IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization

Mengtian Fan; Nana Geng; Xingyue Li; Danyang Yin; Yuyou Yang; Rong Jiang; Cheng Chen; Naibo Feng; Li Liang; Xiaoli Li; Fengtao Luo; Huabing Qi; Qiaoyan Tan; Yangli Xie; Fengjin Guo

doi:10.1016/j.gendis.2022.11.021

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IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization

Full-length article | 更新时间：2024-02-04

- IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization
- Genes & Diseases Vol. 1, Issue 1, Pages: 464-478(2024)
- 作者机构：
  
  1. Laboratory of Developmental Biology, Department of Cell Biology and Genetics, School of Basic Medical Science, Chongqing Medical University,Chongqing,China,400016
  2. Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University,Chongqing,China,400016
  3. Department of Orthopedics, The 1st Affiliated Hospital of Chongqing Medical University,Chongqing,China,400016
  4. Department of Wound Repair and Rehabilitation Medicine, State Key Laboratory of Trauma, Burns and Combined Injury, Trauma Center, Research Institute of Surgery, Daping Hospital, Army Medical University,Chongqing,China,400042
- 作者简介：
- 基金信息：
- DOI：10.1016/j.gendis.2022.11.021
  CLC：
- Published：2024，
  
  Published Online：1 January 2024，
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Mengtian Fan, Nana Geng, Xingyue Li, et al. IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization. [J]. Genes & Diseases 1(1):464-478(2024)
DOI：

Mengtian Fan, Nana Geng, Xingyue Li, et al. IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization. [J]. Genes & Diseases 1(1):464-478(2024) DOI： 10.1016/j.gendis.2022.11.021.

摘要

Abstract

Cartilage development is controlled by the highly synergistic proliferation and differentiation of growth plate chondrocytes

in which the Indian hedgehog (IHH) and parathyroid hormone-related protein-parathyroid hormone-1 receptor (PTHrP-PTH1R) feedback loop is crucial. The inositol-requiring enzyme 1α/X-box-binding protein-1 spliced (IRE1α/XBP1s) branch of the unfolded protein response (UPR) is essential for normal cartilage development. However

the precise role of ER stress effector IRE1α

encoded by endoplasmic reticulum to nucleus signaling 1 (

ERN1

)

in skeletal development remains unknown. Herein

we reported that loss of IRE1α accelerates chondrocyte hypertrophy and promotes endochondral bone growth.

ERN1

acts as a negative regulator of chondrocyte proliferation and differentiation in postnatal growth plates. Its deficiency interrupted PTHrP/PTH1R and IHH homeostasis leading to impaired chondrocyte hypertrophy and differentiation.

XBP1s

produced by p-IRE1α-mediated splicing

binds and up-regulates PTH1R and IHH

which coordinate cartilage development. Meanwhile

ER stress cannot be activated normally in

ERN1

-deficient chondrocytes. In conclusion

ERN1

deficiency accelerates chondrocyte hypertrophy and cartilage mineralization by impairing the homeostasis of the IHH and PTHrP/PTH1R feedback loop and ER stress.

ERN1

may have a potential role as a new target for cartilage growth and maturation.

关键词

Keywords

Cartilage developmentER stressERN1IHHPTHrP/PTH1R

references

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