Calcineurin/NFAT signaling in osteoblasts regulates bone mass.
Development and repair of the vertebrate skeleton requires the precise coordination of bone-forming osteoblasts and bone-resorbing osteoclasts. In diseases such as osteoporosis, bone resorption dominates over bone formation, suggesting a failure to harmonize osteoclast and osteoblast function. Here, we show that mice expressing a constitutively nuclear NFATc1 variant (NFATc1(nuc)) in osteoblasts develop high bone mass. NFATc1(nuc) mice have massive osteoblast overgrowth, enhanced osteoblast proliferation, and coordinated changes in the expression of Wnt signaling components. In contrast, viable NFATc1-deficient mice have defects in skull bone formation in addition to impaired osteoclast development. NFATc1(nuc) mice have increased osteoclastogenesis despite normal levels of RANKL and OPG, indicating that an additional NFAT-regulated mechanism influences osteoclastogenesis in vivo. Calcineurin/NFATc signaling in osteoblasts controls the expression of chemoattractants that attract monocytic osteoclast precursors, thereby coupling bone formation and bone resorption. Our results indicate that NFATc1 regulates bone mass by functioning in both osteoblasts and osteoclasts.
Winslow
Monte M
MM
Program in Immunology, Stanford University, Stanford, California 94305, USA.
Pan
Minggui
M
Starbuck
Michael
M
Gallo
Elena M
EM
Deng
Lei
L
Karsenty
Gerard
G
Crabtree
Gerald R
GR
D000818:Animals; D015519:Bone Density; D019703:Calcineurin / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction; D012886:Skull / Q000166:cytology
D050778:NFATC Transcription Factors; D019703:Calcineurin