Unknown,Transcriptomics,Genomics,Proteomics

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RNA-Seq data from epiphyseal growth plates of young male rats, healthy control rats and dextran sodium sulfate (DSS) induced colitis treated rats

ABSTRACT: Growth failure is a major complication of pediatric inflammatory bowel disease (IBD), a condition whose prevalence has risen sharply over recent decades. Despite advances in medical therapy, linear growth impairment often persists. This underscores the urgent need to elucidate how chronic inflammation disrupts skeletal development at the epiphyseal growth plate (EGP), the central driver of longitudinal bone growth. Our study proposes a novel mechanism, involving the activation of ELANE, a serine proteinase previously shown to be secreted by neutrophils in response to inflammatory stimuli. We report for the first time that EGP chondrocytes express ELANE, with significant upregulation observed in DSS-induced colitis and in ATDC5 cells exposed to LPS. The concomitant induction of ELANE and MMP13 indicates a direct catabolic effect on the extracellular matrix, leading to impaired growth plate function. While ELANE is well established in cartilage degradation and bone remodeling in rheumatoid arthritis and osteoarthritis, its expression in the EGP and its role in growth impairment during IBD represent novel findings. These findings open new perspectives on inflammation-driven growth impairment in pediatric IBD, highlight ELANE as a promising therapeutic target to preserve skeletal development.

INSTRUMENT(S): Illumina NovaSeq X

ORGANISM(S): Rattus norvegicus

SUBMITTER: Chen Menahem

PROVIDER: E-MTAB-16246 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Human adult height reflects the outcome of childhood skeletal growth. Growth plate (epiphyseal) chondrocytes are key determinants of height. As epiphyseal chondrocytes mature and proliferate, they pass through three developmental stages, which are organized into three distinct layers in the growth plate: (i) resting (round), (ii) proliferative (flat), and (iii) hypertrophic. Recent genomewide association studies (GWASs) of human height identified numerous associated loci, which are enriched for genes expressed in growth plate chondrocytes. However, it remains unclear which specific genes expressed in which layers of the growth plate regulate skeletal growth and human height. To connect the genetics of height and growth plate biology, we analyzed GWAS data through the lens of gene expression in the three dissected layers of murine newborn tibial growth plate. For each gene, we derived a specificity score for each growth plate layer and regressed these scores against gene-level p values from recent height GWAS data. We found that specificity for expression in the round cell layer, which contains chondrocytes early in maturation, is significantly associated with height GWAS p values (p = 8.5 × 10−9); this association remains after conditioning on specificity for the other cell layers. The association also remains after conditioning on membership in an “Online Mendelian Inheritance in Man (OMIM) gene set” (genes known to cause monogenic skeletal growth disorders, p < 9.7 × 10−6). We replicated the association in RNA-sequencing (RNA-seq) data from maturing chondrocytes sampled at early and late time points during differentiation in vitro: we found that expression early in differentiation is significantly associated with p values from height GWASs (p = 6.1 × 10−10) and that this association remains after conditioning on expression at 10 days in culture and on the OMIM gene set (p < 0.006). These findings newly implicate genes highlighted by GWASs of height and specifically expressed in the round cell layer as being potentially important regulators of skeletal biology. © 2021 American Society for Bone and Mineral Research (ASBMR).

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RNA-Seq data from epiphyseal growth plates of young male rats, healthy control rats and dextran sodium sulfate (DSS) induced colitis treated rats

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