Role of Klotho in Osteoporosis and Renal Osteodystrophy
Annual rept. 30 Sep 2013-29 Sep 2014
PRESIDENT AND FELLOWS OF HARVARD COLL CAMBRIDGE MA OFFICE OF SPONSORED RESEARCH
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The most significant findings to date are from mice with Klotho ablated specifically from long bones. First, we found that loss of Klotho in bone disrupts normal bone development. Histological analyses showed that bones of 6-week old Prx1creKlothoflfl mice have normal cortical bone but scarce trabeculae relative to controls. In particular, male Prx1creKlothoflfl mice had reduced bone volumetotal volume. The loss was more pronounced at 6 than 24 weeks. This effect was confirmed by in vitro analysis with isolated primary osteoblasts treated to delete Klotho that exhibited a defect in bone mineralization. Moreover, male Prx1creKlothoflfl mice have significantly higher expression of all bone formation markers analyzed than controls. Second, we found that bone morphology in mice with induced CKD was more affected in mice without Klotho expression in long bones. The phenotypic changes in the skeleton of CKD mice were consistent with ricketsosteomalacia, but the long bones of Prx1creKlothoflfl mice with CKD were significantly more compromised than those of controls. Also, CKD Prx1creKlothoflfl mice did not exhibit the expected increase in bone formation markers that was observed in CKD control mice. The results provide new insight into the limb specific role of Klotho.
- Medicine and Medical Research