Distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model

Background: Elevated tumor necrosis factor alpha (TNF-α) expression is correlated with the progression of intervertebral disc degeneration (IVDD). Progranulin binding to tumor necrosis factor receptor (TNFR) and its derivative Atsttrin are effective for treating inflammatory arthritis. We hypothesiz...

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Autores principales:	Shanzheng Wang, Guodong Sun, Pan Fan, Lei Huang, Yaofei Chen, Changhong Chen
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Intervertebral disc degeneration Tumor Necrosis Factor-α TNF receptor type 1 TNF receptor type 2 Progranulin Atsttrin Diseases of the musculoskeletal system RC925-935
Acceso en línea:	https://doaj.org/article/9857b067f1c54e2a897f7f6453973e34
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spelling	oai:doaj.org-article:9857b067f1c54e2a897f7f6453973e342021-12-04T04:34:14ZDistinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model2214-031X10.1016/j.jot.2021.11.003https://doaj.org/article/9857b067f1c54e2a897f7f6453973e342021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2214031X21000954https://doaj.org/toc/2214-031XBackground: Elevated tumor necrosis factor alpha (TNF-α) expression is correlated with the progression of intervertebral disc degeneration (IVDD). Progranulin binding to tumor necrosis factor receptor (TNFR) and its derivative Atsttrin are effective for treating inflammatory arthritis. We hypothesize that Atsttrin has a protective effect in IVDD through different roles of TNFR receptor type 1 (TNFR1) and TNFR receptor type 2 (TNFR2) in degenerated discs. Methods: IVDD models were established in TNFR1−/−, TNFR2−/− mice and their control littermates. Nucleus Pulpous (NP) samples from human patients and IVDD murine models were evaluated by X-ray, micro-MRI, μCT, histological staining and immunofluorescence staining. NP cells isolated from wild-type (WT), TNFR1−/− and TNFR2−/− mice were treated with TNF-α or Atsttrin and then assayed by Western blotting, qRT–PCR, and ELISA. Results: TNFR1 and TNFR2 expression was significantly elevated in the disc tissues of both human patients and IVDD murine models. TNFR1 knockout contributed to reduced disc degeneration. In contrast, TNFR2 knockout was associated with enhanced IVDD severity, including degraded cellular composition, increased cell apoptosis and elevated vertebral destruction. Atsttrin protected against IVDD in WT and TNFR1−/− mouse models but had no effect in TNFR2−/− IVDD models. Additionally, in vitro NP cell-based assays demonstrated that TNF-α-stimulated catabolism and Atsttrin-activated anabolism depended on TNFR1 and TNFR2, respectively. Conclusion: TNFR1 is associated with the degenerative progression of IVDD, while TNFR2 contributes to the protective effect on the discs. Atsttrin protects against IVDD at least partially by inhibiting the TNFα/TNFR1 inflammatory/catabolic pathway and activating the TNFR2 protective/anabolic pathway. The translational potential of this article: This study demonstrates that TNFR1 and TNFR2 have disparate roles in disc degeneration and hlights the potential use of Atsttrin as a therapeutic agent against IVDD in mice.Shanzheng WangGuodong SunPan FanLei HuangYaofei ChenChanghong ChenElsevierarticleIntervertebral disc degenerationTumor Necrosis Factor-αTNF receptor type 1TNF receptor type 2ProgranulinAtsttrinDiseases of the musculoskeletal systemRC925-935ENJournal of Orthopaedic Translation, Vol 31, Iss , Pp 62-72 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Intervertebral disc degeneration Tumor Necrosis Factor-α TNF receptor type 1 TNF receptor type 2 Progranulin Atsttrin Diseases of the musculoskeletal system RC925-935
spellingShingle	Intervertebral disc degeneration Tumor Necrosis Factor-α TNF receptor type 1 TNF receptor type 2 Progranulin Atsttrin Diseases of the musculoskeletal system RC925-935 Shanzheng Wang Guodong Sun Pan Fan Lei Huang Yaofei Chen Changhong Chen Distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model
description	Background: Elevated tumor necrosis factor alpha (TNF-α) expression is correlated with the progression of intervertebral disc degeneration (IVDD). Progranulin binding to tumor necrosis factor receptor (TNFR) and its derivative Atsttrin are effective for treating inflammatory arthritis. We hypothesize that Atsttrin has a protective effect in IVDD through different roles of TNFR receptor type 1 (TNFR1) and TNFR receptor type 2 (TNFR2) in degenerated discs. Methods: IVDD models were established in TNFR1−/−, TNFR2−/− mice and their control littermates. Nucleus Pulpous (NP) samples from human patients and IVDD murine models were evaluated by X-ray, micro-MRI, μCT, histological staining and immunofluorescence staining. NP cells isolated from wild-type (WT), TNFR1−/− and TNFR2−/− mice were treated with TNF-α or Atsttrin and then assayed by Western blotting, qRT–PCR, and ELISA. Results: TNFR1 and TNFR2 expression was significantly elevated in the disc tissues of both human patients and IVDD murine models. TNFR1 knockout contributed to reduced disc degeneration. In contrast, TNFR2 knockout was associated with enhanced IVDD severity, including degraded cellular composition, increased cell apoptosis and elevated vertebral destruction. Atsttrin protected against IVDD in WT and TNFR1−/− mouse models but had no effect in TNFR2−/− IVDD models. Additionally, in vitro NP cell-based assays demonstrated that TNF-α-stimulated catabolism and Atsttrin-activated anabolism depended on TNFR1 and TNFR2, respectively. Conclusion: TNFR1 is associated with the degenerative progression of IVDD, while TNFR2 contributes to the protective effect on the discs. Atsttrin protects against IVDD at least partially by inhibiting the TNFα/TNFR1 inflammatory/catabolic pathway and activating the TNFR2 protective/anabolic pathway. The translational potential of this article: This study demonstrates that TNFR1 and TNFR2 have disparate roles in disc degeneration and hlights the potential use of Atsttrin as a therapeutic agent against IVDD in mice.
format	article
author	Shanzheng Wang Guodong Sun Pan Fan Lei Huang Yaofei Chen Changhong Chen
author_facet	Shanzheng Wang Guodong Sun Pan Fan Lei Huang Yaofei Chen Changhong Chen
author_sort	Shanzheng Wang
title	Distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model
title_short	Distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model
title_full	Distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model
title_fullStr	Distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model
title_full_unstemmed	Distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model
title_sort	distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/9857b067f1c54e2a897f7f6453973e34
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Distinctive roles of tumor necrosis factor receptor type 1 and type 2 in a mouse disc degeneration model

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