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NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism
Antonios O. Aliprantis, … , Bjorn R. Olsen, Laurie H. Glimcher
Antonios O. Aliprantis, … , Bjorn R. Olsen, Laurie H. Glimcher
Published October 9, 2008
Citation Information: J Clin Invest. 2008;118(11):3775-3789. https://doi.org/10.1172/JCI35711.
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Research Article Bone Biology

NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism

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Abstract

Osteoporosis results from an imbalance in skeletal remodeling that favors bone resorption over bone formation. Bone matrix is degraded by osteoclasts, which differentiate from myeloid precursors in response to the cytokine RANKL. To gain insight into the transcriptional regulation of bone resorption during growth and disease, we generated a conditional knockout of the transcription factor nuclear factor of activated T cells c1 (Nfatc1). Deletion of Nfatc1 in young mice resulted in osteopetrosis and inhibition of osteoclastogenesis in vivo and in vitro. Transcriptional profiling revealed NFATc1 as a master regulator of the osteoclast transcriptome, promoting the expression of numerous genes needed for bone resorption. In addition, NFATc1 directly repressed osteoclast progenitor expression of osteoprotegerin, a decoy receptor for RANKL previously thought to be an osteoblast-derived inhibitor of bone resorption. “Cherubism mice”, which carry a gain-of-function mutation in SH3-domain binding protein 2 (Sh3bp2), develop osteoporosis and widespread inflammation dependent on the proinflammatory cytokine, TNF-α. Interestingly, deletion of Nfatc1 protected cherubism mice from systemic bone loss but did not inhibit inflammation. Taken together, our study demonstrates that NFATc1 is required for remodeling of the growing and adult skeleton and suggests that NFATc1 may be an effective therapeutic target for osteoporosis associated with inflammatory states.

Authors

Antonios O. Aliprantis, Yasuyoshi Ueki, Rosalyn Sulyanto, Arnold Park, Kirsten S. Sigrist, Sudarshana M. Sharma, Michael C. Ostrowski, Bjorn R. Olsen, Laurie H. Glimcher

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Figure 6

NFATc1 uncouples bone loss from inflammation in a mouse model of cherubism.

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NFATc1 uncouples bone loss from inflammation in a mouse model of cherubi...
(A) Anteroposterior digital radiograph of the femurs and tibias of 12-week-old female mice. White arrow denotes cystic changes at the distal tibia of Nfatc1fl/flKI/KI mice. Two other Nfatc1Δ/ΔKI/KI mice (1 mouse each at 12 and 17 weeks old) had a similar radiographic appearance to the Nfatc1Δ/ΔKI/KI sample displayed. (B) H&E stain of the liver and (C) lung of 12-week-old female mice. Black arrows in B and C indicate examples of inflammatory infiltrates. The original magnifications used to obtain the images are indicated above each column. The organ histology of Nfatc1fl/flKI/KI mice was identical to that previously described for mice bearing 2 KI alleles (3). A second Nfatc1Δ/ΔKI/KI mouse had similar histology to the Nfatc1Δ/ΔKI/KI sample displayed. (D) qRT-PCR analysis for the expression of Tnf mRNA in BM cells cultured for 5 days with 50 ng/ml M-CSF.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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