TM‐25659 enhances osteogenic differentiation and suppresses adipogenic differentiation by modulating the transcriptional co‐activator TAZ

Abstract

BACKGROUND AND PURPOSEThe 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 PPARg, respectively. Therefore, it would be of interest to identify low MW compounds that modulate nuclear TAZ activity. EXPERIMENTAL APPROACHHigh-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 RESULTSWe 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 PPARg-mediated adipocyte differentiation by facilitating PPARg 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 IMPLICATIONSTM-25659 stimulated nuclear TAZ localization and thus caused TAZ to suppress PPARg-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.

Screening with a Novel Cell-Based Assay for TAZ Activators Identifies a Compound That Enhances Myogenesis in C2C12 Cells and Facilitates Muscle Repair in a Muscle Injury Model

“…The osteogenic and antiadipogenic effects of kaempferol, a dietary flavonoid, depend on TAZ, supporting the notion that TAZ can be a therapeutic target in osteoporosis and obesity (55). Accordingly, the TAZ activator TM-25659 has been proposed to be beneficial in the control of osteoporosis and obesity (56). However, in the treatment of osteoporosis, the patients are females after menopause and relatively young.…”

Osteoblast-Targeted Overexpression of TAZ Increases Bone Mass In Vivo

“…Although 2.3 kb Col 1 promoter drives transgenes specifically in mature osteoblasts [36], previous studies demonstrated that overexpression of Runx2 driven by 2.3 kb Col 1 promoter led to increased bone resorption phenotypes, primarily due to increased RANKL expression [37], [38]. A recent study also showed that treatment with small molecule that activates TAZ could protect ovariectomy-induced bone loss in vivo [39]. However, in our study, the RANKL/OPG expression levels in calvaria cells from Col.1-TAZ mice were not significantly different from those from WT mice.…”

Validation of chemical compound library screening for transcriptional co‐activator with PDZ‐binding motif inhibitors using GFP‐fused transcriptional co‐activator with PDZ‐binding motif

“…Jang et al . expressed GFP‐TAZ in COS‐7 cells and identified novel TAZ activators . In this study, we expressed GFP‐TAZ in U2OS cells and applied small chemical compounds to these cells.…”

“…(44) Jang et al expressed GFP-TAZ in COS-7 cells and identified novel TAZ activators. (45) In this study, we expressed GFP-TAZ in U2OS cells and applied small chemical compounds to these cells. We aimed in this study to validate that this cell-based assay provides the compounds that inhibit TAZ through the Hippo pathway.…”