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The regulatory mechanism of Serinc5 expression in chondrocytes [ATAC-seq]

ABSTRACT: Chondrocytes undergo a series of sequential differentiation steps which result in the formation of a unique hierarchical columnar structure including proliferating, pre-hypertrophic and hypertrophic chondrocytes. Pre-hypertrophic chondrocytes, which exist in the transitional stage between proliferating and hypertrophic chondrocytes, are a rare cell population in the growth plate but critical for endochondral bone development. However, the molecular basis of pre-hypertrophic chondrocytes largely remains elusive. The purpose of this study is to identify novel marker gene and uncover regulatory mechanism of marker gene expression.

ORGANISM(S): Mus musculus

PROVIDER: GSE271633 | GEO | 2024/11/21

REPOSITORIES: GEO

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Project description:C-type natriuretic peptide (CNP) has been recently identified as an important anabolic regulator of endochondral bone growth, but the molecular mechanism mediating these effects are not completely understood. Here we demonstrate that CNP activates the p38 MAP kinase pathway in chondrocytes and that pharmacological inhibition of p38 blocks the anabolic effects of CNP in a tibia organ culture system. We further show that CNP stimulates endochondral bone growth largely through expansion of the hypertrophic zone of the growth plate, while delaying mineralization. Both effects are reversed by p38 inhibition. We performed Affymetrix microarray analyses to identify CNP target genes in the organ culture system. These studies confirmed that hypertrophic chondrocytes are the main targets of CNP signaling in the growth plate, potentially because cGMP-dependent kinases I and II, important transducers of CNP signaling and are expressed at much higher levels in these cells than in other areas of the tibia. One of the genes most strongly induced by CNP was the Ptgs2 gene, encoding Cox2. Real-time PCR confirmed that Cox2 expression was induced by CNP in hypertrophic chondrocytes, but surprisingly in a p38-independent manner. Moreover, Cox2 inhibition â in contrast to p38 inhibition - did not block the anabolic effects of CNP. In summary, our data identify novel target genes of CNP and demonstrate that the p38 pathway is a novel, essential mediator of CNP effects on endochondral ossification, with potential implications for numerous skeletal diseases. Experiment Overall Design: Tibiae from E15.5 day old embryonic mice were isolated and cultured in minimal media in the presence of vehicle, BSA/HCl (1mM), or C-type natriuretic peptide, CNP (10-6M). On the sixth day of treatment cultured tibias were micro-dissected into the resting/proliferating, hypertrophic, and mineralized areas. Distinct zones from approximately 24 bones were pooled together, from which RNA was isolated using the Qiagen RNeasy Lipid Extraction Kit. Once the quality of total RNA from three independent trials was determined using the Agilent 2100 bioanalyzer, microarray analyses were performed at the London Regional Genomics Centre using MOE430_2.0 Affymetrix arrays. Results were analyzed using GeneSpring 7.2 software.

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The regulatory mechanism of Serinc5 expression in chondrocytes [ATAC-seq]

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