■对股骨头坏死(ONFH)的深入了解表明,髋关节软骨的退变在ONFH的进展中起着至关重要的作用。然而,髋关节软骨中导致ONFH进展的潜在分子机制和对环境因素的敏感性仍然难以捉摸。
■我们对ONFH中的髋关节软骨进行了一项多组学研究和化学-基因相互作用分析。通过结合全基因组DNA甲基化分析,在36例患者的成对髋关节软骨样本中鉴定了参与ONFH进展的差异表达基因(DEGs)。基因表达谱分析,和定量蛋白质组学。基因功能富集和途径分析通过基因本体论(GO)和京都基因和基因组百科全书(KEGG)富集分析进行。通过蛋白质-蛋白质相互作用(PPI)网络发现了蛋白质之间的功能联系。通过将DEG与比较毒性基因组学数据库(CTD)中的化学-基因相互作用集整合来鉴定ONFH相关的化学物质。最后,DEGs,包括MMP13和CHI3L1,通过定量实时PCR(qRT-PCR)和免疫组织化学(IHC)进行验证。
■在ONFH软骨的所有三个组学水平上鉴定出22个DEG,其中16个上调,6个下调。含胶原蛋白的细胞外基质(ECM),ECM结构成分,对氨基酸的反应,松弛素信号通路,发现蛋白质的消化和吸收主要参与ONFH的软骨退变。此外,确定了十种与ONFH相关的主要化学物质,包括,苯并(a)芘,丙戊酸,和双酚A。
■总的来说,我们的研究确定了几个候选基因,通路,以及与ONFH软骨退化相关的化学物质,为ONFH进展的病因和生物学过程提供新的线索。
UNASSIGNED: In-depth understanding of osteonecrosis of femoral head (ONFH) has revealed that degeneration of the hip cartilage plays a crucial role in ONFH progression. However, the underlying molecular mechanisms and susceptibility to environmental factors in hip cartilage that contribute to ONFH progression remain elusive.
UNASSIGNED: We conducted a multiomics study and chemical-gene interaction analysis of hip cartilage in ONFH. The differentially expressed genes (DEGs) involved in ONFH progression were identified in paired hip cartilage samples from 36 patients by combining genome-wide DNA methylation profiling, gene expression profiling, and quantitative proteomics. Gene functional enrichment and pathway analyses were performed via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Functional links between proteins were discovered through protein-protein interaction (PPI) networks. The ONFH-associated chemicals were identified by integrating the DEGs with the chemical-gene interaction sets in the Comparative Toxicogenomics Database (CTD). Finally, the DEGs, including MMP13 and CHI3L1, were validated via quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC).
UNASSIGNED: Twenty-two DEGs were identified across all three omics levels in ONFH cartilage, 16 of which were upregulated and six of which were downregulated. The collagen-containing extracellular matrix (ECM), ECM structural constituents, response to amino acids, the relaxin signaling pathway, and protein digestion and absorption were found to be primarily involved in cartilage degeneration in ONFH. Moreover, ten major ONFH-associated chemicals were identified, including, benzo(a)pyrene, valproic acid, and bisphenol A.
UNASSIGNED: Overall, our study identified several candidate genes, pathways, and chemicals associated with cartilage degeneration in ONFH, providing novel clues into the etiology and biological processes of ONFH progression.