ZDHHC14 Attenuates Osteoarthritis Progression through Metabolic Pathways: Multi-omics Fusion and Functional...

Area of Science:

• Biochemistry
• Genetics
• Molecular Biology

Background:

• Osteoarthritis (OA) is a degenerative joint disease with complex genetic underpinnings.
• Palmitoylation, a post-translational modification, plays a role in cellular processes relevant to OA pathogenesis.
• Understanding the genetic factors influencing OA and their regulatory mechanisms is crucial for developing effective treatments.

Purpose of the Study:

• To investigate the association between palmitoylation-related genes and osteoarthritis (OA) progression.
• To identify the downstream regulatory mechanisms of key palmitoylation genes in OA.
• To explore ZDHHC14 as a potential therapeutic target for OA.

Main Methods:

• Mendelian randomization (MR) and summary data-based MR (SMR) analyses integrated eQTL and GWAS data to identify causal gene-OA links.
• RNA-seq, Western blot, and qRT-PCR validated gene expression changes in OA chondrocytes.
• Cellular assays (CCK-8, EdU, transwell) assessed the impact of ZDHHC14 on chondrocyte proliferation and migration.

Main Results:

• MR analysis identified ZDHHC14 as having a significant protective effect against OA.
• ZDHHC14 was found to be downregulated in OA tissues.
• ZDHHC14 knockdown impaired chondrocyte proliferation and migration, affecting key OA-related gene expression and regulating sphingomyelin and 3-hydroxybutyroylglycine levels.

Conclusions:

• ZDHHC14 inhibits OA progression by maintaining metabolic homeostasis.
• This study provides novel insights into the role of palmitoylation in OA pathogenesis.
• ZDHHC14 represents a promising therapeutic target for osteoarthritis treatment strategies.