Adipocytes regulate fibroblast function, and their loss contributes to fibroblast dysfunction in inflammatory...

Area of Science:

• Biochemistry
• Cell Biology
• Immunology

Background:

• Synovial fibroblasts maintain joint homeostasis but can drive pathology in disease states.
• The regulation of healthy synovial fibroblast function remains poorly understood.

Approach:

• RNA sequencing of healthy human synovial tissue identified a lipid metabolism and transport gene signature in fibroblasts.
• Fat-conditioned media and mass spectrometry identified cortisol as a key regulator.
• Experiments with glucocorticoid receptor gene-deleted cells and mouse models lacking synovial adipocytes confirmed these findings.

Key Points:

• Healthy synovial fibroblasts exhibit enhanced fatty acid metabolism and lipid transport.
• Cortisol, produced by synovial adipocytes via Hsd11β1, drives this healthy fibroblast phenotype.
• Cortisol signaling protects against matrix remodeling induced by TNFα and TGFβ.

Conclusions:

• Adipocytes and cortisol signaling are essential for maintaining the healthy synovial fibroblast state.
• Disease states involve the loss of this protective signaling, with cytokines repressing cortisol signaling and adipogenesis.