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Loss of TGFβ signaling in the perichondrium drives longitudinal bone overgrowth in mice with Marfan syndrome

ABSTRACT: Loss of TGFβ signaling in the perichondrium drives longitudinal bone overgrowth in mice with Marfan syndrome

PROVIDER: PRJNA781536 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16975074.fastq.gz	Fastqsanger.gz
	SRR16975075.fastq.gz	Fastqsanger.gz
	SRR16975076.fastq.gz	Fastqsanger.gz
	SRR16975077.fastq.gz	Fastqsanger.gz
	SRR16975078.fastq.gz	Fastqsanger.gz

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Loss of TGFβ signaling in the perichondrium drives longitudinal bone overgrowth in mice with Marfan syndrome

Project description:The goal of this study is to define the main tissue and mechanism implicated in the long bone overgrowth phenotype in mice with Marfan syndrome

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Project description:Using Cdh5-Cre and Sm22-Cre transgenes to characterize the impact of disruption of the angiotensin II type 1a receptor (AT1ar) in vascular endothelial and smooth muscle cells, respectively, of wild type (WT) mice compared to fibrillin-1 hypomorphic mice (Fbn1mgR/mgR mice) that replicate early onset progressively severe Marfan syndrome (MFS) with dissecting thoracic aortic aneurysm (TAA).

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Fibrillin-1 deficiency in the outer perichondrium causes longitudinal bone overgrowth in mice with Marfan syndrome.

Project description:A disproportionate tall stature is the most evident manifestation in Marfan syndrome (MFS), a multisystem condition caused by mutations in the extracellular protein and TGFβ modulator, fibrillin-1. Unlike cardiovascular manifestations, there has been little effort devoted to unravel the molecular mechanism responsible for long bone overgrowth in MFS. By combining the Cre-LoxP recombination system with metatarsal bone cultures, here we identify the outer layer of the perichondrium as the tissue responsible for long bone overgrowth in MFS mice. Analyses of differentially expressed genes in the fibrillin-1-deficient perichondrium predicted that loss of TGFβ signaling may influence chondrogenesis in the neighboring epiphyseal growth plate (GP). Immunohistochemistry revealed that fibrillin-1 deficiency in the outer perichondrium is associated with decreased accumulation of latent TGFβ-binding proteins (LTBPs)-3 and -4, and reduced levels of phosphorylated (activated) Smad2. Consistent with these findings, mutant metatarsal bones grown in vitro were longer and released less TGFβ than the wild-type counterparts. Moreover, addition of recombinant TGFβ1 normalized linear growth of mutant metatarsal bones. We conclude that longitudinal bone overgrowth in MFS is accounted for by diminished sequestration of LTBP-3 and LTBP-4 into the fibrillin-1-deficient matrix of the outer perichondrium, which results in less TGFβ signaling locally and improper GP differentiation distally.

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A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

Project description:Background: Marfan syndrome (MFS) is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results: We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusions: Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value < 3 x 10-6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status). An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater. Keywords: disease state comparison; Marfan syndrome; cultured skin fibroblasts

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Project description:Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 (Fbn1) gene. While aortic rupture is the major cause of mortality in MFS, patients also suffer from poorly understood pulmonary complications. Loss of basal nitric oxide (NO) production and vascular integrity are proposed to take part in MFS aortic root disease, yet their contribution to lung complications has yet to be determined. Due to its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 (PDE5) inhibitor sildenafil (SIL) could attenuate aortic root remodelling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation and exacerbated elastic fibrefiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent micro-array analyses showed changes to gene signatures involved in the inflammatory response in MFS lung treated with SIL, without significant downregulation of connective tissue or TGF-β signalling genes. Since PDE5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodelling.

2019-03-19 | GSE128481 | GEO

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