IRE1a regulates the PTHrP-IHH feedback loop to orchestrate chondrocyte hypertrophy and cartilage mineralization

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

作者地址："[Fan, Mengtian; Geng, Nana; Li, Xingyue; Yin, Danyang; Yang, Yuyou; Feng, Naibo; Liang, Li; Li, Xiaoli; Guo, Fengjin] Chongqing Med Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Lab Dev Biol, Chongqing 400016, Peoples R China; [Jiang, Rong] Chongqing Med Univ, Sch Basic Med Sci, Lab Stem Cells & Tissue Engn, Chongqing 400016, Peoples R China; [Chen, Cheng] Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing 400016, Peoples R China; [Luo, Fengtao; Qi, Huabing; Tan, Qiaoyan; Xie, Yangli] Army Med Univ, Daping Hosp, Res Inst Surg, Trauma Ctr,Dept Wound Repair & Rehabil Med,State K, Chongqing 400042, Peoples R China"

通信作者："Guo, FJ (通讯作者)，Chongqing Med Univ, Sch Basic Med Sci, Dept Cell Biol & Genet, Lab Dev Biol, Chongqing 400016, Peoples R China."

来源：GENES & DISEASES

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001052623300001

JCR分区：Q1

影响因子：6.8

年份：2024

卷号：11

期号：1

开始页：464

结束页：478

文献类型：Article

关键词：Cartilage development; ER stress; ERN1; IHH; PTHrP/PTH1R

摘要："Cartilage development is controlled by the highly synergistic proliferation and dif-ferentiation 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 1a /X-box-binding protein-1 spliced (IRE1a/XBP1s) branch of the unfolded protein response (UPR) is essential for normal cartilage development. However, the precise role of ER stress effector IRE1a, encoded by endoplasmic reticulum to nucleus signaling 1 (ERN1), in skeletal development remains unknown. Herein, we reported that loss of IRE1a 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-IRE1a- mediated splicing, binds and up-regulates PTH1R and IHH, which coordinate cartilage develop-ment. 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. 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/)."

基金机构："National Natural Science Foundation of China [81871769, 82272550, cstc2021jcyj-bshX0214]; Chongqing Science and Technology Bu-reau (China); [81672209]"

基金资助正文："<B>Funding</B> Our experiments were supported by the National Natural Science Foundation of China (No. 81672209, 81871769, 82272550) and the Chongqing Science and Technology Bu-reau (China) (No. cstc2021jcyj-bshX0214) ."