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

Dali Zhang, Junlan Huang, Xianding Sun, Hangang Chen, Shuo Huang, Jing Yang, Xiaolan Du, Qiaoyan Tan, Fengtao Luo, Ruobin Zhang, Siru Zhou, Wanling Jiang, Zhenhong Ni, Zuqiang Wang, Min Jin, Meng Xu, Fangfang Li, Liang Chen, Mi Liu, Nan Su, Xiaoqing Luo, Liangjun Yin, Ying Zhu, Jerry Q. Feng, Di Chen, Huabing Qi (), Lin Chen () and Yangli Xie ()
Additional contact information
Dali Zhang: Army Medical University
Junlan Huang: Army Medical University
Xianding Sun: Army Medical University
Hangang Chen: Army Medical University
Shuo Huang: Army Medical University
Jing Yang: Army Medical University
Xiaolan Du: Army Medical University
Qiaoyan Tan: Army Medical University
Fengtao Luo: Army Medical University
Ruobin Zhang: Army Medical University
Siru Zhou: Army Medical University
Wanling Jiang: Army Medical University
Zhenhong Ni: Army Medical University
Zuqiang Wang: Army Medical University
Min Jin: Army Medical University
Meng Xu: Army Medical University
Fangfang Li: Army Medical University
Liang Chen: Army Medical University
Mi Liu: Army Medical University
Nan Su: Army Medical University
Xiaoqing Luo: Army Medical University
Liangjun Yin: Chongqing Medical University
Ying Zhu: Chongqing Medical University
Jerry Q. Feng: Texas A&M University College of Dentistry
Di Chen: Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
Huabing Qi: Army Medical University
Lin Chen: Army Medical University
Yangli Xie: Army Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24643-2

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