TY - JOUR
T1 - Calcineurin regulates bone formation by the osteoblast
AU - Sun, Li
AU - Blair, Harry C.
AU - Peng, Yuanzhen
AU - Zaidi, Neeha
AU - Adebanjo, Olugbenga A.
AU - Wu, Xue Bin
AU - Wu, Xing Yao
AU - Iqbal, Jameel
AU - Epstein, Solomon
AU - Abe, Etsuko
AU - Moonga, Baljit S.
AU - Zaidi, Mone
PY - 2005/11/22
Y1 - 2005/11/22
N2 - 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.
AB - 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.
KW - FK506
KW - Osteoporosis
KW - runx-2
UR - http://www.scopus.com/inward/record.url?scp=28044473838&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=28044473838&partnerID=8YFLogxK
U2 - 10.1073/pnas.0508480102
DO - 10.1073/pnas.0508480102
M3 - Article
C2 - 16286645
AN - SCOPUS:28044473838
SN - 0027-8424
VL - 102
SP - 17130
EP - 17135
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 47
ER -