TM-25659 enhances osteogenic differentiation and suppresses adipogenic differentiation by modulating the transcriptional co-activator TAZ
- Authors
- Jang, E. J.; Jeong, H.; Kang, J. O.; Kim, N. J.; Kim, M. S.; Choi, S. H.; Yoo, S. E.; Hong, J. H.; Bae, M. A.; Hwang, E. S.
- Issue Date
- 3월-2012
- Publisher
- WILEY-BLACKWELL
- Keywords
- TAZ; RUNX2; PPAR; TM-25659; osteoblast
- Citation
- BRITISH JOURNAL OF PHARMACOLOGY, v.165, no.5, pp.1584 - 1594
- Indexed
- SCIE
SCOPUS
- Journal Title
- BRITISH JOURNAL OF PHARMACOLOGY
- Volume
- 165
- Number
- 5
- Start Page
- 1584
- End Page
- 1594
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/105428
- DOI
- 10.1111/j.1476-5381.2011.01664.x
- ISSN
- 0007-1188
- Abstract
- BACKGROUND AND PURPOSE The transcriptional co-activator with PDZ-binding motif (TAZ) is characterized as a transcriptional modulator of mesenchymal stem cell differentiation into osteoblasts and adipocytes. Moreover, increased TAZ activity in the nucleus enhances osteoblast differentiation and suppresses adipocyte development by interacting with runt-related transcription factor 2 (RUNX2) and PPAR gamma, respectively. Therefore, it would be of interest to identify low MW compounds that modulate nuclear TAZ activity. EXPERIMENTAL APPROACH High-throughput screening was performed using a library of low MW compounds in order to identify TAZ modulators that enhance nuclear TAZ localization. The effects and molecular mechanisms of a TAZ modulator have been characterized in osteoblast and adipocyte differentiation. KEY RESULTS We identified 2-butyl-5-methyl-6-(pyridine-3-yl)-3-[2'-(1H-tetrazole-5-yl)-biphenyl-4-ylmethyl]-3H-imidazo[4,5-b] pyridine] (TM-25659) as a TAZ modulator. TM-25659 enhanced nuclear TAZ localization in a dose-dependent manner and attenuated PPAR gamma-mediated adipocyte differentiation by facilitating PPAR gamma suppression activity of TAZ. In addition, TAZ-induced RUNX2 activity activation was further increased in osteoblasts, causing increased osteoblast differentiation. Accordingly, TM-25659 suppressed bone loss in vivo and decreased weight gain in an obesity model. After oral administration, TM-25659 had a favourable pharmacokinetic profile. CONCLUSION AND IMPLICATIONS TM-25659 stimulated nuclear TAZ localization and thus caused TAZ to suppress PPAR gamma-dependent adipogenesis and enhance RUNX2-induced osteoblast differentiation in vitro and in vivo. Our data suggest that TM-25659 could be beneficial in the control of obesity and bone loss.
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