HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered β-catenin switch

Zixue Jin, Wei Wei, Paul C. Dechow, Yihong Wan

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The bone-resorbing osteoclast is essential for skeletal remodeling, yet its deregulation contributes to diseases such as osteoporosis and cancer bone metastasis. Here we identify histone deacetylase 7 (HDAC7) as a key negative regulator of osteoclastogenesis and bone resorption using both in vitro cellular and molecular analyses and in vivo characterization of conditional HDAC7-knockout mice. Bone marrow osteoclast differentiation assays reveal that HDAC7 overexpression suppresses, whereas HDAC7 deletion enhances, osteoclastogenesis. Mechanistically, in the absence of receptor activator of nuclear factor κ-B ligand (RANKL), HDAC7 attenuates β-catenin function and cyclin D1 expression, thereby reducing precursor proliferation; upon RANKL activation, HDAC7 suppresses NFATc1 and prevents β-catenin down-regulation, thereby blocking osteoclast differentiation. Consequently, HDAC7 deletion in the osteoclast lineage results in a 26% reduction in bone mass (P = 0.003) owing to 102% elevated bone resorption (P = 0.01). These findings are clinically significant in light of the remarkable therapeutic potentials of HDAC inhibitors for several diseases such as cancer, diabetes, and neurodegeneration.

Original languageEnglish (US)
Pages (from-to)325-335
Number of pages11
JournalMolecular Endocrinology
Volume27
Issue number2
DOIs
StatePublished - Feb 2013

Fingerprint

Catenins
Histone Deacetylases
Osteogenesis
Osteoclasts
Bone Resorption
Bone and Bones
Bone Neoplasms
Histone Deacetylase Inhibitors
Cyclin D1
Cytoplasmic and Nuclear Receptors
Knockout Mice
Osteoporosis
Down-Regulation
Bone Marrow
Neoplasm Metastasis
Ligands

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered β-catenin switch. / Jin, Zixue; Wei, Wei; Dechow, Paul C.; Wan, Yihong.

In: Molecular Endocrinology, Vol. 27, No. 2, 02.2013, p. 325-335.

Research output: Contribution to journalArticle

Jin, Zixue ; Wei, Wei ; Dechow, Paul C. ; Wan, Yihong. / HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered β-catenin switch. In: Molecular Endocrinology. 2013 ; Vol. 27, No. 2. pp. 325-335.
@article{9f6988faddee4c1395328ba3fc7349a9,
title = "HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered β-catenin switch",
abstract = "The bone-resorbing osteoclast is essential for skeletal remodeling, yet its deregulation contributes to diseases such as osteoporosis and cancer bone metastasis. Here we identify histone deacetylase 7 (HDAC7) as a key negative regulator of osteoclastogenesis and bone resorption using both in vitro cellular and molecular analyses and in vivo characterization of conditional HDAC7-knockout mice. Bone marrow osteoclast differentiation assays reveal that HDAC7 overexpression suppresses, whereas HDAC7 deletion enhances, osteoclastogenesis. Mechanistically, in the absence of receptor activator of nuclear factor κ-B ligand (RANKL), HDAC7 attenuates β-catenin function and cyclin D1 expression, thereby reducing precursor proliferation; upon RANKL activation, HDAC7 suppresses NFATc1 and prevents β-catenin down-regulation, thereby blocking osteoclast differentiation. Consequently, HDAC7 deletion in the osteoclast lineage results in a 26{\%} reduction in bone mass (P = 0.003) owing to 102{\%} elevated bone resorption (P = 0.01). These findings are clinically significant in light of the remarkable therapeutic potentials of HDAC inhibitors for several diseases such as cancer, diabetes, and neurodegeneration.",
author = "Zixue Jin and Wei Wei and Dechow, {Paul C.} and Yihong Wan",
year = "2013",
month = "2",
doi = "10.1210/me.2012-1302",
language = "English (US)",
volume = "27",
pages = "325--335",
journal = "Molecular Endocrinology",
issn = "0888-8809",
publisher = "The Endocrine Society",
number = "2",

}

TY - JOUR

T1 - HDAC7 inhibits osteoclastogenesis by reversing RANKL-triggered β-catenin switch

AU - Jin, Zixue

AU - Wei, Wei

AU - Dechow, Paul C.

AU - Wan, Yihong

PY - 2013/2

Y1 - 2013/2

N2 - The bone-resorbing osteoclast is essential for skeletal remodeling, yet its deregulation contributes to diseases such as osteoporosis and cancer bone metastasis. Here we identify histone deacetylase 7 (HDAC7) as a key negative regulator of osteoclastogenesis and bone resorption using both in vitro cellular and molecular analyses and in vivo characterization of conditional HDAC7-knockout mice. Bone marrow osteoclast differentiation assays reveal that HDAC7 overexpression suppresses, whereas HDAC7 deletion enhances, osteoclastogenesis. Mechanistically, in the absence of receptor activator of nuclear factor κ-B ligand (RANKL), HDAC7 attenuates β-catenin function and cyclin D1 expression, thereby reducing precursor proliferation; upon RANKL activation, HDAC7 suppresses NFATc1 and prevents β-catenin down-regulation, thereby blocking osteoclast differentiation. Consequently, HDAC7 deletion in the osteoclast lineage results in a 26% reduction in bone mass (P = 0.003) owing to 102% elevated bone resorption (P = 0.01). These findings are clinically significant in light of the remarkable therapeutic potentials of HDAC inhibitors for several diseases such as cancer, diabetes, and neurodegeneration.

AB - The bone-resorbing osteoclast is essential for skeletal remodeling, yet its deregulation contributes to diseases such as osteoporosis and cancer bone metastasis. Here we identify histone deacetylase 7 (HDAC7) as a key negative regulator of osteoclastogenesis and bone resorption using both in vitro cellular and molecular analyses and in vivo characterization of conditional HDAC7-knockout mice. Bone marrow osteoclast differentiation assays reveal that HDAC7 overexpression suppresses, whereas HDAC7 deletion enhances, osteoclastogenesis. Mechanistically, in the absence of receptor activator of nuclear factor κ-B ligand (RANKL), HDAC7 attenuates β-catenin function and cyclin D1 expression, thereby reducing precursor proliferation; upon RANKL activation, HDAC7 suppresses NFATc1 and prevents β-catenin down-regulation, thereby blocking osteoclast differentiation. Consequently, HDAC7 deletion in the osteoclast lineage results in a 26% reduction in bone mass (P = 0.003) owing to 102% elevated bone resorption (P = 0.01). These findings are clinically significant in light of the remarkable therapeutic potentials of HDAC inhibitors for several diseases such as cancer, diabetes, and neurodegeneration.

UR - http://www.scopus.com/inward/record.url?scp=84873019253&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873019253&partnerID=8YFLogxK

U2 - 10.1210/me.2012-1302

DO - 10.1210/me.2012-1302

M3 - Article

C2 - 23204328

AN - SCOPUS:84873019253

VL - 27

SP - 325

EP - 335

JO - Molecular Endocrinology

JF - Molecular Endocrinology

SN - 0888-8809

IS - 2

ER -