Autoamplification of NFATc1 expression determines its essential role in bone homeostasis

被引：711

作者：

Asagiri, M

Sato, K

Usami, T

Ochi, S

Nishina, H

Yoshida, H

Morita, I

Wagner, EF

Mak, TW

Serfling, E

Takayanagi, H ^{[1
]}

机构：

[1] Tokyo Med & Dent Univ, Dept Cell Signaling, Tokyo 1138549, Japan

[2] Tokyo Med & Dent Univ, Dept Med & Rheumatol, Tokyo 1138549, Japan

[3] Tokyo Med & Dent Univ, Grad Sch, Dept Cellular Physiol Chem, Tokyo 1138549, Japan

[4] Tokyo Med & Dent Univ, Ctr Excellence Program Frontier Res Mol Destruct, Tokyo 1138549, Japan

[5] Japan Sci & Technol Agcy, Solut Oriented Res Sci & Technol, Kawaguchi, Saitama 3320012, Japan

[6] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol, Kawaguchi, Saitama 3320012, Japan

[7] Tokyo Med & Dent Univ, Med Res Inst, Lab Recombinant Anim, Tokyo 1010062, Japan

[8] Tokyo Med & Dent Univ, Med Res Inst, Dept Dev & Regenerat Biol, Tokyo 1010062, Japan

[9] Saga Univ, Fac Med, Dept Biomol Sci, Saga, Saga 8498501, Japan

[10] Res Inst Mol Pathol, A-1030 Vienna, Austria

[11] Princess Margaret Hosp, Ontario Canc Inst, Toronto, ON M5G 2M9, Canada

[12] Univ Toronto, Adv Med Discovery Inst, Dept Med Biophys, Toronto, ON M5G 2C1, Canada

[13] Univ Wurzburg, Inst Pathol, Dept Mol Pathol, D-97080 Wurzburg, Germany

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2005年 / 202卷 / 09期

关键词：

D O I：

10.1084/jem.20051150

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

NFATc1 and NFATc2 are functionally redundant in the immune system, but it was suggested that NFATc1 is required exclusively for differentiation of osteoclasts in the skeletal system. Here we provide genetic evidence that NFATc1 is essential for osteoclast differentiation in vivo by adoptive transfer of NFATc1(-/-) hematopoietic stem cells to osteoclast-deficient Fos(-/-) mice, and by Fos(-/-) blastocyst complementation, thus avoiding the embryonic lethality of NFATc1(-/-) mice. However, in vitro osteoclastogenesis in NFATc1-deficient cells was rescued by ectopic expression of NFATc2. The discrepancy between the in vivo essential role of NFATc1 and the in vitro effect of NFATc2 was attributed to selective autoregulation of the NFATc1 gene by NFAT through its promoter region. This suggested that an epigenetic mechanism contributes to the essential function of NFATc1 in cell lineage commitment. Thus, this study establishes that NFATc1 represents a potential therapeutic target for bone disease and reveals a mechanism that underlies the essential role of NFATc1 in bone homeostasis.

引用

页码：1261 / 1269

页数：9

共 34 条

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