TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis

Area of Science:

• Biochemistry
• Immunology
• Orthopedics

Background:

• The mechanisms driving the transition from joint homeostasis to osteoarthritis (OA) are not fully understood.
• Joint development and maintenance rely on complex signaling pathways.
• Osteoarthritis is a prevalent degenerative joint disease with significant unmet medical needs.

Purpose of the Study:

• To elucidate the role of transforming growth factor beta (TGF-β) signaling in joint homeostasis and osteoarthritis.
• To identify potential therapeutic targets for osteoarthritis.
• To investigate the function of the IL-36 cytokine family in joint health and disease.

Main Methods:

• Utilized transgenic mouse models with tissue-specific gene ablation.
• Employed pharmacological inhibition of TGF-β signaling.
• Conducted surgical induction of post-traumatic osteoarthritis in mice.
• Analyzed human cartilage tissues from OA patients.
• Investigated the effects of IL-36 receptor antagonist (IL-36Ra/IL-36RN) in vitro and in vivo.

Main Results:

• TGF-β signaling promotes joint homeostasis via regulation of the IL-36 family.
• Osteoarthritis development correlated with altered expression of IL-36 family members (IL-36α up-regulation, IL-36Ra/IL-36RN down-regulation) in various mouse OA models.
• Human OA cartilage showed decreased TGFBR2 and IL-36RN expression, with increased IL-36α.
• Intra-articular IL-36Ra administration attenuated OA progression in mice.
• IL-36RN treatment reduced matrix metalloproteinase 13 (MMP13) expression in human OA chondrocytes.

Conclusions:

• The interplay between TGFBR2 and the IL-36 family is crucial for maintaining joint homeostasis.
• IL-36RN demonstrates therapeutic potential as a disease-modifying osteoarthritis drug.
• Targeting the TGF-β/IL-36 axis offers a promising strategy for OA treatment.