CDK8 mediated inflammatory microenvironment aggravates osteoarthritis progression

Abstract

• CDK8 exerts its role in the progression of OA by influencing the transcriptional regulation of SASP genes through NF-κB. • The mechanism by which CDK8 affects transcriptional regulation is through its cooperative recruitment with NF-κB to the promoters of SASP genes, followed by the promotion of Rpb1 CTD elongation phosphorylation in the gene-specific context induced by NF-κB. • The expression level of CDK8 can affect the nuclear translocation of p65. • Our study shows that based on ELISA detection of synovial fluid, serum, and cell culture supernatants, the secretion level of SASP may be positively correlated with the progression of OA, providing potential biomarkers for determining the severity of OA. • In the development of OA, CDK8 not only affects the degradation of chondrocytes themselves but also promotes the inflammatory joint microenvironment and osteoclast differentiation of macrophages by regulating the secretion of SASP from chondrocytes. Cyclin-Dependent Kinase 8 (CDK8), a CDK family member, regulates the development of inflammatory processes through transcriptional activation. The involvement of CDK8 in osteoarthritis (OA) progression is not yet understood. This study aims to investigate whether CDK8, through its transcriptional regulatory functions, collaborates with NF-κB in chondrocytes to regulate the transcription of senescence-associated secretory phenotype (SASP) genes, thereby exacerbating the inflammatory microenvironment in the progression of osteoarthritis (OA), and to explore the specific mechanisms involved. The effects of CDK8 silencing or overexpression will be assessed by measuring OA pathological markers through H&E staining, immunoblotting, Western blot, qRT-PCR, immunofluorescence and ELISA. The DMM surgery mouse model will be used as the OA model, and the PAM and Von Frey tests will be employed to measure the pain threshold in mice. Luciferase and ChIP assays will be conducted to explore the transcriptional regulation and elongation mechanisms of CDK8. CDK8 influences OA advancement by being recruited to the SASP promoter region in cooperation with NF-κB, leading to the elongation phosphorylation of Rpb1 CTD within the context of NF-κB-induced gene specificity, thereby regulating SASP transcription. The SASP secreted by chondrocytes during this process promotes the inflammatory microenvironment in the joint and drives macrophage differentiation into osteoclasts, further worsening the severity of osteoarthritis. The SASP secreted by chondrocytes during the OA process plays a crucial role in worsening the severity of the disease. Inhibiting CDK8 expression can decrease its secretion by downregulating the transcription levels of SASP, which are co-regulated by CDK8 and NF-κB. This could offer a new target for osteoarthritis treatment.

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