Comprehensive Analysis of Key Genes, Signaling Pathways and miRNAs in Human Knee Osteoarthritis: Based on Bioinformatics

Abstract

Background: Osteoarthritis (OA) is one of the main causes of disability in the elderly population, accompanied by a series of underlying pathologic changes, such as cartilage degradation, synovitis, subchondral bone sclerosis, and meniscus injury. The present study aimed to identify key genes, signaling pathways, and miRNAs in knee OA associated with the entire joint components, and to explain the potential mechanisms using computational analysis.Methods: The differentially expressed genes (DEGs) in cartilage, synovium, subchondral bone, and meniscus were identified using the Gene Expression Omnibus 2R (GEO2R) analysis based on dataset from GSE43923, GSE12021, GSE98918, and GSE51588, respectively and visualized in Volcano Plot. Venn diagram analyses were performed to identify the overlapping DEGs (overlapping DEGs) that expressed in at least two types of tissues mentioned above. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, protein-protein interaction (PPI) analysis, and module analysis were conducted. Furthermore, qRT-PCR was performed to validate above results using our clinical specimens.Results: As a result, a total of 236 overlapping DEGs were identified, of which 160 were upregulated and 76 were downregulated. Through enrichment analysis and constructing the PPI network and miRNA-mRNA network, knee OA-related key genes, such as HEY1, AHR, VEGFA, MYC, and CXCL12 were identified. Clinical validation by qRT-PCR experiments further supported above computational results. In addition, knee OA-related key miRNAs such as miR-101, miR-181a, miR-29, miR-9, and miR-221, and pathways such as Wnt signaling, HIF-1 signaling, PI3K-Akt signaling, and axon guidance pathways were also identified. Among above identified knee OA-related key genes, pathways and miRNAs, genes such as AHR, HEY1, MYC, GAP43, and PTN, pathways like axon guidance, and miRNAs such as miR-17, miR-21, miR-155, miR-185, and miR-1 are lack of research and worthy for future investigation.Conclusion: The present informatic study for the first time provides insight to the potential therapeutic targets of knee OA by comprehensively analyzing the overlapping genes differentially expressed in multiple joint components and their relevant signaling pathways and interactive miRNAs.

State of the Art: The Immunomodulatory Role of MSCs for Osteoarthritis

“…This database could help us to better understand the role of miRNA in the treatment and diagnosis of OA [180]. Recent studies suggested that the miRNAs such as miR-9, miR-29, miR-101, miR-181a, and miR-221 and pathways such as Wnt, NF-kB, HIF-1, and PI3K-Akt act as a key role for OA regulation [181,182]. In the future, we can set a personalized OA treatment plan for each patient using big-data and artificial intelligence (AI) deep learning [183].…”

Effect of Dietary Polyphenols on Osteoarthritis—Molecular Mechanisms

“…Marked changes in the miRNome are observed in OA’s pathogenesis, reviewed comprehensively by Endisha [ 30 ]. More recently, additional miRNAs involved in knee OA have been identified; these include miR-101, miR-181a, miR-29, miR-9, miR-221, miR-411, miR-455, and miR-132 [ 7 , 31 , 32 , 33 ]. MiRNAs also regulate Wnt/βcatenin pathways [ 34 ], Hypoxia-inducible factor- 1 α (HIF-1) [ 7 ], Hypoxia-inducible factor- 2 α (HIF-2 α), and PTEN/PI3K/AKT signaling pathways [ 30 , 31 ], all of which are implicated in the pathogenesis of OA.…”

“…Nevertheless, there has been some progress in understanding the molecular pathophysiology of OA using high-throughput genomics technologies. A variety of potential therapeutic targets of OA have been identified; these include identifying signaling pathways and the involvement of critical genes and microRNAs (miRNAs) in various musculoskeletal disorders [ 7 ].…”

An evolutionarily conserved cis-regulatory element of Nkx3.2 contributes to early jaw joint morphology in zebrafish

“…The presence of a binding motif in JRS1 suggests that Hey1 may function in repressing dorsal expression of Nkx3.2 , restricting expression to the intermediate domain where the jaw joint is patterned. Hey1 has also been found to be upregulated in osteoarthritis (OA) joint cartilage (Chang et al, 2021).…”

“…Hey1 has also been found to be upregulated in osteoarthritis (OA) joint cartilage (Chang et al, 2021). Tbx1 has shown to interact with Hand2 and Edn1, key regulators of pharyngeal arch development, such that zebrafish Tbx1 mutants show drastic reductions in pharyngeal cartilage (Piotrowski et al, 2003).…”