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https://ir.cnu.edu.tw/handle/310902800/29671
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| Title: | KMUP-1 Promotes Osteoblast Differentiation Through cAMP and cGMP Pathways and Signaling of BMP-2/Smad1/5/8 and Wnt/-Catenin |
| Authors: | Liou, Shu-Fen
Hsu, Jong-Hau
Chu, Hsin-Chieh
Lin, Hung-Hong
Chen, Ing-Jun
Yeh, Jwu-Lai |
| Contributors: | 藥學系 |
| Keywords: | Protein-Kinase-G
Transcription Factor
K+ Channels
Cyclic-Gmp
Osteoprogenitor Cells
Rat Osteoblast
Smooth-Muscle
Bone Mass
Involvement
Expression |
| Date: | 2015-09 |
| Issue Date: | 2016-04-19 19:04:03 (UTC+8) |
| Publisher: | Wiley-Blackwell |
| Abstract: | Phosphodiesterase (PDE) inhibitors have been suggested as a possible candidate for the treatment of osteopenia, including osteoporosis. KMUP-1 is a novel xanthine derivative with inhibitory activities on the PDE 3, 4, and 5 iso-enzymes to suppress the degradation of cAMP and cGMP. This study aimed to investigate the effect of KMUP-1 on osteoblast differentiation and the underlying cellular and molecular mechanisms. Primary osteoblasts and osteoblastic MC3T3-E1 cells were examined. KMUP-1 enhanced alkaline phosphatase (ALP) activity and mineralization compared to untreated controls in primary osteoblasts and MC3T3-E1 cells. KMUP-1 also increased the mRNA expression of the osteoblastic differentiation markers, including collagen type 1a, ALP, osteocalcin, osteoprotegerin, BMP-2, and Runx2, a key transcription regulator for osteoblastic differentiation. The osteogenic effect of KMUP-1 was abolished by BMP signaling inhibitor, noggin. Furthermore, we found that KMUP-1 upregulated Smad1/5/8 phosphorylations with subsequent BRE-Luc activation confirmed by transient transfection assay. In addition, KMUP-1 inactivated glycogen synthase kinase-3 (GSK-3), with associated nuclear translocation of -catenin. Co-treatment with H89 and KT5823, cAMP and cGMP pathway inhibitors, respectively, reversed the KMUP-1-induced activations of Smad1/5/8, -catenin, and Runx2. The findings demonstrate for the first time that KMUP-1 can promote osteoblast maturation and differentiation in vitro via BMP-2/Smad1/5/8 and Wnt/-catenin pathways. These effects are mediated, in part, by the cAMP and cGMP signaling. Thus, KMUP-1 may be a novel osteoblast activator and a potential new therapy for osteoporosis |
| Relation: | Journal of Cellular Physiology, v.230 n.9, pp.2038-2048 |
| Appears in Collections: | [Dept. of Pharmacy] Periodical Articles
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