Progranulin Is Positively Associated with Intervertebral Disc Degeneration by Interaction with IL-10 and IL-17 Through TNF Pathways
- 340 Downloads
Progranulin (PGRN) is a widely expressed growth factor that effectively inhibits tumor necrosis factor α (TNFα)-mediated inflammatory response. TNFα is involved in intervertebral disc degeneration (IDD) and plays a key role. This study aims to determine the role of PGRN in the intervertebral disc degeneration process. We collected intervertebral discs (IVDs) from humans and mice with different genetic backgrounds. We examined the expression of PGRN in IVD tissues by immunohistochemistry staining and Western blotting assay. We examined the peripheral serum level of PGRN by ELISA assay. Murine IVD tissue samples were taken to undergo safranin O, HE, and immunohistochemistry staining. Primary human nucleus pulposus cells were used for ELISA and RT-PCR assays. PGRN as well as interlukin-10 (IL-10) and interlukin-17 (IL-17) expressions were elevated in degenerative discs and peripheral blood sera. Loss of PGRN led to accelerated disc degeneration in the animal model, along with decreased expression of IL-10 and increased expression of IL-17. Additionally, the PGRN level was positively related to levels of IL-10 and IL-17. In vitro study suggested that PGRN protected against disc degeneration by inducing IL-10 and reducing IL-17. PGRN is associated with intervertebral disc degeneration through interfering with IL-10 and IL-17; thus, PGRN could be an interesting biomarker for diagnosis and a potential treatment target.
KEY WORDSprogranulin TNFα intervertebral disc degeneration IL-10 IL-17
matrix metallopeptidase 13
tumor necrosis factor α
The study was supported by grants from the National Natural Science Foundation of China (81572191).
Study concept and design: Lei Cheng and Jianlu Wei.
Raising animals: Shaoyi Wang and Huichao Tian.
Acquisition of data: Shaoyi Wang, Hong Ding and Xiaocong Zhou.
Analysis and interpretation of data: Shaoyi Wang and Jianlu Wei.
Statistical analysis: Shaoyi Wang.
Drafting of the manuscript: Shaoyi Wang, Jianlu Wei, and Yuchen Fan.
Compliance with Ethical Standards
Patients involved in the study provided consent, and the study was approved by medical ethics regulations of the Medical Ethical Committee of Qilu Hospital of Shandong University
Conflict of Interest
The authors declare that they have no conflicts of interest.
- 2.Gautschi, O.P., M.V. Corniola, N.R. Smoll, H. Joswig, K. Schaller, G. Hildebrandt, and M.N. Stienen. 2016. Sex differences in subjective and objective measures of pain, functional impairment, and health-related quality of life in patients with lumbar degenerative disc disease. Pain 157 (5): 1065–1071.CrossRefPubMedGoogle Scholar
- 5.Podichetty, V.K. 2007. The aging spine: The role of inflammatory mediators in intervertebral disc degeneration. Cellular and Molecular Biology (Noisy-le-Grand, France) 53 (5): 4–18.Google Scholar
- 7.Shamji, M.F., L.A. Setton, W. Jarvis, S. So, J. Chen, L. Jing, R. Bullock, R.E. Isaacs, C. Brown, and W.J. Richardson. 2010. Proinflammatory cytokine expression profile in degenerated and herniated human intervertebral disc tissues. Arthritis and Rheumatism 62 (7): 1974–1982.PubMedPubMedCentralGoogle Scholar
- 16.Martens, L.H., J. Zhang, S.J. Barmada, P. Zhou, S. Kamiya, B. Sun, S.W. Min, L. Gan, S. Finkbeiner, E.J. Huang, and R.V. Farese Jr. 2012. Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury. The Journal of Clinical Investigation 122 (11): 3955–3959.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.Tang, W., Y. Lu, Q.Y. Tian, Y. Zhang, F.J. Guo, G.Y. Liu, N.M. Syed, Y. Lai, E.A. Lin, L. Kong, J. Su, F. Yin, A.H. Ding, A. Zanin-Zhorov, M.L. Dustin, J. Tao, J. Craft, Z. Yin, J.Q. Feng, S.B. Abramson, X.P. Yu, and C.J. Liu. 2011. The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice. Science 332 (6028): 478–484.CrossRefPubMedPubMedCentralGoogle Scholar
- 23.Wei, J.L., W. Fu, A. Hettinghouse, W.J. He, K.E. Lipson, and C.J. Liu. 2018. ADAMTS-12 protects against inflammatory arthritis through interacting with and inactivating proinflammatory CTGF. Arthritis & Rhematology. https://doi.org/10.1002/art.40552
- 26.Akitsu, A., H. Ishigame, S. Kakuta, S.H. Chung, S. Ikeda, K. Shimizu, S. Kubo, Y. Liu, M. Umemura, G. Matsuzaki, Y. Yoshikai, S. Saijo, and Y. Iwakura. 2015. IL-1 receptor antagonist-deficient mice develop autoimmune arthritis due to intrinsic activation of IL-17-producing CCR2(+)Vgamma6(+)gammadelta T cells. Nature Communications 6: 7464.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Li, J.K., L. Nie, Y.P. Zhao, Y.Q. Zhang, X. Wang, S.S. Wang, Y. Liu, H. Zhao, and L. Cheng. 2016. IL-17 mediates inflammatory reactions via p38/c-Fos and JNK/c-Jun activation in an AP-1-dependent manner in human nucleus pulposus cells. Journal of Translational Medicine 14: 77.CrossRefPubMedPubMedCentralGoogle Scholar
- 34.Wang, J., D. Markova, D.G. Anderson, Z. Zheng, I.M. Shapiro, and M.V. Risbud. 2011. TNF-alpha and IL-1beta promote a disintegrin-like and metalloprotease with thrombospondin type I motif-5-mediated aggrecan degradation through syndecan-4 in intervertebral disc. The Journal of Biological Chemistry 286 (46): 39738–39749.CrossRefPubMedPubMedCentralGoogle Scholar
- 36.Dudek, M., N. Yang, J.P.D. Ruckshanthi, J. Williams, E. Borysiewicz, P. Wang, A. Adamson, J. Li, J.F. Bateman, M.R. White, R.P. Boot-Handford, J.A. Hoyland, and Q.J. Meng. 2017. The intervertebral disc contains intrinsic circadian clocks that are regulated by age and cytokines and linked to degeneration. Annals of the Rheumatic Diseases 76 (3): 576–584.CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Matsubara, T., A. Mita, K. Minami, T. Hosooka, S. Kitazawa, K. Takahashi, Y. Tamori, N. Yokoi, M. Watanabe, E.I. Matsuo, O. Nishimura, and S. Seino. 2012. PGRN is a key adipokine mediating high fat diet-induced insulin resistance and obesity through IL-6 in adipose tissue. Cell Metabolism 15 (1): 38–50.CrossRefPubMedGoogle Scholar
- 45.Higuchi, Y., C. McTiernan, C.B. Frye, B. McGowan, T.O. Chan, and A.M. Feldman. 2004. Tumor necrosis factor receptors 1 and 2 differentially regulate survival, cardiac dysfunction, and remodeling in transgenic mice with tumor necrosis factor-alpha-induced cardiomyopathy. Circulation 109 (15): 1892–1897.CrossRefPubMedGoogle Scholar