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Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells

The mechanistic basis of obesity-associated intervertebral disc degeneration (IDD) is unclear. Aberrant expression of aggrecan and its degrading enzymes ADAMTS-4 and ADAMTS-5 is implicated in the development of IDD. Here, we investigated the effect of leptin, a hormone with increased circulating lev...

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Autores principales: Li, Zheng, Yu, Xin, Liang, Jinqian, Wu, William Ka Kei, Yu, Jun, Shen, Jianxiong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192299/
https://www.ncbi.nlm.nih.gov/pubmed/25299465
http://dx.doi.org/10.1371/journal.pone.0109595
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author Li, Zheng
Yu, Xin
Liang, Jinqian
Wu, William Ka Kei
Yu, Jun
Shen, Jianxiong
author_facet Li, Zheng
Yu, Xin
Liang, Jinqian
Wu, William Ka Kei
Yu, Jun
Shen, Jianxiong
author_sort Li, Zheng
collection PubMed
description The mechanistic basis of obesity-associated intervertebral disc degeneration (IDD) is unclear. Aberrant expression of aggrecan and its degrading enzymes ADAMTS-4 and ADAMTS-5 is implicated in the development of IDD. Here, we investigated the effect of leptin, a hormone with increased circulating levels in obesity, on the expression of aggrecan and ADAMTSs in primary human nucleus pulposus (NP) cells. Real-time PCR and Western blots showed that leptin increased the mRNA and protein expression of ADAMTS-4 and ADAMTS-5 and reduced the level of aggrecan in NP cells, accompanied by a prominent induction of p38 phosphorylation. Treatment of NP cells with SB203580 (a p38 inhibitor) abolished the regulation of aggrecan and ADAMTSs by leptin. Knockdown of ADAMTS-4 and ADAMTS-5 by siRNAs also attenuated the degradation of aggrecan in leptin-stimulated NP cells. To conclude, we demonstrated that leptin induces p38 to upregulate ADAMTSs and thereby promoting aggrecan degradation in human NP cells. These results provide a novel mechanistic insight into the molecular pathogenesis of obesity-associated IDD.
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spelling pubmed-41922992014-10-14 Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells Li, Zheng Yu, Xin Liang, Jinqian Wu, William Ka Kei Yu, Jun Shen, Jianxiong PLoS One Research Article The mechanistic basis of obesity-associated intervertebral disc degeneration (IDD) is unclear. Aberrant expression of aggrecan and its degrading enzymes ADAMTS-4 and ADAMTS-5 is implicated in the development of IDD. Here, we investigated the effect of leptin, a hormone with increased circulating levels in obesity, on the expression of aggrecan and ADAMTSs in primary human nucleus pulposus (NP) cells. Real-time PCR and Western blots showed that leptin increased the mRNA and protein expression of ADAMTS-4 and ADAMTS-5 and reduced the level of aggrecan in NP cells, accompanied by a prominent induction of p38 phosphorylation. Treatment of NP cells with SB203580 (a p38 inhibitor) abolished the regulation of aggrecan and ADAMTSs by leptin. Knockdown of ADAMTS-4 and ADAMTS-5 by siRNAs also attenuated the degradation of aggrecan in leptin-stimulated NP cells. To conclude, we demonstrated that leptin induces p38 to upregulate ADAMTSs and thereby promoting aggrecan degradation in human NP cells. These results provide a novel mechanistic insight into the molecular pathogenesis of obesity-associated IDD. Public Library of Science 2014-10-09 /pmc/articles/PMC4192299/ /pubmed/25299465 http://dx.doi.org/10.1371/journal.pone.0109595 Text en © 2014 Li et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Li, Zheng
Yu, Xin
Liang, Jinqian
Wu, William Ka Kei
Yu, Jun
Shen, Jianxiong
Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells
title Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells
title_full Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells
title_fullStr Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells
title_full_unstemmed Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells
title_short Leptin Downregulates Aggrecan through the p38-ADAMST Pathway in Human Nucleus Pulposus Cells
title_sort leptin downregulates aggrecan through the p38-adamst pathway in human nucleus pulposus cells
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192299/
https://www.ncbi.nlm.nih.gov/pubmed/25299465
http://dx.doi.org/10.1371/journal.pone.0109595
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