Skip to main content
SpringerLink
Log in

Endoplasmic reticulum stress regulates mechanical stress-induced ossification of posterior longitudinal ligament

  • Original Article
  • Published:
European Spine Journal Aims and scope Submit manuscript

Abstract

Purpose

The pathogenesis of ossification of posterior longitudinal ligament (OPLL) is not completely clear. Previous study has confirmed a single-pass type I endoplasmic reticulum (ER) membrane protein kinase (PERK), which is a major transducer of the ER stress, participates in the process of OPLL in vitro. This study aimed to demonstrate the role of ER stress in mechanical stress (MS)-induced OPLL.

Methods

The posterior longitudinal ligaments were collected intraoperatively. The expression of ER stress markers in ligament tissue samples was compared between OPLL and non-OPLL patients in vivo. Ligament fibroblasts were isolated and cultured. Loaded by MS, the expression of ER stress markers in fibroblasts deriving from non-ossified areas of the ligament tissues from OPLL patients was detected. The influence of inhibition of ER stress on MS-induced OPLL and activation of mitogen-activated protein kinase (MAPK) pathways by MS was also investigated.

Results

We confirmed the ER stress markers were highly expressed in non-ossified areas of the ligament tissues from OPLL patients but could barely be detected in the ligaments from non-OPLL patients in vivo. We also found ER stress could be activated by MS during the process of OPLL in vitro. Moreover, inhibition of ER stress could hinder MS-induced OPLL and activation of MAPK signaling pathways by MS in vitro.

Conclusion

Activated ER stress was observed in OPLL patients both in vitro and in vivo. Mechanical stress could activate ER stress response in posterior longitudinal ligament fibroblasts and further promote OPLL in vitro. In this process, ER stress might work through the MAPK signaling pathways.

Graphic abstract

These slides can be retrieved under Electronic Supplementary Material.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Karner CM, Lee SY, Long F (2017) Bmp induces osteoblast differentiation through both Smad4 and mTORC1 signaling. Mol Cell Biol 37(4):1–12

    Article  Google Scholar 

  2. He L, Lee J, Jang JH et al (2013) Osteoporosis regulation by salubrinal through elF2α mediated differentiation of osteoclast and osteoblast. Cell Signal 25(2):552–560

    Article  CAS  Google Scholar 

  3. Choi YH, Kim YJ, Jeong HM et al (2014) Akt enhances Runx2 protein stability by regulating Smurf2 function during osteoblast differentiation. FEBS J 281(16):3656–3666

    Article  CAS  Google Scholar 

  4. Wysokinski D, Pawlowska E, Blasiak J (2015) RUNX2: a master bone growth regulator that may be involved in the DNA damage response. DNA Cell Biol 34(5):305–315

    Article  CAS  Google Scholar 

  5. Chen Y, Gao H, Yin Q et al (2013) ER stress activating ATF4/CHOP-TNF alpha signaling pathway contributes to alcohol-induced disruption of osteogenic lineage of multipotential mesenchymal stem cell Cellular physiology and biochemistry. Cell Physiol Biochem 32(3):743–754

    Article  CAS  Google Scholar 

  6. Komori T (2016) Glucocorticoid signaling and bone biology. Horm Metab Res 48(11):755–763

    Article  CAS  Google Scholar 

  7. Kondo S, Onari K, Watanabe K et al (2001) Hypertrophy of the posterior longitudinal ligament is a prodromal condition to ossification: a cervical myelopathy case report. Spine 26(1):110–114

    Article  CAS  Google Scholar 

  8. Yokosuka K, Park JS, Jimbo K et al (2007) Immunohistochemical demonstration of advanced glycation end products and the effects of advanced glycation end products in ossified ligament tissues in vitro. Spine 32(11):E337–E339

    Article  Google Scholar 

  9. Chen Y, Wang X, Yang H, Miao J, Liu X, Chen D (2014) Upregulated expression of perk in spinal ligament fibroblasts from the patients with ossification of the posterior longitudinal ligament. Eur Spine J 23:447–454

    Article  Google Scholar 

  10. Inamasu J, Guiot BH, Sachs DC (2006) Ossification of the posterior longitudinal ligament: an update on its biology, epidemiology, and natural history. Neurosurgery 58(6):1027–1039

    Article  Google Scholar 

  11. Kato Y, Kanchiku T, Imajo Y et al (2010) Biomechanical study of the effect of degree of static compression of the spinal cord in ossification of the posterior longitudinal ligament. J Neurosurg Spine 12(3):301–305

    Article  Google Scholar 

  12. Tsukamoto N, Maeda T, Miura H et al (2006) Repetitive tensile stress to rat caudal vertebrae inducing cartilage formation in the spinal ligaments: a possible role of mechanical stress in the development of ossification of the spinal ligaments. J Neurosurg Spine 5(3):234–242

    Article  Google Scholar 

  13. Iwasawa T, Iwasaki K, Sawada T et al (2006) Pathophysiological role of endothelin in ectopic ossification of human spinal ligaments induced by mechanical stress. Calcif Tissue Int 79(6):422–430

    Article  CAS  Google Scholar 

  14. Iwasaki K, Furukawa KI, Tanno M et al (2004) Uniaxial cyclic stretch induces Cbfa1 expression in spinal ligament cells derived from patients with ossification of the posterior longitudinal ligament. Calcif Tissue Int 74(5):448–457

    Article  CAS  Google Scholar 

  15. Yang HS, Lu XH, Chen DY, Yuan W, Yang LL, Chen Y, He HL (2011) Mechanical strain induces Cx43 expression in spinal ligament fibroblasts derived from patients presenting ossification of the posterior longitudinal ligament. Eur Spine J 20:1459–1465

    Article  Google Scholar 

  16. Cheng WP, Wu GJ, Wang BW, Shyu KG (2012) Regulation of PUMA induced by mechanical stress in rat cardiomyocytes. J Biomed Sci 19:72

    Article  CAS  Google Scholar 

  17. Cheng WP, Wu GJ, Wang BW, Shyu KG (2008) The molecular regulation of GADD153 in apoptosis of cultured vascular smooth muscle cells by cyclic mechanical stretch. Cardiovasc Res 77(3):551–559

    Article  CAS  Google Scholar 

  18. Davies PF, Civelek M (2011) Endoplasmic reticulum stress, redox, and proinflammatory environment in athero-susceptible endothelium in vivo at sites of complex hemodynamic shear stress. Antioxid Redox Signal 15(5):1427–1432

    Article  CAS  Google Scholar 

  19. Zhang YH, Zhao CQ, Jiang LS, Dai LY (2011) Cyclic stretch-induced apoptosis in rate annulus fibrosus cells is mediated in part by endoplasmic reticulum stress through nitric oxide production. Eur Spine J 20(8):1233–1243

    Article  Google Scholar 

  20. Yang Shuang-Yan, Wei Fu-Lan, Li-Hua Hu, Wang Chun-Ling (2016) PERK-eIF2α-ATF4 pathway mediated by endoplasmic reticulum stress response is involved in osteodifferentiation of human periodontal ligament cells under cyclic mechanical force. Cell Signal 28(8):880–886

    Article  CAS  Google Scholar 

  21. Chen D, Liu Y, Yang H, Chen D, Zhang X, Fermandes JC, Chen Y (2016) Connexin 43 promotes ossification of the posterior longitudinal ligament through activation of the erk1/2 and p38 mapk pathways. Cell Tissue Res 363:765–773

    Article  CAS  Google Scholar 

  22. Jeong K, Oh Y, Kim S et al (2014) Apelin is transcriptionally regulate by ER stress-induced ATF4 expression via a p38 MAPK-dependent pathway. Apoptosis 19:1399–1410

    Article  CAS  Google Scholar 

  23. Olivares S, Green RM, Henkel AS (2014) Endoplasmic reticulum stress activates the hepatic activator protein 1 complex via mitogen activated protein kinase-dependent signaling pathways. PLoS ONE 9(7):e103828

    Article  Google Scholar 

  24. Krupkova O, Sadowska A, Kameda T et al (2018) p38 MAPK Facilitates crosstalk between endoplasmic reticulum stress and IL-6 release in the intervertebral disc. Front Immunol 9:1706

    Article  Google Scholar 

  25. Ayala P, Montenegro J, Vivar R et al (2012) Attenuation of endoplasmic reticulum stress using the chemical chaperone 4-phenylbutyric acid prevents cardiac fibrosis induced by isoproterenol. Exp Mol Pathol 92(1):97–104

    Article  CAS  Google Scholar 

  26. Wei J, Sheng X, Feng D et al (2008) PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. J Cell Physiol 217(3):693–707

    Article  CAS  Google Scholar 

  27. Saito A, Ochiai K, Kondo S et al (2011) Endoplasmic reticulum stress response mediated by the PERK-elF2a-ATF4 pathway is involved in osteoblast differentiation induced by BMP2. J Biol Chem 286(6):4809–4818

    Article  CAS  Google Scholar 

  28. Brickwood S, Bonthron DT, AI-Gazali LI et al (2003) Wolcott-Rallison syndrome: pathogenicinsights into neonatal diabetes from new mutation and expression studies of EIF2AK3. J Med Genet 40(9):685–689

    Article  CAS  Google Scholar 

Download references

Funding

This study was supported by grants from the National Natural Science Foundation of China (Nos. 81572196).

Author information

Authors and Affiliations

  1. Department of Spine Surgery, Changzheng Hospital, Second Military Medical University, No 415, Fengyang Road, Huangpu District, Shanghai, China

    Lei Shi, Jinhao Miao, Deyu Chen, Jiangang Shi & Yu Chen

Authors
  1. Lei Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinhao Miao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deyu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiangang Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yu Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Ethics Committee of Second Military Medical University. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher's Note

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

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PPTX 27489 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, L., Miao, J., Chen, D. et al. Endoplasmic reticulum stress regulates mechanical stress-induced ossification of posterior longitudinal ligament. Eur Spine J 28, 2249–2256 (2019). https://doi.org/10.1007/s00586-019-06074-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00586-019-06074-2

Keywords

Search

Navigation