Aromatase in adipose tissue exerts an osteoprotective function in male mice via phosphate regulation

Aromatase contributes to maintenance of bone mass because male patients with loss-of-function mutations of CYP19A1 exhibit bone loss. Treatment with aromatase inhibitor also causes bone loss in men and post-menopausal women, suggesting that part of the anabolic effect of testosterone in men is dependent on estradiol (E2) biosynthesized by aromatase in non-gonadal tissues. It remains unclear how locally biosynthesized E2 contributes to maintenance of bone mass. We examined the function of aromatase in local tissues rather than gonads using cell-type specific aromatase knockout (KO) mice. Because osteoblast-specific aromatase KO mice exhibited no bone phenotype, we focused on adipose tissue, known as a reservoir of steroid hormones and analyzed the bone phenotypes of adipose tissue-specific aromatase KO (Aro^ΔaP2) mice. Sixteen-week-old male Aro^ΔaP2 mice exhibited significantly lower bone mineral density in tibia and femur, especially in trabecular bone, than controls. Bone histomorphometry showed that Aro^ΔaP2 mice exhibited an insufficient calcification bone phenotype with increased osteoid volume and width, and decreased osteoclast area and numbers. Moreover, serum phosphate, renal phosphate reabsorption, and FGF23 were significantly lower in Aro^ΔaP2, suggesting that the insufficient calcification phenotype in Aro^ΔaP2 was not caused by excessive FGF23 activities. Finally, we analyzed NaPi2a and NaPi2c, phosphate transporters localized in the kidney and found that protein levels in renal brush border membrane vesicles were lower in Aro^ΔaP2. These results indicate that estrogens locally biosynthesized by aromatase in adipocytes can play a significant role in bone mass maintenance via regulation of phosphate reabsorption in the kidney by NaPi2.