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Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice
In vertebrates, the type 1 parathyroid hormone receptor (PTH1R) is a critical regulator of skeletal development and homeostasis; however, how it is modulated is incompletely understood. Here we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes th...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762753/ https://www.ncbi.nlm.nih.gov/pubmed/33361757 http://dx.doi.org/10.1038/s41392-020-00328-y |
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author | Fu, Xuekun Zhou, Bo Yan, Qinnan Tao, Chu Qin, Lei Wu, Xiaohao Lin, Sixiong Chen, Sheng Lai, Yumei Zou, Xuenong Shao, Zengwu Wang, Meiqing Chen, Di Jin, Wenfei Song, Youqiang Cao, Huiling Zhang, Ge Xiao, Guozhi |
author_facet | Fu, Xuekun Zhou, Bo Yan, Qinnan Tao, Chu Qin, Lei Wu, Xiaohao Lin, Sixiong Chen, Sheng Lai, Yumei Zou, Xuenong Shao, Zengwu Wang, Meiqing Chen, Di Jin, Wenfei Song, Youqiang Cao, Huiling Zhang, Ge Xiao, Guozhi |
author_sort | Fu, Xuekun |
collection | PubMed |
description | In vertebrates, the type 1 parathyroid hormone receptor (PTH1R) is a critical regulator of skeletal development and homeostasis; however, how it is modulated is incompletely understood. Here we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult bone. Single-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts, but not mesenchymal stem cells, chondrocytes and fibroblasts, in non-hematopoietic bone marrow cells, with concomitant depletion of osteoblasts on the bone surfaces, especially those stimulated by PTH. Furthermore, haploinsufficiency of Kindlin-2 and Pth1r genes, but not that of either gene, in mice significantly decreases basal and, to a larger extent, PTH-stimulated bone mass, supporting the notion that both factors function in the same genetic pathway. Mechanistically, Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα. Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in bone. Interestingly, PTH promotes Kindlin-2 expression in vitro and in vivo, thus creating a positive feedback regulatory loop. Finally, estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized mice. Thus, we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis. |
format | Online Article Text |
id | pubmed-7762753 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-77627532021-01-05 Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice Fu, Xuekun Zhou, Bo Yan, Qinnan Tao, Chu Qin, Lei Wu, Xiaohao Lin, Sixiong Chen, Sheng Lai, Yumei Zou, Xuenong Shao, Zengwu Wang, Meiqing Chen, Di Jin, Wenfei Song, Youqiang Cao, Huiling Zhang, Ge Xiao, Guozhi Signal Transduct Target Ther Article In vertebrates, the type 1 parathyroid hormone receptor (PTH1R) is a critical regulator of skeletal development and homeostasis; however, how it is modulated is incompletely understood. Here we report that deleting Kindlin-2 in osteoblastic cells using the mouse 10-kb Dmp1-Cre largely neutralizes the intermittent PTH-stimulated increasing of bone volume fraction and bone mineral density by impairing both osteoblast and osteoclast formation in murine adult bone. Single-cell profiling reveals that Kindlin-2 loss increases the proportion of osteoblasts, but not mesenchymal stem cells, chondrocytes and fibroblasts, in non-hematopoietic bone marrow cells, with concomitant depletion of osteoblasts on the bone surfaces, especially those stimulated by PTH. Furthermore, haploinsufficiency of Kindlin-2 and Pth1r genes, but not that of either gene, in mice significantly decreases basal and, to a larger extent, PTH-stimulated bone mass, supporting the notion that both factors function in the same genetic pathway. Mechanistically, Kindlin-2 interacts with the C-terminal cytoplasmic domain of PTH1R via aa 474–475 and Gsα. Kindlin-2 loss suppresses PTH induction of cAMP production and CREB phosphorylation in cultured osteoblasts and in bone. Interestingly, PTH promotes Kindlin-2 expression in vitro and in vivo, thus creating a positive feedback regulatory loop. Finally, estrogen deficiency induced by ovariectomy drastically decreases expression of Kindlin-2 protein in osteocytes embedded in the bone matrix and Kindlin-2 loss essentially abolishes the PTH anabolic activity in bone in ovariectomized mice. Thus, we demonstrate that Kindlin-2 functions as an intrinsic component of the PTH1R signaling pathway in osteoblastic cells to regulate bone mass accrual and homeostasis. Nature Publishing Group UK 2020-12-26 /pmc/articles/PMC7762753/ /pubmed/33361757 http://dx.doi.org/10.1038/s41392-020-00328-y Text en © The Author(s) 2020 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Fu, Xuekun Zhou, Bo Yan, Qinnan Tao, Chu Qin, Lei Wu, Xiaohao Lin, Sixiong Chen, Sheng Lai, Yumei Zou, Xuenong Shao, Zengwu Wang, Meiqing Chen, Di Jin, Wenfei Song, Youqiang Cao, Huiling Zhang, Ge Xiao, Guozhi Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice |
title | Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice |
title_full | Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice |
title_fullStr | Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice |
title_full_unstemmed | Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice |
title_short | Kindlin-2 regulates skeletal homeostasis by modulating PTH1R in mice |
title_sort | kindlin-2 regulates skeletal homeostasis by modulating pth1r in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762753/ https://www.ncbi.nlm.nih.gov/pubmed/33361757 http://dx.doi.org/10.1038/s41392-020-00328-y |
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