Integrated stress signaling pathways promote adaptive reprogramming for chondrocyte survival in Metaphyseal Chondrodysplasia Type Schmid.

Collagen X, encoded by the Col10a1 gene, is expressed specifically by hypertrophic chondrocytes (HCs) in the cartilage. Mutations of the Col10a1 gene in humans, which increase the endoplasmic reticulum (ER) stress in HCs, lead to metaphyseal chondrodysplasia type Schmid (MCDS). However, the mechanism of how HCs respond to ER stress to affect bone development and growth is not entirely understood. In this study, we generated a new mouse model harboring a 13 bp deletion (13del) in the endogenous Col10a1 gene. These 13del-MCDS mice display all the known clinical characteristics of human MCDS, as well as the molecular and cellular changes within the growth plate cartilage. For the first time, we found that triggering ER stress leads to activation of hypoxia and HIFs pathways in vivo, promoting cellular survival in HCs of the 13del-MCDS mice. To test whether the activated hypoxia and HIFs pathways are triggered by ER stress or extrinsic factors, we generated WT/GFP-MCDS chimera mice. Our findings showed that the activation of hypoxia and the hypoxic pathway is an intrinsic response to ER stress, which may partly occur through activation of ATF4 in HCs of mice. In parallel, p53 pathway changes and autophagy-associated protein-quality-control responses were observed in spatial association with altered chondrocyte differentiation and survival. These findings reveal coordinated engagement of multiple stress-response pathways during the adaptive response of hypertrophic chondrocytes to chronic ER stress.