The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis

Miyauchi, Yoshiteru; Ninomiya, Ken; Miyamoto, Hiroaki; Sakamoto, Akemi; Iwasaki, Ryuichiro; Hoshi, Hiroko; Miyamoto, Kana; Wu, Hao; Yoshida, Shigeyuki; Morioka, Hideo; Chiba, Kazuhiro; Kato, Shigeaki; Tokuhisa, Takeshi; Saitou, Mitinori; Toyama, Yoshiaki; Suda, Toshio; Miyamoto, Takeshi

doi:10.1083/jcb1892oia4

Cited by 48 publications

(84 citation statements)

References 1 publication

Supporting

Mentioning

Contrasting

Order By: Relevance

“…β-actin (Actb) expression served as an internal control. Primers for Nfatc1, Ctsk, Dc-stamp, and Actb were described previously (24). Other primers were purchased from Takara Bio Inc.…”

Section: Methodsmentioning

confidence: 99%

HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis

Miyauchi

Sato²,

Kobayashi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

163

160

View full text Add to dashboard Cite

In women, estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. Here we show that in bone-resorbing osteoclasts, estrogendependent destabilization of hypoxia-inducible factor 1 alpha (HIF1α), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1α was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1α in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1α inactivation antagonized bone loss in Ovx mice and osteoclast-specific estrogen receptor alpha deficient mice, both models of estrogen-deficient osteoporosis. Oral administration of a HIF1α inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1α represents a promising therapeutic target in osteoporosis.B one mass is tightly regulated by a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Estrogen loss in women after menopause frequently promotes activation of osteoclastic bone resorption, causing osteoporosis. Osteoporotic bone phenotypes are seen in ovariectomized female mice, and estrogen deficiency-induced bone loss in both mouse models and women is ameliorated by estrogen treatment (1, 2). However, estrogen administration reportedly increases risk of cardiovascular events and carcinogenesis of the mammary gland and uterus (3). Bioavailable estrogens including selective estrogen receptor modulators (SERMs) also protect bone from estrogen deficiency-induced osteoporosis (4), and estrogen and SERMs primarily act via estrogen receptors (ER), ERα and ERβ (5, 6). However, how SERMs act on bone remains largely unknown. Thus, understanding of osteoclast activation following estrogen loss is crucial for development of safe therapeutic reagents.Both the endosteal zone of bone marrow cavities and epiphyseal growth plates are hypoxic areas, and the hypoxia-inducible factor (HIF) signaling pathway governs chondrocyte and osteoblast function in these respective areas (7,8). The HIF1 transcription factor consists of an oxygen-regulated alpha subunit, HIF1α, and a constitutively expressed beta subunit, HIF1β. Under normoxia, HIF1α is posttranslationally modified by prolyl hydroxylases, which catalyze hydroxylation of proline residues in the presence of O 2 and Fe 2+ . Recognition of hydroxylated HIF1α by the von Hippel-Lindau tumor suppressor protein recruits an E3 ubiquitin ligase complex targeting HIF1α for proteasomal degradation. Conversely, under hypoxia, proline hydroxylation is inhibited by substrate (O 2 ) deprivation, allowing HIF1α accumulation and formation of an active transcriptional complex with HIF1β (9). Recently, regulation of HIF1α protein levels by factors other than O 2 , including reactive ...

show abstract

“…β-actin (Actb) expression served as an internal control. Primers for Nfatc1, Ctsk, Dc-stamp, and Actb were described previously (24). Other primers were purchased from Takara Bio Inc.…”

Section: Methodsmentioning

confidence: 99%

HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis

Miyauchi

Sato²,

Kobayashi³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

163

160

View full text Add to dashboard Cite

show abstract

“…Western Blot Analysis-Whole-cell lysates were prepared from BM cultures, and equivalent amounts of protein were separated by SDS-PAGE and transferred to a PVDF membrane (Millipore) (23). Proteins were detected using the following antibodies: anti-STAT1, anti-phosphorylated STAT1 (Ser-727), and anti-STAT6 were purchased from Cell Signaling Technology (Beverly, MA); anti-phosphorylated STAT6 was from Abcam (Cambridge, MA), and anti-actin was from Sigma.…”

Section: Methodsmentioning

confidence: 99%

An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

Miyamoto

Katsuyama

Miyauchi

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background:The signaling leading to macrophage fusion remains largely unknown. Results: STAT6 deficiency completely inhibited macrophage fusion, although STAT1 deficiency or OC-STAMP/DC-STAMP co-expression was sufficient to promote macrophage fusion. Conclusion: The STAT6-STAT1-OC-STAMP/DC-STAMP axis is required for macrophage fusion. Significance: The STAT6-STAT1-OC-STAMP/DC-STAMP axis is a novel pathway leading to macrophage fusion.

show abstract

“…Bcl-6 inhibited osteoclastogenesis by suppressing the expression of NFATc1 and other genes, its deletion caused osteoporosis in mice [45]. Consistent with this, Blimp1 (B lymphocyte-induced maturation protein-1) inhibited BCL-6 in osteoclasts, and its deletion caused osteopetrosis [45]. The Blimp1-Bcl-6 axis appears to be dependent on calibrating NFATc1 expression for regulating bone homeostasis.…”

Section: Regulation Of Nfatc1 By Other Molecules In Osteoclastsmentioning

confidence: 59%

“…IRF-8 (interferon regulatory factor-8) blocked NFATc1-induced osteoclastogenesis and was suppressed by RANKL, its deletion caused severe osteoporosis in mice [44]. Bcl-6 inhibited osteoclastogenesis by suppressing the expression of NFATc1 and other genes, its deletion caused osteoporosis in mice [45]. Consistent with this, Blimp1 (B lymphocyte-induced maturation protein-1) inhibited BCL-6 in osteoclasts, and its deletion caused osteopetrosis [45].…”

Section: Regulation Of Nfatc1 By Other Molecules In Osteoclastsmentioning

confidence: 63%

NFAT Signaling and Bone Homeostasis

Chen¹,

Pan²

2013

J Hematol Thrombo Diseases

View full text Add to dashboard Cite

Bone homeostasis is a function of the constant balancing acts between osteoclasts and osteoblasts, regulated by numerous factors in cellular and molecular levels. Calcineurin-NFAT pathway plays critical roles in bone homeostasis by regulating many aspects of bone development and remodeling. NFATc1 is the master transcription factor of osteoclasts, acting downstream of RANKL (receptor activator of nuclear factor-κB ligand) to control osteoclastogenesis. NFATc1 also plays important role in osteoblastogenesis, its increased nuclear occupancy in osteoblasts causes osteopetrosis by regulating chemokine and Wnt pathways. Targeting NFAT pathway may provide therapeutic avenues for treating bony disorders.

show abstract

The Blimp1–Bcl6 axis is critical to regulate osteoclast differentiation and bone homeostasis

Cited by 48 publications

References 1 publication

HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis

HIF1α is required for osteoclast activation by estrogen deficiency in postmenopausal osteoporosis

An Essential Role for STAT6-STAT1 Protein Signaling in Promoting Macrophage Cell-Cell Fusion

NFAT Signaling and Bone Homeostasis

Contact Info

Product

Resources

About