2. Academic Validation
  3. IRE1α regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization

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

  • Genes Dis. 2022 Dec 29;11(1):464-478. doi: 10.1016/j.gendis.2022.11.021.
Mengtian Fan 1,  Nana Geng 1,  Xingyue Li 1,  Danyang Yin 1,  Yuyou Yang 1,  Rong Jiang 2,  Cheng Chen 3,  Naibo Feng 1,  Li Liang 1,  Xiaoli Li 1,  Fengtao Luo 4,  Huabing Qi 4,  Qiaoyan Tan 4,  Yangli Xie 4,  Fengjin Guo 1
Affiliations

Affiliations

  • 1 Laboratory of Developmental Biology, Department of Cell Biology and Genetics, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, China.
  • 2 Laboratory of Stem Cells and Tissue Engineering, School of Basic Medical Science, Chongqing Medical University, Chongqing 400016, China.
  • 3 Department of Orthopedics, The 1st Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 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 400042, China.
PMID: 37588212 DOI: 10.1016/j.gendis.2022.11.021
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.

Keywords

Cartilage development; ER stress; ERN1; IHH; PTHrP/PTH1R.

Figures
Products