Microarray analysis of defective cartilage in Hoxc8- and Hoxd4-transgenic mice
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PROVIDER: PRJNA120435 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the following subset Series: GSE18991: Overexpression of Hoxd4 transcription factor alters transcriptional profiles in mouse chondrocytes at E18.5 GSE18992: Overexpression of Hoxc8 transcription factor alters transcriptional profiles in mouse chondrocytes at E18.5!Series_overall_design = Refer to individual Series Refer to individual Series
2010-10-15 | E-GEOD-19002 | biostudies-arrayexpress
Project description:ObjectiveHomeobox genes of the Hox class are required for proper patterning of skeletal elements and play a role in cartilage differentiation. In transgenic mice with overexpression of Hoxc8 and Hoxd4 during cartilage development, the authors observed severe defects, namely, physical instability of cartilage, accumulation of immature chondrocytes, and decreased maturation to hypertrophy. To define the molecular basis underlying these defects, the authors performed gene expression profiling using the Affymetrix microarray platform.ResultsPrimary chondrocytes were isolated from Hoxc8- and Hoxd4-transgenic mouse embryo rib cartilage at 18.5 days of gestation. In both cases, differentially expressed genes were identified that have a role in cell proliferation and cell cycle regulation. A comparison between the controls for both experimental groups did not reveal significant differences, as expected. However, the repertoires of differentially expressed genes were found not to overlap between Hoxc8- and Hoxd4-transgenic cartilage. This included different Wnt genes, cell cycle, and apoptosis regulators.ConclusionOverexpression of Hoxc8 and Hoxd4 transcription factors alters transcriptional profiles in chondrocytes at E18.5. The differences in repertoires of altered gene expression between the 2 transgenic conditions suggest that the molecular mechanisms underlying the cartilage defects may be different in both transgenic paradigms, despite apparently similar phenotypes.
| S-EPMC4297070 | biostudies-literature
Project description:Homeobox genes of the Hox class are required for proper patterning of skeletal elements and play a role in cartilage differentiation. In transgenic mice with overexpression of Hoxc8 during cartilage development, we observed severe defects, namely physical instability of cartilage, accumulation of immature chondrocytes, and decreased maturation to hypertrophy. To define the molecular basis underlying these defects, we performed gene expression profiling using the Affymetrix microarray platform.
2010-10-15 | GSE18992 | GEO
Project description:Homeobox genes of the Hox class are required for proper patterning of skeletal elements and play a role in cartilage differentiation. In transgenic mice with overexpression of Hoxc8 during cartilage development, we observed severe defects, namely physical instability of cartilage, accumulation of immature chondrocytes, and decreased maturation to hypertrophy. To define the molecular basis underlying these defects, we performed gene expression profiling using the Affymetrix microarray platform. Embryos were dissected from four different mouse litters at E18.5. Embryos from each litter were grouped according their genotype: TA=control; TR=transgenic.
2010-10-15 | E-GEOD-18992 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2010-10-15 | GSE19002 | GEO
Project description:Hox genes encode transcription factors, which regulate skeletal patterning and chondrocyte differentiation during the development of cartilage, the precursor to mature bone. Overexpression of the homeobox transcription factors Hoxc8 and Hoxd4 causes severe cartilage defects due to delay in cartilage maturation. Matrix metalloproteinases (MMPs), bone morphogenetic proteins (BMPs) and fibroblastic growth factors (FGFs) are known to play important roles in skeletal development and endochondral bone formation and remodeling. In order to investigate whether these molecules are aberrantly expressed in Hoxc8- and/or Hoxd4-transgenic cartilage, we performed quantitative RT-PCR on chondrocytes from Hox-transgenic mice. Gene expression levels of Bmp4, Fgf8, Fgf10, Mmp9, Mmp13, Nos3, Timp3, Wnt3a and Wnt5a were altered in Hoxc8-transgenic chondrocytes, and Fgfr3, Ihh, Mmp8, and Wnt3a expression levels were altered in Hoxd4-transgenic chondrocytes, respectively. Notably, Wnt3a expression was elevated in Hoxc8- and reduced in Hoxd4-transgenic cartilage. These results suggest that both transcription factors affect cartilage maturation through different molecular mechanisms, and provide the basis for future studies into the role of these genes and possible interactions in pathogenesis of cartilage defects in Hoxc8- and Hoxd4-transgenic mice.
| S-EPMC2814844 | biostudies-literature
Project description:Low-protein diets can mitigate renal fibrosis, yet the critical amino acid responsible for this benefit and its underlying mechanism remain unclear. By screening 15 amino acid–restricted diets in a unilateral ureteral obstruction (UUO) model, we identify methionine restriction (MetR) as the most effective intervention. Integrating transcriptomic and cistromic analyses further uncover Hoxc8 as a central pro-fibrotic transcription factor. Hoxc8 is induced by TGF-β–Smad3, amplifies its own expression, and drives fibrotic gene programs through recruitment of the P-TEFb transcriptional elongation complex. Clinically, HOXC8 is elevated in fibrotic human kidneys, and fibroblast-specific Hoxc8 deletion protects mice from fibrosis. MetR attenuates this pro-fibrotic circuit by reducing active histone marks (H3K4me3 and H3K36me3) at the Hoxc8 locus, thereby suppressing the Hoxc8-dependent fibrotic transcriptional program. Together, these findings establish the TGF-β–Smad3–Hoxc8/P-TEFb axis as a key driver of renal fibrosis and highlight MetR as a promising therapeutic strategy.
2025-12-04 | PXD071531 | Pride
Project description:Renal fibrosis is a hallmark of chronic kidney diseases (CKDs) and a key driver of disease progression. While low-protein diets have been shown to alleviate fibrosis and slow CKD progression, the specific amino acids responsible for these effects remain unclear, and such diets often lead to malnutrition due to the restriction of essential amino acids. In this study, we evaluated 15 amino acid-restricted diets in a unilateral ureteral obstruction (UUO) mouse model and found that methionine restriction (MetR) most effectively reduced renal fibrosis. We further confirmed the efficacy of MetR in alleviating renal fibrosis in the folic acid nephropathy (FAN) mouse model. Mechanistically, we identified Hoxc8 as a key transcription factor responsive to MetR, mediating TGF-β-induced fibrotic gene expression. Our findings suggest that TGF-β-Smad3 signaling activates Hoxc8 during myofibroblast activation, initiating a self-reinforcing feedback loop through Hoxc8 self-activation. Using affinity purification-mass spectrometry, we discovered that Hoxc8 interacts with P-TEFb transcription elongation complex to enhance the expression of fibrotic genes. MetR suppresses Hoxc8 expression by reducing histone modifications, specifically H3K4me3 and H3K36me3, thereby inhibiting the TGF-β/Smad3/Hoxc8/P-TEFb axis and downregulating fibrosis-related gene expression. Notably, elevated HOXC8 expression was observed in CKD patients with kidney fibrosis, while fibroblast-specific Hoxc8 knockout mice demonstrated significantly reduced fibrosis following UUO surgery. These findings establish the TGF-β/Smad3/Hoxc8/P-TEFb axis as a crucial regulator of fibrosis and highlight MetR as a promising therapeutic strategy for the treatment of renal fibrosis.
2025-12-04 | GSE287134 | GEO
Project description:BACKGROUND:Hox transcription factors are well known for their role in skeletal patterning in vertebrates. They regulate gene expression during the development of cartilage, the precursor to mature bone. We previously reported that overexpression of the homeobox genes Hoxc8 and Hoxd4 results in severe cartilage defects, reduced proteoglycan content, accumulation of immature chondrocytes, and decreased maturation to hypertrophy. We have also shown that Hoxd4 transgenic mice whose diets were supplemented with folate had their skeletal development restored. Since folate is required for growth and differentiation of chondrocytes, we hypothesized that the beneficial effect of folate in Hoxd4 transgenic mice might indicate a local deficiency in folate utilization, possibly caused by deregulation of genes encoding folate transport proteins or folate metabolic enzymes. METHODS:We assayed the prevalence of transcripts for 22 folate transport proteins and metabolizing enzymes, here collectively referred to as folate pathway genes. Quantitative real-time PCR was performed on cDNA samples derived from RNA isolated from primary chondrocytes of individual rib cartilages from Hoxd4 and Hoxc8 transgenic mice, respectively. RESULTS:This study shows that the Hox transgenes produce overexpression of Hoxd4 and Hoxc8 in primary chondrocytes from perinatal transgenic mice. However, no differences were found in expression levels of the folate pathway genes in transgenic cells compared to littermate controls. CONCLUSIONS:Our results provide evidence that folate pathway genes are only indirect targets of Hox transgene overexpression in our transgenic animals. These expression studies provide a baseline for future studies into the role of folate metabolism in chondrocyte differentiation.
| S-EPMC3938170 | biostudies-literature
Project description:Timps are natural metalloproteinase inhibitors that direct the cell microenvironment in health and disease, yet the essential requirement of this gene family in mammals is unknown. We generated quadruple Timp deficient mice lacking Timp1, Timp2, Timp3 and Timp4 (TIMPless) and found that Timp function is essential for postnatal lifespan, lung form and function and skeletogenesis. TIMPless mice survive embryogenesis but develop pervasive skeletal aberrations characterized by axial cartilage overgrowth and growth plate closure in long bones. We performed microarray analysis to identify signaling pathways affected by the loss of the entire Timp family in sternal cartilage.
2015-08-31 | GSE60451 | GEO