Adipose-derived leptin and complement factor D mediate osteoarthritis severity and pain

Area of Science:

• Biomedical research
• Metabolic disease research
• Skeletal biology

Background:

• Obesity is a known risk factor for osteoarthritis (OA).
• Adipokines, such as leptin, are implicated in obesity-related OA, but their precise role remains unclear.
• Understanding the mechanisms linking adipose tissue to OA is crucial for developing targeted therapies.

Purpose of the Study:

• To investigate the role of leptin and other fat-secreted factors in the development and severity of knee osteoarthritis (OA).
• To elucidate the communication pathways between adipose tissue and cartilage in OA pathogenesis.
• To establish whether OA can be considered a systemic disease of adipose tissue.

Main Methods:

• Utilized lipodystrophic (LD) mice lacking fat-secreted factors to study OA development.
• Performed fat pad implantation and systemic leptin restoration experiments in LD mice.
• Employed isochronic parabiosis and spatial transcriptomics to analyze fat-joint cross-talk.
• Conducted multiomics analysis of conditioned media from fat implants.

Main Results:

• Fat-secreted factors are essential for knee OA development, indicating a fat-cartilage cross-talk.
• Systemic leptin restoration or implantation of leptin-sufficient fat pads in LD mice led to structural OA and pain.
• Leptin influences adipsin (complement factor D) activity, modulating OA structural and pain phenotypes.
• Evidence supports a role for soluble mediators in the fat-joint communication.

Conclusions:

• Adipokines, particularly leptin, play a significant role in osteoarthritis pathogenesis.
• This study provides conclusive evidence of a fat-joint cross-talk.
• Osteoarthritis should be recognized as a systemic disease linked to adipose tissue dysfunction.