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Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway

Acquired heterotopic ossification (HO) is the extraskeletal bone formation after trauma. Various mesenchymal progenitors are reported to participate in ectopic bone formation. Here we induce acquired HO in mice by Achilles tenotomy and observe that conditional knockout (cKO) of fibroblast growth fac...

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Autores principales: Zhang, Dali, Huang, Junlan, Sun, Xianding, Chen, Hangang, Huang, Shuo, Yang, Jing, Du, Xiaolan, Tan, Qiaoyan, Luo, Fengtao, Zhang, Ruobin, Zhou, Siru, Jiang, Wanling, Ni, Zhenhong, Wang, Zuqiang, Jin, Min, Xu, Meng, Li, Fangfang, Chen, Liang, Liu, Mi, Su, Nan, Luo, Xiaoqing, Yin, Liangjun, Zhu, Ying, Feng, Jerry Q., Chen, Di, Qi, Huabing, Chen, Lin, Xie, Yangli
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289847/
https://www.ncbi.nlm.nih.gov/pubmed/34282140
http://dx.doi.org/10.1038/s41467-021-24643-2
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author Zhang, Dali
Huang, Junlan
Sun, Xianding
Chen, Hangang
Huang, Shuo
Yang, Jing
Du, Xiaolan
Tan, Qiaoyan
Luo, Fengtao
Zhang, Ruobin
Zhou, Siru
Jiang, Wanling
Ni, Zhenhong
Wang, Zuqiang
Jin, Min
Xu, Meng
Li, Fangfang
Chen, Liang
Liu, Mi
Su, Nan
Luo, Xiaoqing
Yin, Liangjun
Zhu, Ying
Feng, Jerry Q.
Chen, Di
Qi, Huabing
Chen, Lin
Xie, Yangli
author_facet Zhang, Dali
Huang, Junlan
Sun, Xianding
Chen, Hangang
Huang, Shuo
Yang, Jing
Du, Xiaolan
Tan, Qiaoyan
Luo, Fengtao
Zhang, Ruobin
Zhou, Siru
Jiang, Wanling
Ni, Zhenhong
Wang, Zuqiang
Jin, Min
Xu, Meng
Li, Fangfang
Chen, Liang
Liu, Mi
Su, Nan
Luo, Xiaoqing
Yin, Liangjun
Zhu, Ying
Feng, Jerry Q.
Chen, Di
Qi, Huabing
Chen, Lin
Xie, Yangli
author_sort Zhang, Dali
collection PubMed
description Acquired heterotopic ossification (HO) is the extraskeletal bone formation after trauma. Various mesenchymal progenitors are reported to participate in ectopic bone formation. Here we induce acquired HO in mice by Achilles tenotomy and observe that conditional knockout (cKO) of fibroblast growth factor receptor 3 (FGFR3) in Col2(+) cells promote acquired HO development. Lineage tracing studies reveal that Col2(+) cells adopt fate of lymphatic endothelial cells (LECs) instead of chondrocytes or osteoblasts during HO development. FGFR3 cKO in Prox1(+) LECs causes even more aggravated HO formation. We further demonstrate that FGFR3 deficiency in LECs leads to decreased local lymphatic formation in a BMPR1a-pSmad1/5-dependent manner, which exacerbates inflammatory levels in the repaired tendon. Local administration of FGF9 in Matrigel inhibits heterotopic bone formation, which is dependent on FGFR3 expression in LECs. Here we uncover Col2(+) lineage cells as an origin of lymphatic endothelium, which regulates local inflammatory microenvironment after trauma and thus influences HO development via FGFR3-BMPR1a pathway. Activation of FGFR3 in LECs may be a therapeutic strategy to inhibit acquired HO formation via increasing local lymphangiogenesis.
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spelling pubmed-82898472021-07-23 Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway Zhang, Dali Huang, Junlan Sun, Xianding Chen, Hangang Huang, Shuo Yang, Jing Du, Xiaolan Tan, Qiaoyan Luo, Fengtao Zhang, Ruobin Zhou, Siru Jiang, Wanling Ni, Zhenhong Wang, Zuqiang Jin, Min Xu, Meng Li, Fangfang Chen, Liang Liu, Mi Su, Nan Luo, Xiaoqing Yin, Liangjun Zhu, Ying Feng, Jerry Q. Chen, Di Qi, Huabing Chen, Lin Xie, Yangli Nat Commun Article Acquired heterotopic ossification (HO) is the extraskeletal bone formation after trauma. Various mesenchymal progenitors are reported to participate in ectopic bone formation. Here we induce acquired HO in mice by Achilles tenotomy and observe that conditional knockout (cKO) of fibroblast growth factor receptor 3 (FGFR3) in Col2(+) cells promote acquired HO development. Lineage tracing studies reveal that Col2(+) cells adopt fate of lymphatic endothelial cells (LECs) instead of chondrocytes or osteoblasts during HO development. FGFR3 cKO in Prox1(+) LECs causes even more aggravated HO formation. We further demonstrate that FGFR3 deficiency in LECs leads to decreased local lymphatic formation in a BMPR1a-pSmad1/5-dependent manner, which exacerbates inflammatory levels in the repaired tendon. Local administration of FGF9 in Matrigel inhibits heterotopic bone formation, which is dependent on FGFR3 expression in LECs. Here we uncover Col2(+) lineage cells as an origin of lymphatic endothelium, which regulates local inflammatory microenvironment after trauma and thus influences HO development via FGFR3-BMPR1a pathway. Activation of FGFR3 in LECs may be a therapeutic strategy to inhibit acquired HO formation via increasing local lymphangiogenesis. Nature Publishing Group UK 2021-07-19 /pmc/articles/PMC8289847/ /pubmed/34282140 http://dx.doi.org/10.1038/s41467-021-24643-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Zhang, Dali
Huang, Junlan
Sun, Xianding
Chen, Hangang
Huang, Shuo
Yang, Jing
Du, Xiaolan
Tan, Qiaoyan
Luo, Fengtao
Zhang, Ruobin
Zhou, Siru
Jiang, Wanling
Ni, Zhenhong
Wang, Zuqiang
Jin, Min
Xu, Meng
Li, Fangfang
Chen, Liang
Liu, Mi
Su, Nan
Luo, Xiaoqing
Yin, Liangjun
Zhu, Ying
Feng, Jerry Q.
Chen, Di
Qi, Huabing
Chen, Lin
Xie, Yangli
Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
title Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
title_full Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
title_fullStr Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
title_full_unstemmed Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
title_short Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway
title_sort targeting local lymphatics to ameliorate heterotopic ossification via fgfr3-bmpr1a pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289847/
https://www.ncbi.nlm.nih.gov/pubmed/34282140
http://dx.doi.org/10.1038/s41467-021-24643-2
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