Cellular and molecular consequences of calcineurin A alpha gene deletion.
Here we briefly review our studies that have unraveled an important role for the calcium- and calmodulin-sensitive enzyme calcineurin (CN) in bone remodeling. We find that the genetic deletion of the calcineurin Aalpha isoform results in osteoporosis, which is recapitulated in humans following calcineurin inhibitor therapy widely used after solid organ transplantation. Mechanistically, however, while both calcineurin inhibitors cyclosporine and tacrolimus initially stimulate osteoclastic bone resorption in humans, the predominant feature in the CNAalpha null mouse is a profound reduction in bone formation. We speculate that the so-called "calcineurin inhibitors" may interact with molecules other than calcineurin. The clinical relevance of these observations is explored.
Sun
Li
L
Mount Sinai Bone Program and Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA. li.sun@mssm.edu
Zhu
Ling-Ling
LL
Zaidi
Neeha
N
Yang
Guozhe
G
Moonga
Baljit S
BS
Abe
Etsuko
E
Iqbal
Jameel
J
Epstein
Solomon
S
Blair
Harry C
HC
Huang
Christopher L-H
CL
Zaidi
Mone
M
D016723:Bone Remodeling; D019703:Calcineurin / Q000235:genetics* / Q000378:metabolism; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D017353:Gene Deletion; D006720:Homozygote; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D010006:Osteoblasts / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin; C525673:PPP3CA protein, human; D016559:Tacrolimus