Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function

Area of Science:

• Cell Biology
• Molecular Biology
• Developmental Biology

Background:

• Endoplasmic reticulum (ER) stress signaling (ERSS) activates in protein folding disorders to prevent apoptosis.
• The functional recovery of ER stress-surviving cells remains largely unknown.
• Terminally differentiating hypertrophic chondrocytes (HCs) are crucial for endochondral bone formation.

Purpose of the Study:

• To investigate the in vivo impact of ER stress on chondrocyte differentiation during endochondral bone formation.
• To determine if chondrocytes surviving ER stress can resume normal function.

Main Methods:

• Utilized transgenic mice with a Col10a1 13-base pair deletion (13del) causing mutant collagen X accumulation and ER stress in HCs.
• Performed histological and gene expression analyses to assess chondrocyte differentiation and ER stress markers.
• Examined phenotypes in mice with mutations in collagen II and aggrecan.

Main Results:

• Misfolded collagen X in HCs induced ERSS, leading to chondrocyte survival but interrupted differentiation and delayed endochondral ossification, resulting in chondrodysplasia.
• Surviving chondrocytes re-entered the cell cycle, re-expressed prehypertrophic genes, and reduced mutant mRNA levels, alleviating ER stress.
• Similar phenotypes of abnormal chondrocyte differentiation and growth plate architecture were observed in mice with collagen II and aggrecan mutations.

Conclusions:

• ERSS in chondrocytes allows survival from misfolded protein stress but alters their differentiation program.
• This adaptive response, while facilitating survival, disrupts endochondral ossification, leading to chondrodysplasia.
• Altered chondrocyte differentiation is a key factor in the pathogenesis of certain skeletal dysplasias.