Adipose-Derived FAM19A5 Inhibits Both Vascular Calcification and Osteoporosis in Mice

Area of Science:

• Biomedical research
• Endocrinology
• Vascular biology

Background:

• Vascular calcification and osteoporosis frequently co-occur, increasing mortality.
• FAM19A5 (family with sequence similarity 19, member A5) is a novel protective adipokine.
• The role of adipose-derived FAM19A5 in vascular calcification and osteoporosis is not well understood.

Purpose of the Study:

• To investigate the relationship between circulating FAM19A5, coronary artery calcification, and osteoporosis.
• To elucidate the molecular mechanisms by which FAM19A5 influences vascular calcification and bone health.
• To explore the therapeutic potential of FAM19A5 for vascular calcification and osteoporosis.

Main Methods:

• Cross-sectional study in patients and mouse models.
• Gain and loss-of-function studies using adipose-specific FAM19A5 transgenic mice and AAV8-adipo-shFAM19A5.
• In vivo models: ovariectomy followed by Vitamin D3 overload (OVX-VitD3) and adenine diet.
• Molecular analyses: calcium assays, micro-CT, Western blot, RT-qPCR, luciferase reporter assays, ChIP-qPCR.
• Therapeutic evaluation using AAV8-adipoq-FAM19A5 and S1PR2 global knockout mice.

Main Results:

• Circulating FAM19A5 showed a negative correlation with coronary artery calcification and osteoporosis.
• FAM19A5 transgenic mice exhibited reduced aortic calcification and preserved bone mass.
• FAM19A5 knockdown exacerbated vascular calcification and bone loss.
• FAM19A5 mitigated vascular calcification via S1PR2-Gi-PKA signaling and promoted osteoblast differentiation via S1PR2-Gq-PKCδ signaling.
• AAV8-adipoq-FAM19A5 administration rescued vascular calcification and osteoporosis in a S1PR2-dependent manner.

Conclusions:

• Adipose-derived FAM19A5 is crucial for maintaining vascular-bone homeostasis.
• FAM19A5 orchestrates vascular calcification and osteoporosis through selective S1PR2 activation.
• The FAM19A5-S1PR2 axis represents a promising therapeutic target for vascular calcification and osteoporosis.