Hippo Signaling Modulates the Inflammatory Response of Chondrocytes to Mechanical Compressive Loading

Area of Science:

• Biomedical Engineering
• Cell Biology
• Molecular Biology

Background:

• Knee osteoarthritis (KOA) pathogenesis involves chondrocyte inflammation and extracellular matrix degradation due to mechanical overload.
• Signaling pathways sensing mechanical stress in KOA remain incompletely understood, limiting therapeutic development.
• The Hippo signaling pathway is increasingly recognized for its role in sensing mechanical cues and its potential involvement in osteoarthritis.

Approach:

• Investigated the role of Hippo signaling in chondrocyte mechanotransduction.
• Applied mechanical compressional force to 3D-cultured chondrocytes to mimic KOA conditions.
• Utilized genetic manipulation (YAP, LATS1/2 knockout) and pharmacological inhibitors (LATS1/2, PKC inhibitors) to dissect signaling pathways.

Key Points:

• Mechanical loading activates NFκB-mediated inflammation and matrix degradation (IL1β, ADAMTS4) in chondrocytes.
• This mechanoresponse is dependent on the Hippo pathway, specifically involving YAP and LATS1/2.
• Protein Kinase C (PKC) activation by mechanical loading is upstream of NFκB p65 phosphorylation, and this process is regulated by the Hippo pathway.

Conclusions:

• The Hippo signaling pathway and PKC interplay to regulate NFκB-mediated chondrocyte responses to mechanical loading.
• Targeting Hippo signaling or PKC presents a promising therapeutic strategy for knee osteoarthritis by mitigating inflammation and matrix degradation.