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Gene expression analysis of ER-stressed growth plate chondrocytes in two mouse models of Schmid chondrodysplasia

ABSTRACT: We set out to generate transcriptional maps of chondrocyte UPR gene networks in vivo using two mouse models (Schmid and Cog) of Schmid chondrodysplasia, in order to define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy, thus providing insights into ER stress signaling and its impact on cartilage pathophysiology. Our data demonstrate that both models displayed similar unfolded protein responses (UPRs), involving activation of ER stress sensors Ire1 and Atf6 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. Moreover, we transcriptionally profiled the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones, in order to define the differentiation status of ER-stressed chondrocytes 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE30628 | GEO | 2012/01/01

SECONDARY ACCESSION(S): PRJNA144579

REPOSITORIES: GEO

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Gene expression analysis of ER-stressed growth plate chondrocytes in two mouse models of Schmid chondrodysplasia

Project description:We set out to generate transcriptional maps of chondrocyte UPR gene networks in vivo using two mouse models (Schmid and Cog) of Schmid chondrodysplasia, in order to define the consequences of UPR activation for the adaptation, differentiation, and survival of chondrocytes experiencing ER stress during hypertrophy, thus providing insights into ER stress signaling and its impact on cartilage pathophysiology. Our data demonstrate that both models displayed similar unfolded protein responses (UPRs), involving activation of ER stress sensors Ire1 and Atf6 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. Moreover, we transcriptionally profiled the expression of wildtype growth plate zone gene signatures in the mutant hypertrophic zones, in order to define the differentiation status of ER-stressed chondrocytes 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. For the mutant hypertrophic zone gene expression profiling, the hypertrophic zone from one tibia from each of three two week old Schmid, wildtype (Schmid background), Cog, and wildtype (Cog background) mice was microdissected. In all cases, total RNA was extracted and amplified through two rounds of linear amplification, labelled with Cy3, and interrogated by microarray analysis using the Agilent 44K, mouse whole genome platform.

2012-01-01 | E-GEOD-30628 | biostudies-arrayexpress

Analysis of the IRE1/XBP1 unfolded protein response (UPR) pathway in Schmid metaphyseal chondrodysplasia hypertrophic chondrocyte endoplasmic reticulum (ER) stress

Project description:We set out to determine the role of the IRE1/XBP1 pathway, the most ancient and highly conserved endoplasmic reticulum (ER) stress-sensing pathway of the unfolded protein response (UPR), in Schmid metaphyseal chondrodysplasia (MCDS). RNA derived from hypertrophic zones microdissected from growth plates of wildtype mice, mice lacking XBP1 activity in chondrocytes (Xbp1Cart?Ex2), mice carrying a COL10A1 pN617K mutation (ColXN617K), and compound mutants (C/X) was analyzed by whole genome microarray analysis. 1633 probes were differentially expressed between ColXN617K and wildtype, 215 probes were differentially expressed between Xbp1Cart?Ex2 and wildtype, and 1337 probes were differentially expressed between C/X and wildtype. 885 probes were differentially expressed between ColXN617K and wildtype but not Xbp1Cart?Ex2 and wildtype or C/X and wildtype, thus representing the XBP1-dependent response to hypertrophic chondrocyte ER stress. 688 probes were differentially expressed between ColXN617K and wildtype and between C/X and wildtype but not Xbp1Cart?Ex2 and wildtype, thus representing the XBP1-independent response to hypertrophic chondrocyte ER stress. Results were validated by qPCR. Entire growth plate hypertrophic zones were microdissected from one tibia from each of three 2-week old wildtype mice, three 2-week old mice carrying a COL10A1 p.N617K mutation (ColXN617K), three 2-week old mice lacking XBP1 activity in chondrocytes (Xbp1Cart?Ex2), and three 2-week old mice resulting from a cross between ColXN617K and Xbp1Cart?Ex2 (C/X).

2015-08-21 | E-GEOD-72261 | biostudies-arrayexpress

Analysis of the IRE1/XBP1 unfolded protein response (UPR) pathway in Schmid metaphyseal chondrodysplasia hypertrophic chondrocyte endoplasmic reticulum (ER) stress

Project description:We set out to determine the role of the IRE1/XBP1 pathway, the most ancient and highly conserved endoplasmic reticulum (ER) stress-sensing pathway of the unfolded protein response (UPR), in Schmid metaphyseal chondrodysplasia (MCDS). RNA derived from hypertrophic zones microdissected from growth plates of wildtype mice, mice lacking XBP1 activity in chondrocytes (Xbp1CartΔEx2), mice carrying a COL10A1 pN617K mutation (ColXN617K), and compound mutants (C/X) was analyzed by whole genome microarray analysis. 1633 probes were differentially expressed between ColXN617K and wildtype, 215 probes were differentially expressed between Xbp1CartΔEx2 and wildtype, and 1337 probes were differentially expressed between C/X and wildtype. 885 probes were differentially expressed between ColXN617K and wildtype but not Xbp1CartΔEx2 and wildtype or C/X and wildtype, thus representing the XBP1-dependent response to hypertrophic chondrocyte ER stress. 688 probes were differentially expressed between ColXN617K and wildtype and between C/X and wildtype but not Xbp1CartΔEx2 and wildtype, thus representing the XBP1-independent response to hypertrophic chondrocyte ER stress. Results were validated by qPCR.

2015-08-21 | GSE72261 | GEO

Label free quantitative proteomics reveals survival mechanisms developed by Hypertrophic chondrocytes under ER stress

Project description:Emerging evidence implicates ER stress caused by unfolded mutant proteins in chondrocytes as the underlying pathology of chondrodysplasias. ER stress is triggered in hypertrophic chondrocytes (HCs) in a mouse model (13del) of metaphyseal chondrodysplasia type Schmid (MCDS) caused by misfolded mutant collagen X proteins, but the HCs do not undergo apoptosis, rather chondrocyte differentiation is altered causing skeletal abnormality. How 13del HCs can escape from apoptosis and survive ER stress is not understood. We compared using label-free quantitative mass spectrometry approach the proteomes of HCs isolated from 13del growth plates with normal HCs. In this paper we reveal significant changes in levels of proteins involved in in actin remodeling, glycolysis and ER-mitochondria communication in 13del HCs chondrocytes. Previous in vitro studies of chronic ER stress showed down-regulation of glycolysis and disrupted mitochondrial function leading to cell death. Our data showed that glucose uptake was maintained in ATDC5 chondrocytic cell lines expressing 13del collagen X. Furthermore expression of mitochondrial calcium channels was reduced while mitochondrial membrane polarity was maintained in in vivo 13del chondrocytes. Thus we propose that 13del HCs survive by a mechanism whereby changes in ER-mitochondria communication reduce import of calcium coupled with maintenance of mitochondrial membrane polarity.

2015-11-25 | PXD002125 | Pride

Expression data of chondrocytes subpopulations from WT, 13del and 13del:Chop-/- mice at P10 stage

Project description:The human metaphyseal chondrodysplasia type Schmid is an autosomal dominant disorder associated with mutations in COL10A1 gene that result in ER retention of misfolded alpha(X) collagen in hypertrophic chondrocytes (HCs). In a MCDS transgenic mouse model (13del), we have previously implicated HC response and adaptation to ER stress as the underlying molecular pathogenesis of the disease. We generate microarray data from chondrocytes in WT, 13del and 13del:Chop-/- mice to elucidate the etiological role of ER stress signaling in MCDS.

2017-05-26 | GSE99306 | GEO

Transcription profiling of Bos taurus hypertrophic growth plate chondrocytes vs. reserve zone chondrocytes

Project description:Growth plate chondrocytes were isolated from the distal metacarpus of young dairy cattle (all under 10 mo of age), the chondrocytes were released from the extracellular matrix by digestion with Collagenase P for 4 hours, and the various zones of the growth plate were separated by density centrifugation. The least-dense Hypertrophic Zone (HZ) cells were compared to the most-dense Reserve Zone (RZ) cells. 6 pairs of HZ vs RZ were compared by microarray. Experiment Overall Design: Growth plate chondrocytes were isolated from the distal metacarpus of young dairy cattle (all under 10 mo of age), the chondrocytes were released from the extracellular matrix by digestion with Collagenase P for 4 hours, and the various zones of the growth plate were separated by density centrifugation. The least-dense Hypertrophic Zone (HZ) cells were compared to the most-dense Reserve Zone (RZ) cells. Six independent sample pairs of HZ vs RZ were compared by microarray.

2009-10-30 | E-GEOD-18738 | biostudies-arrayexpress

Sorting of Growth Plate Chondrocytes Allows the Isolation and Characterization of Cells of a Defined Differentiation Status

Project description:Axial growth of long bones occurs through a coordinated process of growth plate chondrocyte proliferation and differentiation. This maturation of chondrocytes is reflected in a zonal change in gene expression and cell morphology from resting to proliferative, prehypertrophic, and hypertrophic chondrocytes of the growth plate followed by ossification. A major experimental limitation in understanding growth plate biology and pathophysiology is the lack of a robust technique to isolate cells from the different zones, particularly from small animals. Here, we report on a new strategy for separating distinct chondrocyte populations from mouse growth plates. By transcriptome profiling of microdissected zones of growth plates, we identified novel, zone-specific cell surface markers and used these for flow cytometry and immunomagnetic cell separation to quantify, enrich, and characterize chondrocytes populations with respect to their differentiation status. This approach provides a novel platform to study cartilage development and characterize mouse growth plate chondrocytes to reveal unique cellular phenotypes of the distinct subpopulations within the growth plate.

2020-02-29 | GSE144362 | GEO

Gene Expression Across the Human Growth Plate

2013-09-13 | GSE9160 | GEO

Gene Expression Across the Human Growth Plate

Project description:Chondrocytes advance through the long bone growth plate in synchrony, allowing their segregation into one of four zones each corresponding to a different phase of maturation. Beginning from the epiphysis the recognized zones are: reserve, proliferative, prehypertrophic, and hypertrophic. A fifth zone, the perichondrium is located in apposition to the growth plate at its circumferential surface. The progression of chondrocytes through these zones, and hence growth, is regulated by a complex interplay of signaling pathways, defects in which lead to osteochondrodysplasias. At present, there are over 370 recognized skeletal disorders, slightly more than half of which have been explained at the molecular level. Through a combination of laser microdissection, linear mRNA amplification, and GeneChip analysis, our laboratory has acquired the zone specific expression profile of chondrocytes from the distal femoral growth plates of two normal patients. On average, transcripts interrogated by 12,193 or 18,454 GeneChip probe sets (out of a possible 54,000 probe sets) were present in patients 1 and 2, respectively. The homologous inter-array correlations for the log(2) intensities were M-bM-^IM-% 0.91M-BM-10.01. Keywords: Chondrocyte differentiation program. Populations of cells corresponding to the hypertrophic, prehypertrophic, proliferative, reserve, and perichondrium, were separately isolated by laser microdissection from cryostat sections of human growth plates using a Leica AS-LMD microscope. RNA was prepared from the isolated cells, amplified using a T7 linear amplification protocol, and analyzed by hybridization to Affymetrix microarrays. The distal femoral growth plate (left or right) was exclusively used for this study. Patient 1 of this study is an 11-10/12 year old Caucasian female and patient 2 is a 13-3/12 year old Caucasian male.

2013-09-13 | E-GEOD-9160 | biostudies-arrayexpress

Mus musculus

Project description:Analysis of the IRE1/XBP1 unfolded protein response (UPR) pathway in Schmid metaphyseal chondrodysplasia hypertrophic chondrocyte endoplasmic reticulum (ER) stress

| PRJNA293517 | ENA

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