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Repositioning Potential of PAK4 to Osteoclastic Bone Resorption
Author(s) -
Choi SikWon,
Yeon JeongTae,
Ryu Byung Jun,
Kim KwangJin,
Moon SeongHee,
Lee Hyuk,
Lee Myeung Su,
Lee Sam Youn,
Heo JinChul,
Park SangJoon,
Kim Seong Hwan
Publication year - 2015
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.2468
Subject(s) - bone resorption , resorption , medicine
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. © 2015 American Society for Bone and Mineral Research © 2015 American Society for Bone and Mineral Research.