HDAC9 inhibits osteoclastogenesis via mutual suppression of PPARγ/RANKL signaling

Zixue Jin, Wei Wei, HoangDinh Huynh, Yihong Wan

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Recent studies suggest that the class II histone deacetylase (HDAC)9 plays important roles in physiology such as metabolism and immunity. Here, we report that HDAC9 also controls bone turnover by suppressing osteoclast differentiation and bone resorption. HDAC9 expression is down-regulated during osteoclastogenesis. Ex vivo osteoclast differentiation is accelerated by HDAC9 deletion but diminished by HDAC9 overexpression. HDAC9 knockout mice exhibit elevated bone resorption and lower bone mass. Bone marrow transplantation reveal that the osteoclastogenic defects are intrinsic to the hematopoietic lineage, because the excessive bone resorption phenotype can be conferred in wild-type (WT) mice receiving HDAC9-null bone marrow, and rescued in HDAC9-null mice receiving WT bone marrow. Mechanistically, HDAC9 forms a negative regulatory loop with peroxisome proliferator-activated receptor gamma (PPARg) and receptor activator of nuclear factor kappa-B ligand (RANKL) signaling. On one hand, PPARγ and nuclear factor κB suppress HDAC9 expression, on the other hand, HDAC9 inhibits PPARγ activity in synergy with silencing mediator of retinoic acid and thyroid hormone receptors (SMRT)/NCoR corepressors. These findings identify HDAC9 as a novel, important and physiologically relevant modulator of bone remodeling and skeletal homeostasis.

Original languageEnglish (US)
Pages (from-to)730-738
Number of pages9
JournalMolecular Endocrinology
Volume29
Issue number5
DOIs
StatePublished - 2015

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RANK Ligand
Peroxisome Proliferator-Activated Receptors
Nuclear Receptor Co-Repressor 2
Bone Resorption
Osteogenesis
Bone Remodeling
Osteoclasts
Bone Marrow
Histone Deacetylases
PPAR gamma
Bone Marrow Transplantation
Knockout Mice
Immunity
Homeostasis
Phenotype
Bone and Bones

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

HDAC9 inhibits osteoclastogenesis via mutual suppression of PPARγ/RANKL signaling. / Jin, Zixue; Wei, Wei; Huynh, HoangDinh; Wan, Yihong.

In: Molecular Endocrinology, Vol. 29, No. 5, 2015, p. 730-738.

Research output: Contribution to journalArticle

Jin, Zixue ; Wei, Wei ; Huynh, HoangDinh ; Wan, Yihong. / HDAC9 inhibits osteoclastogenesis via mutual suppression of PPARγ/RANKL signaling. In: Molecular Endocrinology. 2015 ; Vol. 29, No. 5. pp. 730-738.
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