Hnrnpk protects against osteoarthritis through targeting WWC1 mRNA and inhibiting Hippo signaling pathway

Area of Science:

• Biochemistry
• Molecular Biology
• Orthopedics

Background:

• Osteoarthritis (OA) is a degenerative joint disease involving articular cartilage breakdown.
• The regulatory mechanisms maintaining articular cartilage homeostasis are not fully understood.

Purpose of the Study:

• To investigate the role of heterogeneous nuclear ribonucleoprotein K (hnRNPK) in maintaining articular cartilage homeostasis.
• To elucidate the molecular mechanisms by which hnRNPK influences OA development.

Main Methods:

• Analysis of hnRNPK expression in human and mouse OA cartilage.
• Generation of Hnrnpk-deficient mice to study OA progression.
• Investigation of the interaction between hnRNPK and WWC1 mRNA.
• Assessment of Hippo signaling pathway activation.
• Therapeutic interventions using intra-articular injections (LPA, AAV-WWC1-shRNA, AAV-hnRNPK).

Main Results:

• Hnrnpk expression is significantly reduced in OA cartilage.
• Hnrnpk deletion exacerbates both post-traumatic and age-dependent OA in mice.
• Hnrnpk directly binds and degrades WWC1 mRNA, suppressing its expression.
• Hnrnpk deficiency leads to increased WWC1, activating Hippo signaling and worsening OA.
• Intra-articular delivery of hnRNPK or WWC1 inhibition ameliorates OA phenotypes.

Conclusions:

• Hnrnpk plays a critical inhibitory role in OA pathogenesis.
• The mechanism involves hnRNPK-mediated suppression of WWC1 and subsequent Hippo signaling in chondrocytes.
• Hnrnpk represents a potential therapeutic target for OA prevention and treatment.