Aromatase in adipose tissue exerts osteoprotective function in male mice via phosphorus regulation

Aromatase contributes to the maintenance of bone mass because male patients with loss-of-function mutations of CYP19A1 exhibit bone loss. Furthermore, treatment with aromatase inhibitor also causes bone loss in men as well as post-menopausal women, in whom serum estrogen level is very low, suggesting that a part of the anabolic effects of testosterone in men is dependent on estradiol (E2) biosynthesized by aromatase in non-gonadal tissues. However, it remains unclear how locally biosynthesized E2 contributes to the maintenance of bone mass. We examined the function of aromatase in local tissues rather than gonad using cell type specific aromatase KO mice. Because osteoblast-specific aromatase KO mice exhibited no bone phenotype, we focused on adipose tissue, which is known as reservoir of steroid hormones, and analyzed the bone phenotypes of adipose tissue-specific aromatase KO mice (AroΔaP2). Sixteen-week-old male AroΔaP2 mice exhibit significantly lower bone mineral density in tibia and femur, especially in trabecular bone compared to the control. Bone histomorphometry showed that AroΔaP2 mice exhibited an osteomalacia-like bone phenotype with increased osteoid volume and width, and decreased osteoclast area and numbers. Moreover, serum PI and renal phosphorus reabsorption were significantly decreased but FGF23 level was decreased in AroΔaP2, suggesting that an osteomalacia-like phenotype in AroΔaP2 was not caused by abnormal FGF23 level. Finally, we analyzed NaPi2a and NaPi2c, a phosphate transporter localized in the kidney, and found that protein levels in renal brush border membrane vesicles were decreased in AroΔaP2. These results indicate that locally biosynthesized estrogens by aromatase in adipocytes can play a significant role in bone mass maintenance via regulate phosphorus reabsorption in kidney by NaPi2.