Journal
KIDNEY INTERNATIONAL
Volume 92, Issue 3, Pages 599-611Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.kint.2017.02.014
Keywords
bone; FGF23; hyperparathyroidism
Categories
Funding
- Department of Defense [PR120411]
- NIH [R01DK097105, R01AR059357, R01AT008754]
- JSPS Postdoctoral Fellowships for Research Abroad
- Kanae Foundation for the Promotion of Medical Science
- Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship
- Uehara Memorial Foundation
- Veterans Administration [BX002104]
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Osteocytes within the mineralized bone matrix control bone remodeling by regulating osteoblast and osteoclast activity. Osteocytes express the aging suppressor Klotho, but the functional role of this protein in skeletal homeostasis is unknown. Here we identify Klotho expression in osteocytes as a potent regulator of bone formation and bone mass. Targeted deletion of Klotho from osteocytes led to a striking increase in bone formation and bone volume coupled with enhanced osteoblast activity, in sharp contrast to what is observed in Klotho hypomorphic (kl/kl) mice. Conversely, overexpression of Klotho in cultured osteoblastic cells inhibited mineralization and osteogenic activity during osteocyte differentiation. Further, the induction of chronic kidney disease with high-turnover renal osteodystrophy led to downregulation of Klotho in bone cells. This appeared to offset the skeletal impact of osteocyte-targeted Klotho deletion. Thus, our findings establish a key role of osteocyte-expressed Klotho in regulating bone metabolism and indicate a new mechanism by which osteocytes control bone formation.
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