Praeruptorin A inhibits in vitro migration of preosteoclasts and in vivo bone erosion, possibly due to its potential to target calmodulin.
Excessive activity and/or increased number of osteoclasts lead to bone resorption-related disorders. Here, we investigated the potential of praeruptorin A to inhibit migration/fusion of preosteoclasts in vitro and bone erosion in vivo. Praeruptorin A inhibited the RANKL-induced migration/fusion of preosteoclasts accompanied by the nuclear translocation of NFATc1, a master regulator of osteoclast differentiation. Antimigration/fusion activity of praeruptorin A was also confirmed by evaluating the mRNA expression of fusion-mediating molecules. In silico binding studies and several biochemical assays further revealed the potential of praeruptorin A to bind with Ca(2+)/calmodulin and inhibit its downstream signaling pathways, including the Ca(2+)/calmodulin-CaMKIV-CREB and Ca(2+)/calmodulin-calcineurin signaling axis responsible for controlling NFATc1. In vivo application of praeruptorin A significantly reduced lipopolysaccharide-induced bone erosion, indicating its possible use to treat bone resorption-related disorders. In conclusion, praeruptorin A has the potential to inhibit migration/fusion of preosteoclasts in vitro and bone erosion in vivo by targeting calmodulin and inhibiting the Ca(2+)/calmodulin-CaMKIV-CREB-NFATc1 and/or Ca(2+)/calmodulin-calcineurin-NFATc1 signaling axis.
†Research Institute of Basic Science and §Department of Pharmacy, Sunchon National University, Suncheon 540-742, Republic of Korea.|‡Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, ⊥Korea Chemical Bank, and ∥Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
Jeong-Tae
JT
Yeon
†Research Institute of Basic Science and §Department of Pharmacy, Sunchon National University, Suncheon 540-742, Republic of Korea.|‡Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, ⊥Korea Chemical Bank, and ∥Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
Sik-Won
SW
Choi
†Research Institute of Basic Science and §Department of Pharmacy, Sunchon National University, Suncheon 540-742, Republic of Korea.|‡Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, ⊥Korea Chemical Bank, and ∥Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
Byung Jun
BJ
Ryu
†Research Institute of Basic Science and §Department of Pharmacy, Sunchon National University, Suncheon 540-742, Republic of Korea.|‡Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, ⊥Korea Chemical Bank, and ∥Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
Kwang-Jin
KJ
Kim
†Research Institute of Basic Science and §Department of Pharmacy, Sunchon National University, Suncheon 540-742, Republic of Korea.|‡Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, ⊥Korea Chemical Bank, and ∥Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
Joo Yun
JY
Lee
†Research Institute of Basic Science and §Department of Pharmacy, Sunchon National University, Suncheon 540-742, Republic of Korea.|‡Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, ⊥Korea Chemical Bank, and ∥Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
Byung Jin
BJ
Byun
†Research Institute of Basic Science and §Department of Pharmacy, Sunchon National University, Suncheon 540-742, Republic of Korea.|‡Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, ⊥Korea Chemical Bank, and ∥Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
Young-Jin
YJ
Son
†Research Institute of Basic Science and §Department of Pharmacy, Sunchon National University, Suncheon 540-742, Republic of Korea.|‡Laboratory of Translational Therapeutics, Pharmacology Research Center, Drug Discovery Division, ⊥Korea Chemical Bank, and ∥Drug Discovery Platform Technology Group, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
Seong Hwan
SH
Kim
D002147:Calmodulin / Q000378:metabolism*; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000494:pharmacology; D015394:Molecular Structure; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D053245:RANK Ligand / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
D002147:Calmodulin; D003374:Coumarins; D008070:Lipopolysaccharides; D053245:RANK Ligand; C441070:praeruptorin A