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

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

Research output: Contribution to journalArticle

161 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3775-3789
Number of pages15
JournalJournal of Clinical Investigation
Volume118
Issue number11
DOIs
StatePublished - Nov 3 2008
Externally publishedYes

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Cherubism
NFATC Transcription Factors
Osteoprotegerin
Metabolic Bone Diseases
Osteoclasts
Bone Resorption
Osteogenesis
Osteoporosis
Inflammation
Bone Density Conservation Agents
Cytokines
Osteopetrosis
Bone Matrix
src Homology Domains
Osteoblasts
Transcriptome
Skeleton
Carrier Proteins
Transcription Factors
Gene Expression

ASJC Scopus subject areas

  • Medicine(all)

Cite this

NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. / Aliprantis, Antonios O.; Ueki, Yasuyoshi; Sulyanto, Rosalyn; Park, Arnold; Sigrist, Kirsten S.; Sharma, Sudarshana M.; Ostrowski, Michael C.; Olsen, Bjorn R.; Glimcher, Laurie H.

In: Journal of Clinical Investigation, Vol. 118, No. 11, 03.11.2008, p. 3775-3789.

Research output: Contribution to journalArticle

Aliprantis, AO, Ueki, Y, Sulyanto, R, Park, A, Sigrist, KS, Sharma, SM, Ostrowski, MC, Olsen, BR & Glimcher, LH 2008, 'NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism', Journal of Clinical Investigation, vol. 118, no. 11, pp. 3775-3789. https://doi.org/10.1172/JCI35711
Aliprantis, Antonios O. ; Ueki, Yasuyoshi ; Sulyanto, Rosalyn ; Park, Arnold ; Sigrist, Kirsten S. ; Sharma, Sudarshana M. ; Ostrowski, Michael C. ; Olsen, Bjorn R. ; Glimcher, Laurie H. / NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 11. pp. 3775-3789.
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