Decreased bone resorption in Ezh2 myeloid cell conditional knockout mouse model

Caviness, Perry C.; Gai, Dongzheng; Lazarenko, Oxana P.; Blackburn, Michael L.; Zhan, Fenghuang; Chen, Jin‐Ran

doi:10.1096/fj.202201673rr

Cited by 4 publications

(1 citation statement)

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“…15 EZH2 deletion in mature macrophages increases bone volume in vivo. 16 As G9a is involved in the differentiation of the hematopoietic lineage including osteoclast progenitor cells, we hypothesized that G9a plays a pivotal role during osteoclastic differentiation. To explore its role, we first examined the effects of G9a deletion on the in vitro osteoclastic differentiation of bone marrow macrophages (BMMs) isolated from G9a fl/fl mice.…”

Section: Introductionmentioning

confidence: 99%

The G9a histone methyltransferase represses osteoclastogenesis and bone resorption by regulating NFATc1 function

Komatsu,

Ideno,

Nakashima

et al. 2024

The FASEB Journal

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Epigenetic modifications affect cell differentiation via transcriptional regulation. G9a/EHMT2 is an important epigenetic modifier that catalyzes the methylation of histone 3 lysine 9 (H3K9) and interacts with various nuclear proteins. In this study, we investigated the role of G9a in osteoclast differentiation. When we deleted G9a by infection of Cre‐expressing adenovirus into bone marrow macrophages (BMMs) from G9afl/fl (Ehmt2fl/fl) and induced osteoclastic differentiation by the addition of macrophage colony‐stimulating factor (M‐CSF) and receptor activator of NF‐κB ligand (RANKL), the number of TRAP‐positive multinucleated osteoclasts significantly increased compared with control. Furthermore, the mRNA expression of osteoclast markers, TRAP, and cathepsin K, and to a lesser extent, NFATc1, a critical transcription factor, increased in G9a KO cells. Infection of wild‐type (WT) G9a‐expressing adenovirus in G9a KO cells restored the number of TRAP‐positive multinucleated cells. In G9a KO cells, increased nuclear accumulation of NFATc1 protein and decreased H3K9me2 accumulation were observed. Furthermore, ChIP experiments revealed that NFATc1 binding to its target, Ctsk promoter, was enhanced by G9a deletion. For in vivo experiments, we created G9a conditional knock‐out (cKO) mice by crossing G9afl/fl mice with Rank Cre/+ (Tnfrsf11aCre/+) mice, in which G9a is deleted in osteoclast lineage cells. The trabecular bone volume was significantly reduced in female G9a cKO mice. The serum concentration of the C‐terminal telopeptide of type I collagen (CTX), a bone‐resorbing indicator, was higher in G9a cKO mice. In addition, osteoclasts differentiated from G9a cKO BMMs exhibited greater bone‐resorbing activity. Our findings suggest that G9a plays a repressive role in osteoclastogenesis by modulating NFATc1 function.

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Section: Introductionmentioning

confidence: 99%