Klotho expression in osteocytes regulates bone metabolism and controls bone formation

Hirotaka Komaba, Jovana Kaludjerovic, Dorothy Z. Hu, Kenichi Nagano, Katsuhiko Amano, Noriko Ide, Tadatoshi Sato, Michael J. Densmore, Jun ichi Hanai, Hannes Olauson, Teresita Bellido, Tobias E. Larsson, Roland Baron, Beate Lanske

Research output: Contribution to journalArticlepeer-review

61 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)599-611
Number of pages13
JournalKidney International
Volume92
Issue number3
DOIs
Publication statusPublished - Sep 2017
Externally publishedYes

Keywords

  • bone
  • FGF23
  • hyperparathyroidism

ASJC Scopus subject areas

  • Nephrology

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