Abstract
Osteoblasts are derived from mesenchymal progenitors. Differentiation to osteoblasts and adipocytes is reciprocally regulated. Transcriptional coactivator with a PDZ-binding motif (TAZ) is a transcriptional coactivator that induces differentiation of mesenchymal cells into osteoblasts while blocking differentiation into adipocytes. To investigate the role of TAZ on bone metabolism in vivo, we generated transgenic mice that overexpress TAZ under the control of the procollagen type 1 promoter (Col1-TAZ). Whole body bone mineral density (BMD) of 6- to 19-week-old Col-TAZ mice was 4% to 7% higher than that of their wild-type (WT) littermates, whereas no difference was noticed in Col.1-TAZ female mice. Microcomputed tomography analyses of proximal tibiae at 16 weeks of age demonstrated a significant increase in trabecular bone volume (26.7%) and trabecular number (26.6%) with a reciprocal decrease in trabecular spacing (14.2%) in Col1-TAZ mice compared with their WT littermates. In addition, dynamic histomorphometric analysis of the lumbar spine revealed increased mineral apposition rate (42.8%) and the serum P1NP level was also significantly increased (53%) in Col.1-TAZ mice. When primary calvaria cells were cultured in osteogenic medium, alkaline phosphatase (ALP) activity was significantly increased and adipogenesis was significantly suppressed in Col1-TAZ mice compared with their WT littermates. Quantitative real-time polymerase chain reaction analyses showed that expression of collagen type 1, bone sialoprotein, osteocalcin, ALP, osterix, and Runx2 was significantly increased in calvaria cells from Col1-TAZ mice compared to their WT littermates. In vitro, TAZ enhanced Runx2-mediated transcriptional activity while suppressing the peroxisome proliferator-activated receptor gamma signaling pathway. TAZ also enhanced transcriptional activity from 3TP-Lux, which reflects transforming growth factor-beta (TGF-β)-mediated signaling. In addition, TAZ enhanced TGF-β-dependent nuclear translocation of Smad2/3 and Smad4. Taken together, these results suggest that TAZ positively regulates bone formation in vivo, which seems to be mediated by enhancing both Runx2 and TGF-β signaling.
Highlights
Osteoblasts are derived from mesenchymal stem cells, which are capable of differentiating into adipocytes, chondrocytes, and myocytes
There is a high degree of plasticity between osteogenic and adipogenic pathways, and differentiation to a particular lineage is accompanied by reciprocal inhibition of the alternative pathway, which is controlled by transcription factors
Our analyses were performed on transgenic mice (Col.1- Transcriptional coactivator with a PDZ-binding motif (TAZ)) in the fourth to sixth generations using WT littermate mice as controls
Summary
Osteoblasts are derived from mesenchymal stem cells, which are capable of differentiating into adipocytes, chondrocytes, and myocytes. Differentiation to a particular lineage is regulated by key transcription factors; Runx and osterix regulate osteoblastogenesis and peroxisome proliferator-activated receptor gamma (PPARc) and C/EBPa regulate adipogenesis [1,2,3,4,5]. Genetic ablation of Runx results in a complete lack of bone formation [3]. Osterix null mice exhibit a similar phenotype, showing complete absence of bone formation and osteoblasts at the embryo stage Runx is normally expressed [6]. Overexpression of PPARc2, the key transcription factor for adipogenesis, in stromal cell lines results in suppression of Runx while promoting terminal differentiation to adipocytes [7,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
