Open AccessNegative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1
Author(s) -
Shinya Nakamura,
Takuma Koyama,
Naohiro Izawa,
Seitaro Nomura,
Takanori Fujita,
Yasunori Omata,
Takashi Minami,
Morio Matsumoto,
Masaya Nakamura,
Eriko Fujita-Jimbo,
Takashi Momoi,
Takeshi Miyamoto,
Hiroyuki Aburatani,
Sakae Tanaka
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0175632
Subject(s) - h3k4me3 , histone h3 , rankl , microbiology and biotechnology , osteoclast , histone , chromatin immunoprecipitation , biology , bone resorption , chemistry , cancer research , gene expression , activator (genetics) , receptor , endocrinology , biochemistry , gene , promoter
Trimethylation of histone H3 lysine 4 and lysine 27 (H3K4me3 and H3K27me3) at gene promoter regions critically regulates gene expression. Key developmental genes tend to exhibit changes in histone modification patterns from the H3K4me3/H3K27me3 bivalent pattern to the H3K4me3 monovalent pattern. Using comprehensive chromatin immunoprecipitation followed by sequencing in bone marrow-derived macrophages (BMMs) and mature osteoclasts, we found that cell surface adhesion molecule 1 (Cadm1) is a direct target of nuclear factor of activated T cells 1 (NFATc1) and exhibits a bivalent histone pattern in BMMs and a monovalent pattern in osteoclasts. Cadm1 expression was upregulated in BMMs by receptor activator of nuclear factor kappa B ligand (RANKL), and blocked by a calcineurin/NFATc1 inhibitor, FK506. Cadm1 -deficient mice exhibited significantly reduced bone mass compared with wild-type mice, which was due to the increased osteoclast differentiation, survival and bone-resorbing activity in Cadm1 -deficient osteoclasts. These results suggest that Cadm1 is a direct target of NFATc1, which is induced by RANKL through epigenetic modification, and regulates osteoclastic bone resorption in a negative feedback manner.