Repositioning Potential of PAK4 to Osteoclastic Bone Resorption

Sik Won Choi; Jeong Tae Yeon; Byung Jun Ryu; Kwang Jin Kim; Seong Hee Moon; Hyuk Lee; Myeung Su Lee; Sam Youn Lee; Jin Chul Heo; Sang Joon Park; Seong Hwan Kim

doi:10.1002/jbmr.2468

Repositioning Potential of PAK4 to Osteoclastic Bone Resorption

Sik Won Choi, Jeong Tae Yeon, Byung Jun Ryu, Kwang Jin Kim, Seong Hee Moon, Hyuk Lee, Myeung Su Lee, Sam Youn Lee, Jin Chul Heo, Sang Joon Park, Seong Hwan Kim

Department of Veterinary Medicine

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

7 Scopus citations

Abstract

Drug repositioning is a rational approach for expanding the use of existing drugs or candidate drugs to treat additional disorders. Here we investigated the possibility of using the anticancer p21-activated kinase 4 (PAK4)-targeted inhibitor PF-3758309 to treat osteoclast-mediated disorders. PAK4 was highly expressed in bone marrow cells and was phosphorylated during their differentiation into osteoclasts, and osteoclast differentiation was significantly inhibited by the dominant negative form of PAK4 and by PF-3758309. Specifically, PF-3758309 significantly inhibited the fusion of preosteoclasts, the podosome formation, and the migration of preosteoclasts. PF-3758309 also had in vivo antiresorptive activity in a lipopolysaccharide-induced bone erosion model and in vitro antiosteoclastogenic activity in the differentiation of human bone marrow-derived cells and peripheral blood mononuclear cells into osteoclasts. These data demonstrate the relevance of PAK4 in osteoclast differentiation and the potential of PAK4 inhibitors for treating osteoclast-related disorders.

Original language	English
Pages (from-to)	1494-1507
Number of pages	14
Journal	Journal of Bone and Mineral Research
Volume	30
Issue number	8
DOIs	https://doi.org/10.1002/jbmr.2468
State	Published - 1 Aug 2015

Keywords

DRUG REPOSITION
OSTEOCLAST
OSTEOCLAST FUSION
PAK4 INHIBITOR
PODOSOME

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/jbmr.2468

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title = "Repositioning Potential of PAK4 to Osteoclastic Bone Resorption",

abstract = "Drug repositioning is a rational approach for expanding the use of existing drugs or candidate drugs to treat additional disorders. Here we investigated the possibility of using the anticancer p21-activated kinase 4 (PAK4)-targeted inhibitor PF-3758309 to treat osteoclast-mediated disorders. PAK4 was highly expressed in bone marrow cells and was phosphorylated during their differentiation into osteoclasts, and osteoclast differentiation was significantly inhibited by the dominant negative form of PAK4 and by PF-3758309. Specifically, PF-3758309 significantly inhibited the fusion of preosteoclasts, the podosome formation, and the migration of preosteoclasts. PF-3758309 also had in vivo antiresorptive activity in a lipopolysaccharide-induced bone erosion model and in vitro antiosteoclastogenic activity in the differentiation of human bone marrow-derived cells and peripheral blood mononuclear cells into osteoclasts. These data demonstrate the relevance of PAK4 in osteoclast differentiation and the potential of PAK4 inhibitors for treating osteoclast-related disorders.",

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author = "Choi, {Sik Won} and Yeon, {Jeong Tae} and Ryu, {Byung Jun} and Kim, {Kwang Jin} and Moon, {Seong Hee} and Hyuk Lee and Lee, {Myeung Su} and Lee, {Sam Youn} and Heo, {Jin Chul} and Park, {Sang Joon} and Kim, {Seong Hwan}",

note = "Publisher Copyright: {\textcopyright} 2015 American Society for Bone and Mineral Research {\textcopyright} 2015 American Society for Bone and Mineral Research. {\textcopyright} 2015 American Society for Bone and Mineral Research.",

year = "2015",

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doi = "10.1002/jbmr.2468",

language = "English",

volume = "30",

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AU - Choi, Sik Won

AU - Yeon, Jeong Tae

AU - Ryu, Byung Jun

AU - Kim, Kwang Jin

AU - Moon, Seong Hee

AU - Lee, Hyuk

AU - Lee, Myeung Su

AU - Lee, Sam Youn

AU - Heo, Jin Chul

AU - Park, Sang Joon

AU - Kim, Seong Hwan

PY - 2015/8/1

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N2 - Drug repositioning is a rational approach for expanding the use of existing drugs or candidate drugs to treat additional disorders. Here we investigated the possibility of using the anticancer p21-activated kinase 4 (PAK4)-targeted inhibitor PF-3758309 to treat osteoclast-mediated disorders. PAK4 was highly expressed in bone marrow cells and was phosphorylated during their differentiation into osteoclasts, and osteoclast differentiation was significantly inhibited by the dominant negative form of PAK4 and by PF-3758309. Specifically, PF-3758309 significantly inhibited the fusion of preosteoclasts, the podosome formation, and the migration of preosteoclasts. PF-3758309 also had in vivo antiresorptive activity in a lipopolysaccharide-induced bone erosion model and in vitro antiosteoclastogenic activity in the differentiation of human bone marrow-derived cells and peripheral blood mononuclear cells into osteoclasts. These data demonstrate the relevance of PAK4 in osteoclast differentiation and the potential of PAK4 inhibitors for treating osteoclast-related disorders.

AB - Drug repositioning is a rational approach for expanding the use of existing drugs or candidate drugs to treat additional disorders. Here we investigated the possibility of using the anticancer p21-activated kinase 4 (PAK4)-targeted inhibitor PF-3758309 to treat osteoclast-mediated disorders. PAK4 was highly expressed in bone marrow cells and was phosphorylated during their differentiation into osteoclasts, and osteoclast differentiation was significantly inhibited by the dominant negative form of PAK4 and by PF-3758309. Specifically, PF-3758309 significantly inhibited the fusion of preosteoclasts, the podosome formation, and the migration of preosteoclasts. PF-3758309 also had in vivo antiresorptive activity in a lipopolysaccharide-induced bone erosion model and in vitro antiosteoclastogenic activity in the differentiation of human bone marrow-derived cells and peripheral blood mononuclear cells into osteoclasts. These data demonstrate the relevance of PAK4 in osteoclast differentiation and the potential of PAK4 inhibitors for treating osteoclast-related disorders.

KW - DRUG REPOSITION

KW - OSTEOCLAST

KW - OSTEOCLAST FUSION

KW - PAK4 INHIBITOR

KW - PODOSOME

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SN - 0884-0431

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JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

IS - 8

ER -

Repositioning Potential of PAK4 to Osteoclastic Bone Resorption

Abstract

Keywords

UN SDGs

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