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KMUP-1 suppresses RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss: roles of MAPKs, Akt, NF-κB and calcium/calcineurin/NFATc1 pathways.
PLoS One. 2013; 8(7):e69468.Plos

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-1β, IL-6, TNF-α and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-κB), 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.

Authors+Show Affiliations

Department of Pharmacy, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan.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

23936022

Citation

Liou, Shu-Fen, et al. "KMUP-1 Suppresses RANKL-induced Osteoclastogenesis and Prevents Ovariectomy-induced Bone Loss: Roles of MAPKs, Akt, NF-κB and calcium/calcineurin/NFATc1 Pathways." PloS One, vol. 8, no. 7, 2013, pp. e69468.
Liou SF, Hsu JH, Lin IL, et al. KMUP-1 suppresses RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss: roles of MAPKs, Akt, NF-κB and calcium/calcineurin/NFATc1 pathways. PLoS One. 2013;8(7):e69468.
Liou, S. F., Hsu, J. H., Lin, I. L., Ho, M. L., Hsu, P. C., Chen, L. W., Chen, I. J., & Yeh, J. L. (2013). KMUP-1 suppresses RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss: roles of MAPKs, Akt, NF-κB and calcium/calcineurin/NFATc1 pathways. PloS One, 8(7), e69468. https://doi.org/10.1371/journal.pone.0069468
Liou SF, et al. KMUP-1 Suppresses RANKL-induced Osteoclastogenesis and Prevents Ovariectomy-induced Bone Loss: Roles of MAPKs, Akt, NF-κB and calcium/calcineurin/NFATc1 Pathways. PLoS One. 2013;8(7):e69468. PubMed PMID: 23936022.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - KMUP-1 suppresses RANKL-induced osteoclastogenesis and prevents ovariectomy-induced bone loss: roles of MAPKs, Akt, NF-κB and calcium/calcineurin/NFATc1 pathways. AU - Liou,Shu-Fen, AU - Hsu,Jong-Hau, AU - Lin,I-Ling, AU - Ho,Mei-Ling, AU - Hsu,Pei-Chuan, AU - Chen,Li-Wen, AU - Chen,Ing-Jun, AU - Yeh,Jwu-Lai, Y1 - 2013/07/25/ PY - 2013/01/14/received PY - 2013/06/10/accepted PY - 2013/8/13/entrez PY - 2013/8/13/pubmed PY - 2014/3/7/medline SP - e69468 EP - e69468 JF - PloS one JO - PLoS One VL - 8 IS - 7 N2 - 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-1β, IL-6, TNF-α and HMGB1. In addition, KMUP-1 inhibited RANKL-induced activation of signaling molecules (Akt, MAPKs, calcium and NF-κB), 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/23936022/KMUP_1_suppresses_RANKL_induced_osteoclastogenesis_and_prevents_ovariectomy_induced_bone_loss:_roles_of_MAPKs_Akt_NF_��B_and_calcium/calcineurin/NFATc1_pathways_ L2 - https://dx.plos.org/10.1371/journal.pone.0069468 DB - PRIME DP - Unbound Medicine ER -