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

Tsang, Kwok Yeung; Chan, Danny; Cheslett, Deborah; Chan, Wilson C W; So, Chi Leong; Melhado, Ian G; Chan, Tori W Y; Kwan, Kin Ming; Hunziker, Ernst B; Yamada, Yoshihiko; Bateman, John F; Cheung, Kenneth M C; Cheah, Kathryn S E (2007). Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function. PLoS biology, 5(3), e44. Lawrence, Kans.: Public Library of Science 10.1371/journal.pbio.0050044

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In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded alpha1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Orthopädische Chirurgie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Orthopädische Chirurgie
UniBE Contributor:	Hunziker, Ernst Bruno
ISSN:	1544-9173
ISBN:	17298185
Publisher:	Public Library of Science
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:01
Last Modified:	05 Dec 2022 14:19
Publisher DOI:	10.1371/journal.pbio.0050044
PubMed ID:	17298185
Web of Science ID:	000245243500016
URI:	https://boris.unibe.ch/id/eprint/26628 (FactScience: 75553)