In:
Journal of Cellular Physiology, Wiley, Vol. 230, No. 9 ( 2015-09), p. 2038-2048
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‐3β (GSK‐3β), with associated nuclear translocation of β‐catenin. Co‐treatment with H89 and KT5823, cAMP and cGMP pathway inhibitors, respectively, reversed the KMUP‐1‐induced activations of Smad1/5/8, β‐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/β‐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. J. Cell. Physiol. 230: 2038–2048, 2015. © 2014 Wiley Periodicals, Inc.
Type of Medium:
Online Resource
ISSN:
0021-9541
,
1097-4652
Language:
English
Publisher:
Wiley
Publication Date:
2015
detail.hit.zdb_id:
1478143-8
SSG:
12
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