Skeletal Actions of Fasting-Induced Adipose Factor (FIAF)

Several adipokines are known to influence skeletal metabolism. Fasting-induced adipose factor (FIAF) is an adipokine that gives rise to 2 further peptides in vivo, the N-terminal coiled-coil domain (FIAF(CCD)) and C-terminal fibrinogen-like domain (FIAF(FLD)). The skeletal action of these peptides is still uncertain. Our results show that FIAF(CCD) is a potent inhibitor of osteoclastogenesis and function, as seen in mouse bone marrow and RAW(264.7) cell cultures, and in a resorption assay using isolated primary mature osteoclasts. The inhibitory effects at 500 ng/mL were approximately 90%, 50% and 90%, respectively, in these assays. FIAF(CCD) also stimulated osteoblast mitogenesis by approximately 30% at this concentration. In comparison, FIAF(FLD) was only active in decreasing osteoblast mitogenesis, and intact FIAF had no effect in any of these assays. In murine bone marrow cultures, FIAF(CCD) reduced the expression of macrophage colony-stimulating factor (M-CSF), nuclear factor of activated T-cells c1 (NFATc1) and dendritic cell-specific transmembrane protein (DC-STAMP), and to lesser extent suppressed the expression of connective tissue growth factor (CTGF). FIAF(CCD) also decreased expression of M-CSF and CTGF in stromal/osteoblastic ST2 cells. Its effect on receptor activator of nuclear factor kappa B (RANKL) and osteoprotegerin expression in bone marrow was not consistent with its inhibitory action on osteoclastogenesis, but it decreased RANKL expression in ST2 cells. In RAW(264.7) cell cultures, FIAF(CCD) significantly reduced the expression of NFATc1 and DC-STAMP. In conclusion, FIAF(CCD) inhibits osteoclast differentiation and function in vitro and decreases expression of genes encoding key osteoclastogenic factors such as M-CSF, CTGF, NFATc1, and DC-STAMP. FIAF(CCD)'s action on osteoclasts may be independent of the RANKL/osteoprotegerin pathway. These results suggest a novel mechanism by which adipose tissue may regulate bone resorption and skeletal health.