Loss of Axin1 in limb mesenchymal cells leads to multiple synostoses syndrome-like phenotype in mice

Dan Yi; Rong Xie; Daofu Zeng; Jun Xiao; Guozhi Xiao; Hongting Jin; Liping Tong; Di Chen

doi:10.59717/j.xinn-med.2024.100053

The Innovation Medicine > 2024 Vol. 2 > No. 1 > 100053

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Loss of Axin1 in limb mesenchymal cells leads to multiple synostoses syndrome-like phenotype in mice

1.
Research Center for Computer-aided Drug Discovery, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518005, China
2.
Faculty of Pharmaceutical Sciences, Shenzhen Institute of Advanced Technology, Shenzhen 518055, China
3.
Department of Orthopedic Surgery, Rush University Medical Center, Chicago 60612, USA
4.
Department of Orthopaedics, NanFang Hospital, Southern Medical University, Guangzhou 510515, China
5.
School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China
6.
The First College of Clinical Medicine, Zhejiang Chinese Medical University and Institute of Orthopaedics and Traumatology of Zhejiang Province, Hangzhou 310053, China

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Corresponding authors: di.chen@siat.ac.cn (D.C.); lp.tong@siat.ac.cn (L.T.); hongtingjin@163.com (H.J.)
Received Date: 20 July 2023

Accepted Date: 30 January 2024

Published Online: 22 February 2024

The Innovation Medicine 2(1), https://doi.org/10.59717/j.xinn-med.2024.100053 | Cite this article

GRAPHICAL ABSTRACT

GRAPHICAL ABSTRACT

PUBLIC SUMMARY

PUBLIC SUMMARY
1. Loss-of-Axin1 or Axin1/Axin2 in limb MSCs in mice results in a phenotype resembling SYNS.
  
  Loss-of-Axins in limb MSCs in mice lead to the activation of β-catenin-BMP signaling in the cKO mice model.
  
  The SYNS phenotype in Axin1 cKO mice could be partially reversed by β-catenin or BMP signaling inhibitor.
  
  The genetic mouse model with SYNS-like phenotype could serve as important tools for SYNS disease.

ABSTRACT

ABSTRACT

Multiple synostoses syndrome (SYNS) is a disease characterized by the fusion of multiple joints. Unfortunately, the underlying and critical signaling pathways of this disorder remain poorly understood. Given the pivotal role of Wnt/β-catenin signaling in skeletal development and the key regulatory effect of Axin1 and Axin2 in the β-catenin pathway, limb mesenchymal stem cell (MSC) specific Axin1 conditional KO (cKO) mice and Axin1/Axin2 double KO (dKO) mice were generated to explore their involvement in joint formation. Abnormalities, such as developmental defects in joints and fusions in multiple joint tissues were observed in both Axin1 cKO and Axin1/Axin2 dKO mice, which resemble to the characteristics of human SYNS disease including synostoses of carpal and tarsal bones, as well as ankylosis of elbow joint and knee joint. Administration of β-catenin or BMP inhibitor significantly reversed the joint fusion phenotype in Axin1 cKO mice. Our findings suggest that Axin1 plays a key role in joint formation by inhibiting β-catenin-BMP signaling and could potentially serve as a therapeutic target for SYNS.

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REFERENCES

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Yi D., Xie R., Zeng D., et al., (2024). Loss of Axin1 in limb mesenchymal cells leads to multiple synostoses syndrome-like phenotype in mice. The Innovation Medicine 2(1): 100053. https://doi.org/10.59717/j.xinn-med.2024.100053

Yi D., Xie R., Zeng D., et al., (2024). Loss of Axin1 in limb mesenchymal cells leads to multiple synostoses syndrome-like phenotype in mice. The Innovation Medicine 2(1): 100053. https://doi.org/10.59717/j.xinn-med.2024.100053

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Loss of Axin1 in limb mesenchymal cells leads to multiple synostoses syndrome-like phenotype in mice

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Loss of Axin1 in limb mesenchymal cells leads to multiple synostoses syndrome-like phenotype in mice

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