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ENPP1 deletion causes mouse osteoporosis via the MKK3/p38 MAPK/PCNA signaling pathway
BACKGROUND: Apart from the current understanding of enzyme function, the mechanism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) deficiency-associated osteoporosis is unknown. We aimed to explore the changes in the expression of signaling pathways of bone tissues involved in Enpp1 de...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9571425/ https://www.ncbi.nlm.nih.gov/pubmed/36243801 http://dx.doi.org/10.1186/s13018-022-03349-1 |
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author | Wang, Qiang Gao, Zhiqiang Guo, Kai Lu, Jiawei Wang, Feng Huang, Yufeng Wu, Desheng |
author_facet | Wang, Qiang Gao, Zhiqiang Guo, Kai Lu, Jiawei Wang, Feng Huang, Yufeng Wu, Desheng |
author_sort | Wang, Qiang |
collection | PubMed |
description | BACKGROUND: Apart from the current understanding of enzyme function, the mechanism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) deficiency-associated osteoporosis is unknown. We aimed to explore the changes in the expression of signaling pathways of bone tissues involved in Enpp1 deficiency. METHODS: The body weights and morphology and histology of the bones of male Enpp1 knockout (KO) and wild-type (WT) mice were assessed. The humeri of WT and Enpp1 KO mice at 12 weeks of age were subjected to high-throughput quantitative molecular measurements, and bioinformatics analysis was performed. Proteins from humeri and calvarial pre-osteoblasts (Pobs) were used to verify the differentially expressed signaling pathways and to explain the mechanism of Enpp1 deficiency-associated osteoporosis. RESULTS: Enpp1 KO mice had significantly lower body weight and trabecular bone mass in the hindlimbs than WT mice. Proteomics and immunoblotting showed that Enpp1 deletion downregulated the expression of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in bones. Lysophosphatidic acid (LPA) was involved in activating the MKK3/p38 MAPK/PCNA pathway and proliferating Pobs in Enpp1 KO mice, whereas a p38 MAPK inhibitor suppressed the LPA-induced pro-proliferation phenotype (p < 0.05). CONCLUSION: The inhibition of MKK3/p38 MAPK/PCNA pathway plays an important role in the development of osteoporosis caused by Enpp1 deficiency, and LPA partially rescued the proliferation of pre-osteoblasts via the MKK3/p38 MAPK/PCNA pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13018-022-03349-1. |
format | Online Article Text |
id | pubmed-9571425 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-95714252022-10-17 ENPP1 deletion causes mouse osteoporosis via the MKK3/p38 MAPK/PCNA signaling pathway Wang, Qiang Gao, Zhiqiang Guo, Kai Lu, Jiawei Wang, Feng Huang, Yufeng Wu, Desheng J Orthop Surg Res Research Article BACKGROUND: Apart from the current understanding of enzyme function, the mechanism of ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) deficiency-associated osteoporosis is unknown. We aimed to explore the changes in the expression of signaling pathways of bone tissues involved in Enpp1 deficiency. METHODS: The body weights and morphology and histology of the bones of male Enpp1 knockout (KO) and wild-type (WT) mice were assessed. The humeri of WT and Enpp1 KO mice at 12 weeks of age were subjected to high-throughput quantitative molecular measurements, and bioinformatics analysis was performed. Proteins from humeri and calvarial pre-osteoblasts (Pobs) were used to verify the differentially expressed signaling pathways and to explain the mechanism of Enpp1 deficiency-associated osteoporosis. RESULTS: Enpp1 KO mice had significantly lower body weight and trabecular bone mass in the hindlimbs than WT mice. Proteomics and immunoblotting showed that Enpp1 deletion downregulated the expression of the p38 mitogen-activated protein kinase (MAPK) signaling pathway in bones. Lysophosphatidic acid (LPA) was involved in activating the MKK3/p38 MAPK/PCNA pathway and proliferating Pobs in Enpp1 KO mice, whereas a p38 MAPK inhibitor suppressed the LPA-induced pro-proliferation phenotype (p < 0.05). CONCLUSION: The inhibition of MKK3/p38 MAPK/PCNA pathway plays an important role in the development of osteoporosis caused by Enpp1 deficiency, and LPA partially rescued the proliferation of pre-osteoblasts via the MKK3/p38 MAPK/PCNA pathway. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13018-022-03349-1. BioMed Central 2022-10-15 /pmc/articles/PMC9571425/ /pubmed/36243801 http://dx.doi.org/10.1186/s13018-022-03349-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Wang, Qiang Gao, Zhiqiang Guo, Kai Lu, Jiawei Wang, Feng Huang, Yufeng Wu, Desheng ENPP1 deletion causes mouse osteoporosis via the MKK3/p38 MAPK/PCNA signaling pathway |
title | ENPP1 deletion causes mouse osteoporosis via the MKK3/p38 MAPK/PCNA signaling pathway |
title_full | ENPP1 deletion causes mouse osteoporosis via the MKK3/p38 MAPK/PCNA signaling pathway |
title_fullStr | ENPP1 deletion causes mouse osteoporosis via the MKK3/p38 MAPK/PCNA signaling pathway |
title_full_unstemmed | ENPP1 deletion causes mouse osteoporosis via the MKK3/p38 MAPK/PCNA signaling pathway |
title_short | ENPP1 deletion causes mouse osteoporosis via the MKK3/p38 MAPK/PCNA signaling pathway |
title_sort | enpp1 deletion causes mouse osteoporosis via the mkk3/p38 mapk/pcna signaling pathway |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9571425/ https://www.ncbi.nlm.nih.gov/pubmed/36243801 http://dx.doi.org/10.1186/s13018-022-03349-1 |
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