In addition, osteoclast differentiation, FoxO, MAPK and PI3K/Akt signaling pathways were revealed to be imperative for the pathogenesis of OA, as these 4 pivotal signaling pathways were observed to be tightly linked through 4 key TFs Fos Proto-Oncogene, JUN, JunD Proto-Oncogene and MYC, and 4 DEGs Vascular Endothelial Growth Factor A, Growth Arrest and DNA Damage Inducible α, Growth Arrest and DNA Damage Inducible β and Cyclin D1.
The qRT-PCR result showed that the expression level of IL6, VEGFA, JUN, IL-1<i>β</i>, and ATF3 was significantly increased in OA samples (p < 0.05), and these candidate genes could be used as potential diagnostic biomarkers and therapeutic targets of OA.
This analysis revealed eight TFs, including JUN, Early growth response (EGR)1, JUND, FOSL2, MYC, KLF4, RELA, and FOS that both target large numbers of dysregulated genes in OA and are themselves suppressed in OA.
Cartilage damage in osteoarthritis (OA) is largely mediated by interleukin-1β (IL-1β) via activation of various transcription factors, including NF‑κB and activator protein‑1.
Pharmacological inhibition of BATF/JUN transcriptional activity reduced the expression of matrix-degrading enzymes and protected against experimental OA in mice.
Unexpectedly, aberrant overexpression of MT2, but not MT1, induced upregulation of matrix-degrading enzymes and downregulation of matrix molecules through nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1) activation, ultimately leading to OA.
Also, immunohistochemical studies revealed that the PUMA and c-Jun proteins were upregulated in chondrocytes from the articular cartilage of OA patients.
Our results also showed that CORM-2 significantly decreased the activation of nuclear factor-κB and activator protein-1 regulating the transcription of chemokines and MMPs in OA synoviocytes.