Expression of Renal Vitamin D and Phosphatonin-Related Genes in a Sheep Model of Osteoporosis

SIMPLE SUMMARY: Osteoporosis is a significant public health issue around the world, with post-menopausal osteoporosis due to estrogen deficiency resulting in approximately ¾ of cases. Treatment with glucocorticoids is another common cause of osteoporosis in humans. Sheep are a well-established model for osteoporosis in humans. In this study, aged sheep had their ovaries removed (ovariectomy) to simulate estrogen deficiency, and some sheep were also treated with glucocorticoids. The results showed that expression of the gene klotho in the kidney had the most marked difference in ovariectomized sheep treated with glucocorticoids for 2 months followed by a recovery period of 3 months. Klotho is known as the “anti-aging” hormone and is an important regulator of calcium and phosphorus metabolism. It may therefore be involved in the recovery of bone mineral density seen in ovariectomized sheep treated with glucocorticoids for 2 months followed by euthanasia at 5 months. As such, it could be an important treatment target for osteoporosis in humans. ABSTRACT: Osteoporosis is a significant public health issue around the world, with post-menopausal osteoporosis due to estrogen deficiency resulting in approximately ¾ of cases. In this study, 18 aged Merino ewes were ovariectomized, and 10 were controls. Three of the ovariectomized ewes were treated weekly with 400 mg of methylprednisolone for 5 months and three were treated weekly for 2 months, followed by a 3-month recovery period. At 2 months, five control animals and six ovariectomized animals were euthanized. At 5 months, all the remaining ewes were euthanized. Kidney samples were collected postmortem for qPCR analysis of NPT1, PTH1R, NPT2a, NPT2c, Klotho, FGFR1IIIc, VDR, CYP24A1, CYP27B1, TRPV5, TRPV6, CalD9k, CalD28k, PMCA and NCX1. Ovariectomized sheep had significantly greater VDR expression compared with other groups. Ovariectomized sheep treated with glucocorticoids for 2 months followed by euthanasia at 5 months showed significant differences in TRPV5, CYP24A1 and klotho gene expression compared to other groups. Differences in klotho expression were most marked after adjustment for repeated measures (p = 0.1). Klotho is known as the “anti-aging” hormone and is involved in calcium and phosphorus metabolism. Klotho may be involved in the recovery of bone mineral density in ovariectomized sheep treated with glucocorticoids for 2 months followed by euthanasia at 5 months. Further research on the role of klotho is recommended.