Pharmacological activation of TAZ enhances osteogenic differentiation and bone formation of adipose-derived stem cells

Abstract

BackgroundAdipose-derived stem cells (ADSCs) are an attractive cell source for bone tissue engineering and have great potential for bone regeneration and defect repair. The transcriptional coactivator with PDZ-binding motif (TAZ) has been demonstrated to modulate osteogenic and adipogenic differentiation of mesenchymal stem cells. However, its roles during ADSC differentiation and therapeutic potentials for bone regeneration have as yet not been well established.MethodsTAZ expression was measured during osteogenic differentiation of ADSCs in vitro. Both loss-of-function and gain-of-function approaches by TAZ knockdown or enforced overexpression were utilized to determine its functions during osteogenic differentiation of ADSCs. TM-25659, a chemical activator of TAZ, was used to determine whether pharmacological activation of TAZ in ADSCs enhanced osteogenic differentiation in vitro and bone formation in animal models. The molecular mechanisms underlying TAZ in promoting osteogenesis of ADSCs were also explored.ResultsIncreased TAZ expression was observed during osteogenic differentiation of human ADSCs. TAZ knockdown resulted in compromised osteogenic differentiation and enhanced adipogenic differentiation of ADSCs. In contrast, enforced TAZ overexpression yielded increased osteogenic differentiation and bone regeneration in vivo, and impaired adipogenic differentiation of ADSCs. Pharmacological activation of TAZ by its chemical activator TM-25659 facilitated osteogenic differentiation of ADSCs. Noticeably, transient treatment of ADSCs with TM-25659 or intraperitoneal injection of TM-25659 significantly enhanced bone regeneration of ADSCs loaded with porous β-TCP in vivo. Mechanistically, TM-25659 exposure significantly promoted TAZ phosphorylation and nuclear translocation, and potentiated the assembly of the TAZ-Runx2 complex. Subsequently, the TAZ-Runx2 complex was further recruited to the promoter of osteocalcin and in turn enhanced its transcription.ConclusionsOur findings indicate that TAZ is a key mediator that promotes ADSC commitment to the osteoblast lineage. Pharmacological activation of TAZ in ADSCs might become a feasible and promising approach to enhance bone regeneration and repair.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-0799-z) contains supplementary material, which is available to authorized users.

RETRACTED ARTICLE: Polydatin improves osteogenic differentiation of human bone mesenchymal stem cells by stimulating TAZ expression via BMP2-Wnt/β-catenin signaling pathway

“…As a transcriptional coactivator in the Hippo signaling pathway, transcriptional coactivator with Tafazzin (TAZ) plays a regulatory role in the Wnt signaling pathway [20]. A previous study confirmed the functions of TAZ, such as its mediation of the osteogenic differentiation of adipose-derived stem cells [21]; remarkably, TAZ obviously accelerated the osteogenesis of BMSCs through increasing the expression of RUNX2, a key transcription factor in the BMP and Wnt/β-catenin pathways [22,23]. All these findings indicate that TAZ serves as a vital osteogenesis mediator in BMSCs.…”

Lipopolysaccharide from Escherichia coli stimulates osteogenic differentiation of human periodontal ligament stem cells through Wnt/β‐catenin–induced TAZ elevation

“…TAZ, a transcriptional co‐activator regulated by interactions with 14‐3‐3 and PDZ domain proteins, has been shown to promote osteogenic differentiation of MSCs . Stimuli that promote bone formation transcriptionally up‐regulate TAZ, including LPS used in the present study.…”

Tankyrase inhibitor XAV-939 enhances osteoblastogenesis and mineralization of human skeletal (mesenchymal) stem cells

“…SH3BP2 is important for the activation of the tyrosine kinase ABL, essential for osteoblast differentiation together with the transcriptional coactivator TAZ 4 . Tankyrase inhibitors were found to increase SH3BP2 and the nuclear expression of ABL, TAZ, and RUNX2 in murine primary calvaria cells, which consequently activated the ABL-TAZ complex, and therefore enhanced the osteoblast differentiation and maturation evidenced by the significant increase in the expression of osteoblast differentiation genes and mineral deposition 4,[20][21][22] . However, the mechanism of Tankyrase signaling in bone metabolism remains to be elucidated.…”