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

BACKGROUND: Vascular calcification and osteoporosis often co-occur during postmenopause, end-stage renal disease, advancing age, and diabetes, leading to increased mortality and significant challenges in therapy. FAM19A5 (family with sequence similarity 19 [chemokine (C-C motif)-like], member A5), as a novel protective adipokine, has been identified to suppress postinjury neointima formation. However, the involvement of adipose-derived FAM19A5 in vascular calcification and osteoporosis remains unclear. METHODS: A cross-sectional study was conducted to assess the relationship among circulating FAM19A5, coronary artery calcification, and osteoporosis. Adipose-specific FAM19A5 transgenic mice and AAV8 (adeno-associated virus serum type 8)-adipo-shFAM19A5 were employed to study gain or loss of function of FAM19A5 in 2 distinct mouse models: ovariectomy followed by Vitamin D3 overload (OVX-VitD3) and adenine diet. Calcium assays, micro-CT, Western blot, RT-qPCR, luciferase reporter assays, and ChIP-qPCR were performed to clarify the phenotype and elucidate the molecular mechanisms. Finally, administration of AAV8-adipoq-FAM19A5 and S1PR2 (sphingosine 1-phosphate receptor 2) global knockout mice was used to investigate their therapeutic effects. RESULTS: Circulating FAM19A5 was negatively correlated with coronary artery calcification and osteoporosis in patients and mouse models. Adipose-specific FAM19A5 transgenic mice exhibited milder aortic calcification and preserved bone mass via S1PR2 in both OVX-VitD3 and adenine diet models. Although adipose-specific knockdown of FAM19A5 aggravates aortic calcification and bone mass loss. Interestingly, FAM19A5 mitigated vascular smooth muscle cells' calcification by activating S1PR2-Gi-PKA signaling and promoted mice osteoblasts differentiation by triggering S1PR2-Gq-PKCδ (protein kinase C delta isoform) signaling. Finally, administration of AAV8-adipoq-FAM19A5 effectively rescued vascular calcification and osteoporosis, but exerted no beneficial effects in S1PR2 knockout mice. CONCLUSIONS: Adipose-derived FAM19A5 plays an essential role in orchestrating vascular calcification and osteoporosis through the selective activation of S1PR2. Our findings provide novel insight into the previously unexplored role of adipose tissue in maintaining vascular-bone homeostasis. FAM19A5-S1PR2 may be considered as a potential therapeutic strategy for vascular calcification and osteoporosis.