CDK8 mediated inflammatory microenvironment aggravates osteoarthritis progression.

Area of Science:

• Biochemistry
• Molecular Biology
• Immunology

Background:

• Cyclin-Dependent Kinase 8 (CDK8) is a transcriptional regulator involved in inflammatory processes.
• The specific role of CDK8 in osteoarthritis (OA) pathogenesis remains largely unexplored.

Purpose of the Study:

• To investigate if CDK8 collaborates with NF-κB in chondrocytes to regulate senescence-associated secretory phenotype (SASP) gene transcription.
• To determine if this interaction exacerbates the OA inflammatory microenvironment.
• To elucidate the underlying molecular mechanisms.

Main Methods:

• Utilized a DMM surgery mouse model for OA.
• Assessed OA pathology and pain using H&E staining, Western blot, qRT-PCR, ELISA, PAM, and Von Frey tests.
• Employed luciferase and ChIP assays to explore transcriptional regulation and elongation mechanisms.

Main Results:

• CDK8 is recruited to the SASP promoter with NF-κB, promoting SASP transcription via Rpb1 CTD phosphorylation.
• CDK8-mediated SASP secretion by chondrocytes enhances joint inflammation and drives osteoclast differentiation.
• This process exacerbates osteoarthritis severity.

Conclusions:

• Chondrocyte-derived SASP significantly contributes to OA severity.
• CDK8 and NF-κB co-regulate SASP transcription, making CDK8 inhibition a potential therapeutic strategy.
• Targeting CDK8 offers a novel approach for osteoarthritis treatment by reducing SASP secretion.