Department of Orthopedics, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
Department of Orthopedics, First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan, China.
Front Endocrinol (Lausanne). 2024 Aug 26;15:1419742. doi: 10.3389/fendo.2024.1419742. eCollection 2024.
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.
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).
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.
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.
深入了解股骨头坏死（ONFH）后发现，髋关节软骨退变在 ONFH 进展中起着关键作用。然而，导致髋关节软骨发生 ONFH 并易受环境因素影响的潜在分子机制仍不清楚。
我们对 ONFH 髋关节软骨进行了多组学研究和化学-基因相互作用分析。通过结合全基因组 DNA 甲基化谱、基因表达谱和定量蛋白质组学，对 36 例患者配对髋关节软骨样本进行分析，鉴定出与 ONFH 进展相关的差异表达基因（DEGs）。通过基因本体论（GO）和京都基因与基因组百科全书（KEGG）富集分析进行基因功能富集和通路分析。通过蛋白质-蛋白质相互作用（PPI）网络发现蛋白质之间的功能联系。通过将 DEGs 与比较毒理学基因组数据库（CTD）中的化学-基因相互作用集整合，鉴定与 ONFH 相关的化学物质。最后，通过定量实时 PCR（qRT-PCR）和免疫组织化学（IHC）验证包括 MMP13 和 CHI3L1 在内的 DEGs。
在 ONFH 软骨的所有三种组学水平上共鉴定出 22 个 DEGs，其中 16 个上调，6 个下调。富含胶原蛋白的细胞外基质（ECM）、ECM 结构成分、对氨基酸的反应、松弛素信号通路以及蛋白质消化和吸收被认为是 ONFH 软骨退变的主要途径。此外，还鉴定出 10 种主要的与 ONFH 相关的化学物质，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与 ONFH 软骨退变相关的候选基因、途径和化学物质，为 ONFH 进展的病因和生物学过程提供了新的线索。
