R, Zeh HJ 3rd, Lotze MT. High-mobility group box 1, oxidative stress, and disease. Antioxid Redox Signal. 2011;14(7):1315–35. doi: 10.1089/ars.2010.3356 20969478

25. Wolf M, Lossdorfer S, Kupper K, Jager A. Regulation of high mobility group box protein 1 expression following mechanical loading by orthodontic forces in vitro and in vivo. European journal of orthodontics. 2013.

26. Lv S, Li J, Feng W, Liu H, Du J, Sun J, et al. Expression of HMGB1 in the periodontal tissue subjected to orthodontic force application by Waldo’s method in mice. J Mol Histol. 2015;46(1):107–14. doi: 10.1007/s10735-014-9606-z 25523715

27. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418(6894):191–5. doi: 10.1038/nature00858 12110890

28. Venereau E, Casalgrandi M, Schiraldi M, Antoine DJ, Cattaneo A, De Marchis F, et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med. 2012;209(9):1519–28. doi: 10.1084/jem.20120189 22869893

29. Venereau E, Schiraldi M, Uguccioni M, Bianchi ME. HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol Immunol. 2013;55(1):76–82. doi: 10.1016/j.molimm.2012.10.037 23207101

30. Tsung A, Tohme S, Billiar TR. High-mobility group box-1 in sterile inflammation. Journal of internal medicine. 2014;276(5):425–43. doi: 10.1111/joim.12276 24935761

31. Kang R, Chen R, Zhang Q, Hou W, Wu S, Cao L, et al. HMGB1 in health and disease. Mol Aspects Med. 2014;40:1–116. doi: 10.1016/j.mam.2014.05.001 25010388

32. Yang H, Wang H, Chavan SS, Andersson U. High Mobility Group Box Protein 1 (HMGB1): The Prototypical Endogenous Danger Molecule. Mol Med. 2015;21 Suppl 1:S6–S12.

33. Erlandsson Harris H, Andersson U. Mini-review: The nuclear protein HMGB1 as a proinflammatory mediator. European Journal of Immunology. 2004;34(6):1503–12. doi: 10.1002/eji.200424916 15162419

34. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annual review of immunology. 2011;29:139–62. doi: 10.1146/annurev-immunol-030409-101323 21219181

35. Wahamaa H, Schierbeck H, Hreggvidsdottir HS, Palmblad K, Aveberger AC, Andersson U, et al. High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts. Arthritis research & therapy. 2011;13(4):R136.

36. Millar NL, Murrell GA, McInnes IB. Alarmins in tendinopathy: unravelling new mechanisms in a common disease. Rheumatology (Oxford). 2013;52(5):769–79.

37. Akbar M, Gilchrist DS, Kitson SM, Nelis B, Crowe LAN, Garcia-Melchor E, et al. Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis. RMD Open. 2017;3(2):e000456. doi: 10.1136/rmdopen-2017-000456 28879051

38. Mosca MJ, Carr AJ, Snelling SJB, Wheway K, Watkins B, Dakin SG. Differential expression of alarmins-S100A9, IL-33, HMGB1 and HIF-1alpha in supraspinatus tendinopathy before and after treatment. BMJ open sport & exercise medicine. 2017;3(1):e000225.

39. Thankam FG, Roesch ZK, Dilisio MF, Radwan MM, Kovilam A, Gross RM, et al. Association of Inflammatory Responses and ECM Disorganization with HMGB1 Upregulation and NLRP3 Inflammasome Activation in the Injured Rotator Cuff Tendon. Sci Rep. 2018;8(1):8918. doi: 10.1038/s41598-018-27250-2 29891998

40. Li XL, Zhou AG, Zhang L, Chen WJ. Antioxidant status and immune activity of glycyrrhizin in allergic rhinitis mice. International journal of molecular sciences. 2011;12(2):905–16. doi: 10.3390/ijms12020905 21541033

41. Gwak GY, Moon TG, Lee DH, Yoo BC. Glycyrrhizin attenuates HMGB1-induced hepatocyte apoptosis by inhibiting the p38-dependent mitochondrial pathway. World journal of gastroenterology. 2012;18(7):679–84. doi: 10.3748/wjg.v18.i7.679 22363140

42. Yang PS, Kim DH, Lee YJ, Lee SE, Kang WJ, Chang HJ, et al. Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats. Respir Res. 2014;15:148. doi: 10.1186/s12931-014-0148-4 25420924

43. Yuan T, Zhang J, Zhao G, Zhou Y, Zhang C-Q, Wang JHC. Creating an Animal Model of Tendinopathy by Inducing Chondrogenic Differentiation with Kartogenin. PLoS ONE. 2016;11(2):e0148557. doi: 10.1371/journal.pone.0148557 26848746

44. Xu Y, Murrell GA. The basic science of tendinopathy. Clinical orthopaedics and related research. 2008;466(7):1528–38. doi: 10.1007/s11999-008-0286-4 18478310

45. Abate M, Silbernagel KG, Siljeholm C, Di Iorio A, De Amicis D, Salini V, et al. Pathogenesis of tendinopathies: inflammation or degeneration? Arthritis research & therapy. 2009;11(3):235.

46. Battery L, Maffulli N. Inflammation in overuse tendon injuries. Sports medicine and arthroscopy review. 2011;19(3):213–7. doi: 10.1097/JSA.0b013e31820e6a92 21822104

47. Thankam FG, Dilisio MF, Dietz NE, Agrawal DK. TREM-1, HMGB1 and RAGE in the Shoulder Tendon: Dual Mechanisms for Inflammation Based on the Coincidence of Glenohumeral Arthritis. PLoS ONE. 2016;11(10):e0165492. doi: 10.1371/journal.pone.0165492 27792788

48. Andersson U, Harris HE. The role of HMGB1 in the pathogenesis of rheumatic disease. Biochim Biophys Acta. 2010;1799(1–2):141–8. doi: 10.1016/j.bbagrm.2009.11.003 20123076

49. Sawa H, Ueda T, Takeyama Y, Yasuda T, Shinzeki M, Nakajima T, et al. Blockade of high mobility group box-1 protein attenuates experimental severe acute pancreatitis. World journal of gastroenterology. 2006;12(47):7666–70. doi: 10.3748/wjg.v12.i47.7666 17171797

50. Kokkola R, Li J, Sundberg E, Aveberger AC, Palmblad K, Yang H, et al. Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis and rheumatism. 2003;48(7):2052–8. doi: 10.1002/art.11161 12847700

51. Mollica L, De Marchis F, Spitaleri A, Dallacosta C, Pennacchini D, Zamai M, et al. Glycyrrhizin binds to high-mobility group box 1 protein and inhibits its cytokine activities. Chem Biol. 2007;14(4):431–41. doi: 10.1016/j.chembiol.2007.03.007 17462578

52. Akamatsu H, Komura J, Asada Y, Niwa Y. Mechanism of anti-inflammatory action of glycyrrhizin: effect on neutrophil functions including reactive oxygen species generation. Planta Med. 1991;57(2):119–21. doi: 10.1055/s-2006-960045 1891493

53. Genovese T, Menegazzi M, Mazzon E, Crisafulli C, Di Paola R, Dal Bosco M, et al. Glycyrrhizin reduces secondary inflammatory process after spinal cord compression injury in mice. Shock. 2009;31(4):367–75. doi: 10.1097/SHK.0b013e3181833b08 18665052

54. Fu Y, Zhou E, Wei Z, Liang D, Wang W, Wang T, et al. Glycyrrhizin inhibits the inflammatory response in mouse mammary epithelial cells and a mouse mastitis model. Febs j. 2014;281(11):2543–57. doi: 10.1111/febs.12801 24698106

55. Kim YM, Kim HJ, Chang KC. Glycyrrhizin reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and endotoxemic mice by p38/Nrf2-dependent induction of HO-1. Int Immunopharmacol. 2015;26(1):112–8. doi: 10.1016/j.intimp.2015.03.014 25812767

56. van Rossum TG, Vulto AG, de Man RA, Brouwer JT, Schalm SW. Review article: glycyrrhizin as a potential treatment for chronic hepatitis C. Aliment Pharmacol Ther. 1998;12(3):199–205. doi: 10.1046/j.1365-2036.1998.00309.x 9570253

57. Armanini D, Calo L, Semplicini A. Pseudohyperaldosteronism: pathogenetic mechanisms. Crit Rev Clin Lab Sci. 2003;40(3):295–335. doi: 10.1080/713609355 12892318

58. Leclerc P, Wähämaa H, Idborg H, Jakobsson PJ, Harris HE, Korotkova M. IL-1β/HMGB1 Complexes Promote The PGE(2) Biosynthesis Pathway in Synovial Fibroblasts. Scandinavian Journal of Immunology. 2013;77(5):350–60. doi: 10.1111/sji.12041 23488692

59. Zhang J, Wang JH. BMP-2 mediates PGE(2) -induced reduction of proliferation and osteogenic differentiation of human tendon stem cells. Journal of orthopaedic research: official publication of the Orthopaedic Research Society. 2012;30(1):47–52.

60. Zhang J, Wang JH. The effects of mechanical loading on tendons—an in vivo and in vitro model study. PLoS ONE. 2013;8(8):e71740. doi: 10.1371/journal.pone.0071740 23977130

61. Shah SL, Wahid F, Khan N, Farooq U, Shah AJ, Tareen S, et al. Inhibitory Effects of Glycyrrhiza glabra and Its Major Constituent Glycyrrhizin on Inflammation-Associated Corneal Neovascularization. Evid Based Complement Alternat Med. 2018;2018:8438101. doi: 10.1155/2018/8438101 29849730

Článek vyšel v časopise


2019 Číslo 9