title: Transcriptional profiling of chondrodysplasia growth plate cartilage reveals adaptive ER-stress networks that allow survival but disrupt hypertrophy.
abstract: Metaphyseal chondrodysplasia, Schmid type (MCDS) is characterized by mild short stature and growth plate hypertrophic zone expansion, and caused by collagen X mutations. We recently demonstrated the central importance of ER stress in the pathology of MCDS by recapitulating the disease phenotype by expressing misfolding forms of collagen X (Schmid) or thyroglobulin (Cog) in the hypertrophic zone. Here we characterize the Schmid and Cog ER stress signaling networks by transcriptional profiling of microdissected mutant and wildtype hypertrophic zones. Both models displayed similar unfolded protein responses (UPRs), involving activation of canonical ER stress sensors and upregulation of their downstream targets, including molecular chaperones, foldases, and ER-associated degradation machinery. Also upregulated were the emerging UPR regulators Wfs1 and Syvn1, recently identified UPR components including Armet and Creld2, and genes not previously implicated in ER stress such as Steap1 and Fgf21. Despite upregulation of the Chop/Cebpb pathway, apoptosis was not increased in mutant hypertrophic zones. Ultrastructural analysis of mutant growth plates revealed ER stress and disrupted chondrocyte maturation throughout mutant hypertrophic zones. This disruption was defined by profiling the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones. Hypertrophic zone gene upregulation and proliferative zone gene downregulation were both inhibited in Schmid hypertrophic zones, resulting in the persistence of a proliferative chondrocyte-like expression profile in ER-stressed Schmid chondrocytes. Our findings provide a transcriptional map of two chondrocyte UPR gene networks in vivo, and define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy. Thus they provide important insights into ER stress signaling and its impact on cartilage pathophysiology.
authors.affiliation: Murdoch Childrens Research Institute, Parkville, Victoria, Australia.
authors.forename: Trevor L
authors.initials: TL
authors.lastname: Cameron
authors.forename: Katrina M
authors.initials: KM
authors.lastname: Bell
authors.forename: Liliana
authors.initials: L
authors.lastname: Tatarczuch
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Mackie
authors.forename: M Helen
authors.initials: MH
authors.lastname: Rajpar
authors.forename: Ben T
authors.initials: BT
authors.lastname: McDermott
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Boot-Handford
authors.forename: John F
authors.initials: JF
authors.lastname: Bateman
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002356:Cartilage / Q000166:cytology* / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods*; D006132:Growth Plate / Q000166:cytology* / Q000378:metabolism; D017403:In Situ Hybridization; D020287:In Situ Nick-End Labeling; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D042282:Microdissection; D046529:Microscopy, Electron, Transmission; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010009:Osteochondrodysplasias / Q000473:pathology*; D016133:Polymerase Chain Reaction
chemical_list: D000951:Antigens, Neoplasm; C561361:CRELD2 protein, mouse; D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; C534671:MANF protein, mouse; D008565:Membrane Proteins; D009414:Nerve Growth Factors; C486624:Steap protein, mouse; C414620:fibroblast growth factor 21; C114987:wolframin protein; D005346:Fibroblast Growth Factors