Abstract
ObjectivesPolydatin (PD), extracted from Polygonum cuspidatum, has shown potential therapeutic applications due to its antiosteoporotic and anti-inflammatory activities. Our previous study suggested that PD promotes the osteogenesis of human bone marrow stromal cells (hBMSCs) via the BMP2-Wnt/β-catenin pathway. The aim of our present study was to further explore the role of PD-mediated regulation of Tafazzin (TAZ), a transcriptional coactivator with a PDZ-binding motif, in osteogenesis.Materials and methodshBMSCs were isolated and treated with PD at various concentrations. Alizarin red staining and RT-qPCR were performed to identify calcium complex deposition in hBMSCs as well as the expression of specific osteoblast-related markers, respectively, in each group. Next, TAZ-silenced hBMSCs were generated by lentivirus-produced TAZ shRNA. After treatment with PD, the osteogenic abilities of the TAZ-silenced and control hBMSCs were estimated by ALP activity assay, and expression of the TAZ protein was detected by Western blot analysis and immunofluorescence staining. In vitro, an ovariectomized (OVX) mouse model was established and used to evaluate the effect of PD on bone destruction by micro-CT, immunohistochemistry, and ELISA.ResultsIn vitro, 30 μM PD significantly improved the proliferation and calcium deposition of hBMSCs and markedly stimulated the expression of the mRNAs RUNX2, Osteopontin, DLX5, β-catenin, TAZ, and Osteocalcin (OCN). Osteogenic differentiation induced by PD was blocked by lentivirus-mediated TAZ shRNA. Furthermore, Noggin (a regulator of bone morphogenic protein 2 (BMP2)) and DKK1 (an inhibitor of the Wnt/β-catenin pathway) were found to inhibit the increase in TAZ expression induced by PD. In vivo, PD prevented estrogen deficiency-induced bone loss in the OVX mouse model.ConclusionTaken together, our findings suggest that PD improved the osteogenic differentiation of hBMSCs and maintained the bone matrix in the OVX mouse model through the activation of TAZ, a potential target gene of the BMP2-Wnt/β-catenin pathway.
Highlights
Osteoporosis (OP) is a bone metabolic disease characterized by reduced bone density and an increased risk of bone fracture [1, 2]
Taken together, our findings suggest that PD improved the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) and maintained the bone matrix in the OVX mouse model through the activation of TAZ, a potential target gene of the Bone morphogenetic protein 2 (BMP2)-Wnt/β-catenin pathway
We aimed to investigate whether TAZ acts as a downstream transcriptional factor of the BMP2-Wnt/β-catenin pathways during the osteogenic differentiation of hBMSCs stimulated with PD
Summary
Osteoporosis (OP) is a bone metabolic disease characterized by reduced bone density and an increased risk of bone fracture [1, 2]. Wnt3a, a ligand of Wnt, has been proven to bind BMP proteins to activate a series of downstream reactions and promote osteogenic differentiation of BMSCs [16]. BMP2, one of the most important cytokines of the TGFβ1 superfamily [17], can promote the expression of Wnt3a and FZ and the activity of TCF/LEF and increase the expression of Wnt3a protein [18, 19]. BMP2 has the capacity to stimulate osteogenic differentiation of BMSCs by increasing the expression and phosphorylation of β-catenin [15]. All these findings support the critical roles of the BMP2 and Wnt/β-catenin pathways and their crosstalk in inducing osteoblastic differentiation of BMSCs
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