Transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice

Abstract Severe skeletal alterations are common symptoms in patients with mucolipidosis type II (MLII), a rare lysosomal storage disorder of childhood. We have previously reported that progressive bone loss in a mouse model for MLII is caused by an increased number of bone-resorbing osteoclasts, whi...

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Autores principales:	Lena Marie Westermann, Anke Baranowsky, Giorgia Di Lorenzo, Tatyana Danyukova, Jamie Soul, Jean-Marc Schwartz, Gretl Hendrickx, Michael Amling, Stefan Rose-John, Christoph Garbers, Thorsten Schinke, Sandra Pohl
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/aed06d1d61d54a08bc3375460b5e6bcb
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spelling	oai:doaj.org-article:aed06d1d61d54a08bc3375460b5e6bcb2021-12-02T14:11:31ZTransgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice10.1038/s41598-021-82802-32045-2322https://doaj.org/article/aed06d1d61d54a08bc3375460b5e6bcb2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82802-3https://doaj.org/toc/2045-2322Abstract Severe skeletal alterations are common symptoms in patients with mucolipidosis type II (MLII), a rare lysosomal storage disorder of childhood. We have previously reported that progressive bone loss in a mouse model for MLII is caused by an increased number of bone-resorbing osteoclasts, which is accompanied by elevated expression of the cytokine interleukin-6 (IL-6) in the bone microenvironment. In the present study we addressed the question, if pharmacological blockade of IL-6 can prevent the low bone mass phenotype of MLII mice. Since the cellular IL-6 response can be mediated by either the membrane-bound (classic signaling) or the soluble IL-6 receptor (trans-signaling), we first performed cell culture assays and found that both pathways can increase osteoclastogenesis. We then crossed MLII mice with transgenic mice expressing the recombinant soluble fusion protein sgp130Fc, which represents a natural inhibitor of IL-6 trans-signaling. By undecalcified histology and bone-specific histomorphometry we found that high circulating sgp130Fc levels do not affect skeletal growth or remodeling in wild-type mice. Most importantly, blockade of IL-6 trans-signaling did neither reduce osteoclastogenesis, nor increase bone mass in MLII mice. Therefore, our data clearly demonstrate that the bone phenotype of MLII mice cannot be corrected by blocking the IL-6 trans-signaling.Lena Marie WestermannAnke BaranowskyGiorgia Di LorenzoTatyana DanyukovaJamie SoulJean-Marc SchwartzGretl HendrickxMichael AmlingStefan Rose-JohnChristoph GarbersThorsten SchinkeSandra PohlNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lena Marie Westermann Anke Baranowsky Giorgia Di Lorenzo Tatyana Danyukova Jamie Soul Jean-Marc Schwartz Gretl Hendrickx Michael Amling Stefan Rose-John Christoph Garbers Thorsten Schinke Sandra Pohl Transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice
description	Abstract Severe skeletal alterations are common symptoms in patients with mucolipidosis type II (MLII), a rare lysosomal storage disorder of childhood. We have previously reported that progressive bone loss in a mouse model for MLII is caused by an increased number of bone-resorbing osteoclasts, which is accompanied by elevated expression of the cytokine interleukin-6 (IL-6) in the bone microenvironment. In the present study we addressed the question, if pharmacological blockade of IL-6 can prevent the low bone mass phenotype of MLII mice. Since the cellular IL-6 response can be mediated by either the membrane-bound (classic signaling) or the soluble IL-6 receptor (trans-signaling), we first performed cell culture assays and found that both pathways can increase osteoclastogenesis. We then crossed MLII mice with transgenic mice expressing the recombinant soluble fusion protein sgp130Fc, which represents a natural inhibitor of IL-6 trans-signaling. By undecalcified histology and bone-specific histomorphometry we found that high circulating sgp130Fc levels do not affect skeletal growth or remodeling in wild-type mice. Most importantly, blockade of IL-6 trans-signaling did neither reduce osteoclastogenesis, nor increase bone mass in MLII mice. Therefore, our data clearly demonstrate that the bone phenotype of MLII mice cannot be corrected by blocking the IL-6 trans-signaling.
format	article
author	Lena Marie Westermann Anke Baranowsky Giorgia Di Lorenzo Tatyana Danyukova Jamie Soul Jean-Marc Schwartz Gretl Hendrickx Michael Amling Stefan Rose-John Christoph Garbers Thorsten Schinke Sandra Pohl
author_facet	Lena Marie Westermann Anke Baranowsky Giorgia Di Lorenzo Tatyana Danyukova Jamie Soul Jean-Marc Schwartz Gretl Hendrickx Michael Amling Stefan Rose-John Christoph Garbers Thorsten Schinke Sandra Pohl
author_sort	Lena Marie Westermann
title	Transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice
title_short	Transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice
title_full	Transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice
title_fullStr	Transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice
title_full_unstemmed	Transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice
title_sort	transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type ii mice
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/aed06d1d61d54a08bc3375460b5e6bcb
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Transgenic inhibition of interleukin-6 trans-signaling does not prevent skeletal pathologies in mucolipidosis type II mice

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