Dynamin-related protein 1 positively regulates osteoclast differentiation and bone loss

Sol Jeong; Ji Hye Seong; Ju Hee Kang; Dong Seok Lee; Mijung Yim

doi:10.1002/1873-3468.13963

Dynamin-related protein 1 positively regulates osteoclast differentiation and bone loss

Sol Jeong, Ji Hye Seong, Ju Hee Kang, Dong Seok Lee, Mijung Yim

Sookmyung Women's University

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

Dynamin-related protein 1 (DRP1) is a mitochondrial membrane GTPase and regulates mitochondrial fission. In this study, we found that the cytokine RANKL increased the expression of DRP1 and its receptor proteins, Fis1, Mid49, and Mid 51, during osteoclast formation in mouse bone marrow-derived macrophages. Inactivation of the kinase GSK3β appeared to induce DRP1 expression. DRP1 knockdown or the DRP1 inhibitor Mdivi1 suppressed osteoclast differentiation via downregulation of c-Fos and NFATc1, the key transcription factor for osteoclast formation. Finally, the DRP1 inhibitor suppressed lipopolysaccharide-induced osteoclast formation in a calvarial model and ovariectomy-induced bone loss in vivo. Taken together, our data demonstrate that DRP1 positively contributes to RANKL-induced osteoclast differentiation by regulating the c-Fos–NFATc1 axis, suggesting the importance of mitochondrial DRP1 in osteoclastogenesis.

Original language	English
Pages (from-to)	58-67
Number of pages	10
Journal	FEBS Letters
Volume	595
Issue number	1
DOIs	https://doi.org/10.1002/1873-3468.13963
State	Published - Jan 2021

Keywords

bone loss
DRP1
NFATc1
osteoclastogenesis
RANKL

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title = "Dynamin-related protein 1 positively regulates osteoclast differentiation and bone loss",

abstract = "Dynamin-related protein 1 (DRP1) is a mitochondrial membrane GTPase and regulates mitochondrial fission. In this study, we found that the cytokine RANKL increased the expression of DRP1 and its receptor proteins, Fis1, Mid49, and Mid 51, during osteoclast formation in mouse bone marrow-derived macrophages. Inactivation of the kinase GSK3β appeared to induce DRP1 expression. DRP1 knockdown or the DRP1 inhibitor Mdivi1 suppressed osteoclast differentiation via downregulation of c-Fos and NFATc1, the key transcription factor for osteoclast formation. Finally, the DRP1 inhibitor suppressed lipopolysaccharide-induced osteoclast formation in a calvarial model and ovariectomy-induced bone loss in vivo. Taken together, our data demonstrate that DRP1 positively contributes to RANKL-induced osteoclast differentiation by regulating the c-Fos–NFATc1 axis, suggesting the importance of mitochondrial DRP1 in osteoclastogenesis.",

keywords = "bone loss, DRP1, NFATc1, osteoclastogenesis, RANKL",

author = "Sol Jeong and Seong, {Ji Hye} and Kang, {Ju Hee} and Lee, {Dong Seok} and Mijung Yim",

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year = "2021",

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doi = "10.1002/1873-3468.13963",

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T1 - Dynamin-related protein 1 positively regulates osteoclast differentiation and bone loss

AU - Jeong, Sol

AU - Seong, Ji Hye

AU - Kang, Ju Hee

AU - Lee, Dong Seok

AU - Yim, Mijung

PY - 2021/1

Y1 - 2021/1

N2 - Dynamin-related protein 1 (DRP1) is a mitochondrial membrane GTPase and regulates mitochondrial fission. In this study, we found that the cytokine RANKL increased the expression of DRP1 and its receptor proteins, Fis1, Mid49, and Mid 51, during osteoclast formation in mouse bone marrow-derived macrophages. Inactivation of the kinase GSK3β appeared to induce DRP1 expression. DRP1 knockdown or the DRP1 inhibitor Mdivi1 suppressed osteoclast differentiation via downregulation of c-Fos and NFATc1, the key transcription factor for osteoclast formation. Finally, the DRP1 inhibitor suppressed lipopolysaccharide-induced osteoclast formation in a calvarial model and ovariectomy-induced bone loss in vivo. Taken together, our data demonstrate that DRP1 positively contributes to RANKL-induced osteoclast differentiation by regulating the c-Fos–NFATc1 axis, suggesting the importance of mitochondrial DRP1 in osteoclastogenesis.

AB - Dynamin-related protein 1 (DRP1) is a mitochondrial membrane GTPase and regulates mitochondrial fission. In this study, we found that the cytokine RANKL increased the expression of DRP1 and its receptor proteins, Fis1, Mid49, and Mid 51, during osteoclast formation in mouse bone marrow-derived macrophages. Inactivation of the kinase GSK3β appeared to induce DRP1 expression. DRP1 knockdown or the DRP1 inhibitor Mdivi1 suppressed osteoclast differentiation via downregulation of c-Fos and NFATc1, the key transcription factor for osteoclast formation. Finally, the DRP1 inhibitor suppressed lipopolysaccharide-induced osteoclast formation in a calvarial model and ovariectomy-induced bone loss in vivo. Taken together, our data demonstrate that DRP1 positively contributes to RANKL-induced osteoclast differentiation by regulating the c-Fos–NFATc1 axis, suggesting the importance of mitochondrial DRP1 in osteoclastogenesis.

KW - bone loss

KW - DRP1

KW - NFATc1

KW - osteoclastogenesis

KW - RANKL

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Dynamin-related protein 1 positively regulates osteoclast differentiation and bone loss

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Keywords

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