Calcineurin regulates bone formation by the osteoblast

Li Sun, Harry C. Blair, Yuanzhen Peng, Neeha Zaidi, Olugbenga A. Adebanjo, Xue Bin Wu, Xing Yao Wu, Jameel Iqbal, Solomon Epstein, Etsuko Abe, Baljit S. Moonga, Mone Zaidi

Research output: Contribution to journalArticlepeer-review

Abstract

Two of the most commonly used immunosuppressants, cyclosporine A and tacrolimus (FK506), inhibit the activity of a ubiquitously expressed Ca 2+ /calmodulin-sensitive phosphatase, calcineurin. Because both drugs also cause profound bone loss in humans and in animal models, we explored whether calcineurin played a role in regulating skeletal remodeling. We found that osteoblasts contained mRNA and protein for all isoforms of calcineurin A and B. TAT-assisted transduction of fusion protein TAT-calcineurin Aα into osteoblasts resulted in the enhanced expression of the osteoblast differentiation markers Runx-2, alkaline phosphatase, bone sialoprotein, and osteocalcin. This expression was associated with a dramatic enhancement of bone formation in intact calvarial cultures. Calcineurin Aα-/- mice displayed severe osteoporosis, markedly reduced mineral apposition rates, and attenuated colony formation in 10-day ex vivo stromal cell cultures. The latter was associated with significant reductions in Runx2, bone sialoprotein, and osteocalcin expression, paralleled by similar decreases in response to FK506. Together, the gain- and loss-of-function experiments indicate that calcineurin regulates bone formation through an effect on osteoblast differentiation.

Original languageEnglish (US)
Pages (from-to)17130-17135
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number47
DOIs
StatePublished - Nov 22 2005
Externally publishedYes

Keywords

  • FK506
  • Osteoporosis
  • runx-2

ASJC Scopus subject areas

  • General

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