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Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice.
Biochem Pharmacol. 2013 Sep 15; 86(6):782-90.BP

Abstract

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.

Authors+Show Affiliations

Department of Cell and Developmental Biology, Dental Research Institute, School of Dentistry, Seoul National University, Seoul 110-749, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23928189

Citation

Kim, Sun-Don, et al. "Trapidil, a Platelet-derived Growth Factor Antagonist, Inhibits Osteoclastogenesis By Down-regulating NFATc1 and Suppresses Bone Loss in Mice." Biochemical Pharmacology, vol. 86, no. 6, 2013, pp. 782-90.
Kim SD, Kim HN, Lee JH, et al. Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice. Biochem Pharmacol. 2013;86(6):782-90.
Kim, S. D., Kim, H. N., Lee, J. H., Jin, W. J., Hwang, S. J., Kim, H. H., Ha, H., & Lee, Z. H. (2013). Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice. Biochemical Pharmacology, 86(6), 782-90. https://doi.org/10.1016/j.bcp.2013.07.015
Kim SD, et al. Trapidil, a Platelet-derived Growth Factor Antagonist, Inhibits Osteoclastogenesis By Down-regulating NFATc1 and Suppresses Bone Loss in Mice. Biochem Pharmacol. 2013 Sep 15;86(6):782-90. PubMed PMID: 23928189.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Trapidil, a platelet-derived growth factor antagonist, inhibits osteoclastogenesis by down-regulating NFATc1 and suppresses bone loss in mice. AU - Kim,Sun-Don, AU - Kim,Ha-Neui, AU - Lee,Jong-Ho, AU - Jin,Won Jong, AU - Hwang,Soon Jung, AU - Kim,Hong-Hee, AU - Ha,Hyunil, AU - Lee,Zang Hee, Y1 - 2013/08/06/ PY - 2013/05/14/received PY - 2013/07/18/revised PY - 2013/07/24/accepted PY - 2013/8/10/entrez PY - 2013/8/10/pubmed PY - 2013/10/30/medline KW - BMMs KW - Bone destruction KW - CREB KW - Ca(2+) KW - Ca(2+)/calmodulin-dependent kinase KW - CaMK KW - Calcium oscillation KW - M-CSF KW - MAPK KW - NFATc1 KW - OPG KW - PDGF KW - PGE(2) KW - PLCγ KW - PTH KW - RANKL KW - TRAP KW - Trapidil KW - bone marrow-derived macrophages KW - cAMP response element-binding protein KW - calcium KW - macrophage colony stimulation factor KW - mitogen-activated protein kinase KW - nuclear factor of activated T cells, cytoplasmic 1 KW - osteoprotegerin KW - parathyroid hormone KW - phospholipase Cγ KW - platelet-derived growth factor KW - prostaglandin E(2) KW - receptor activator of NF-κB ligand KW - tartrate-resistant acid phosphatase SP - 782 EP - 90 JF - Biochemical pharmacology JO - Biochem. Pharmacol. VL - 86 IS - 6 N2 - 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. SN - 1873-2968 UR - https://www.unboundmedicine.com/medline/citation/23928189/Trapidil_a_platelet_derived_growth_factor_antagonist_inhibits_osteoclastogenesis_by_down_regulating_NFATc1_and_suppresses_bone_loss_in_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-2952(13)00451-6 DB - PRIME DP - Unbound Medicine ER -