KMUP-1 Suppresses RANKL-Induced Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss: Roles of MAPKs, Akt, NF-kappa B and Calcium/Calcineurin/NFATc1 Pathways

doi:10.1371/journal.pone.0069468

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Title:	KMUP-1 Suppresses RANKL-Induced Osteoclastogenesis and Prevents Ovariectomy-Induced Bone Loss: Roles of MAPKs, Akt, NF-kappa B and Calcium/Calcineurin/NFATc1 Pathways
Authors:	Liou, Shu-Fen Hsu, Jong-Hau Lin, I-Ling Ho, Mei-Ling Hsu, Pei-Chuan Chen, Li-Wen Chen, Ing-Jun Yeh, Jwu-Lai
Contributors:	藥學系
Keywords:	Receptor Activator Smooth-Muscle K+ Channels Cyclic-Gmp Phosphodiesterase-4 Inhibitor Cardiac-Hypertrophy Signal-Transduction Down-Regulation Differentiation Cells
Date:	2013-07
Issue Date:	2014-05-26 10:47:23 (UTC+8)
Publisher:	Public Library Science
Abstract:	Background: KMUP-1 is a xanthine derivative with inhibitory activities on the phosphodiesterase (PDE) 3,4 and 5 isoenzymes to suppress the degradation of cyclic AMP and cyclic GMP. However, the effects of KMUP-1 on osteoclast differentiation are still unclear. In this study, we investigated whether KMUP-1 inhibits osteoclastogenesis induced by RANKL in RAW 264.7 cells and bone loss induced by ovariectomy in mice, and the underlying mechanisms.Principal Findings: In vitro, KMUP-1 inhibited RANKL-induced TRAP activity, the formation of multinucleated osteoclasts and resorption-pit formation. It also inhibited key mediators of osteoclastogenesis including IL-1 beta, IL-6, TNF-alpha and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-kappa B), mRNA expression of osteoclastogensis-associated genes (TRAP, MMP-9, Fra-1, and cathepsin K) and transcription factors (c-Fos and NFATc1). Furthermore, most inhibitory effects of KMUP-1 on RANKL-mediated signal activations were reversed by a protein kinase A inhibitor (H89) and a protein kinase G inhibitor (KT5823). In vivo, KMUP-1 prevented loss of bone mineral content, preserved serum alkaline phosphate and reduced serum osteocalcin in ovariectomized mice.Conclusions: KMUP-1 inhibits RANKL-induced osteoclastogenesis in vitro and protects against ovariectomy-induced bone loss in vivo. These effects are mediated, at least in part, by cAMP and cGMP pathways. Therefore, KMUP-1 may have a role in pharmacologic therapy of osteoporosis.
Relation:	Plos One, v.8 n.7, e69468
Appears in Collections:	[Dept. of Pharmacy] Periodical Articles

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