Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice.
Trapidil, a platelet-derived growth factor antagonist, was originally developed as a vasodilator and anti-platelet agent and has been used to treat patients with ischemic coronary heart, liver, and kidney disease. In this study, we investigated the effects of trapidil on osteoclastogenesis and elucidated the possible mechanism of action of trapidil. Trapidil strongly inhibited osteoclast formation in co-cultures of bone marrow cells and osteoblasts without affecting receptor activator of NF-κB ligand (RANKL) or osteoprotegerin expression in osteoblasts. In addition, trapidil suppressed RANKL-induced osteoclast formation from osteoclast precursors. Trapidil reduced RANKL-induced expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), a master transcription factor for osteoclastogenesis, without affecting the expression of c-Fos that functions as a key upstream activator of NFATc1 during osteoclastogenesis. Ectopic expression of a constitutively active form of NFATc1 reversed the anti-osteoclastogenic effect of trapidil, indicating that NFATc1 is a critical target of the anti-osteoclastogenic action of trapidil. RANKL-induced calcium oscillation and Pim-1 expression, which are required for NFATc1 induction and osteoclastogenesis, were abrogated by trapidil. Consistent with the in vitro results, trapidil had a potent inhibitory effect on osteoclast formation and bone resorption induced by interleukin-1 in an animal model. Taken together, our data demonstrate that trapidil abrogates RANKL-induced calcium oscillation and Pim-1 expression required for NFATc1 induction, thereby inhibiting osteoclastogenesis.
Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.
Sun-Don
SD
Kim
Ha-Neui
HN
Kim
Jong-Ho
JH
Lee
Won Jong
WJ
Jin
Soon Jung
SJ
Hwang
Hong-Hee
HH
Kim
Hyunil
H
Ha
Zang Hee
ZH
Lee
D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000187:drug effects; D007375:Interleukin-1; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014192:Trapidil / Q000494:pharmacology*
D050071:Bone Density Conservation Agents; D007375:Interleukin-1; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053244:Osteoprotegerin; D010975:Platelet Aggregation Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C496636:Pim1 protein, mouse; D051573:Proto-Oncogene Proteins c-pim-1; D014192:Trapidil; D002118:Calcium
BMMs; Bone destruction; CREB; Ca(2+); Ca(2+)/calmodulin-dependent kinase; CaMK; Calcium oscillation; M-CSF; MAPK; NFATc1; OPG; PDGF; PGE(2); PLCγ; PTH; RANKL; TRAP; Trapidil; bone marrow-derived macrophages; cAMP response element-binding protein; calcium; macrophage colony stimulation factor; mitogen-activated protein kinase; nuclear factor of activated T cells, cytoplasmic 1; osteoprotegerin; parathyroid hormone; phospholipase Cγ; platelet-derived growth factor; prostaglandin E(2); receptor activator of NF-κB ligand; tartrate-resistant acid phosphatase