Abstract
Bone morphogenetic protein 9 (BMP9) is one of the most efficacious osteogenic cytokines. PTEN and Wnt10b are both implicated in regulating the osteogenic potential of BMP9, but the potential relationship between them is unknown. In this study, we determined whether PTEN could reduce the expression of Wnt10b during the osteogenic process initialized by BMP9 in mesenchymal stem cells (MSCs) and the possible molecular mechanism. We find that PTEN is inhibited by BMP9 in MSCs, but Wnt10b is increased simultaneously. The BMP9-induced osteogenic markers are reduced by PTEN but increased by silencing PTEN. The effects of knockdown PTEN on elevating BMP9-induced osteogenic markers are almost abolished by knockdown of Wnt10b. On the contrary, the BMP9-increased ALP activities and mineralization are both inhibited by PTEN but almost reversed by the combination of Wnt10b. Bone masses induced by BMP9 are enhanced by knockdown of PTEN, which is reduced by knockdown of Wnt10b. The BMP9-increased Wnt10b is decreased by PTEN but enhanced by knockdown of PTEN. Meanwhile, the BMP9-induced Wnt10b is also reduced by a PI3K-specific inhibitor (Ly294002) or rapamycin, respectively. The BMP9-induced phosphorylation of CREB or Smad1/5/9 is also reduced by PTEN, but enhanced by PTEN knockdown. In addition, p-CREB interacts with p-Smad1/5/9 in MSCs, and p-CREB or p-Smad1/5/9 are both enriched at the promoter region of Wnt10b. Our findings indicate that inhibitory effects of PTEN on BMP9's osteogenic potential may be partially mediated through decreasing the expression of Wnt10b via the disturbance of interaction between CREB and BMP/Smad signaling.
Highlights
As a member of the bone morphogenetic protein (BMP) family, Bone morphogenetic protein 9 (BMP9) exhibits more efficacious osteogenic potential than that of BMP2 and/or BMP7 in mesenchymal stem cells (MSCs) (Kang et al, 2004; McKie et al, 2014; Xie and Bu, 2019)
PTEN or Wnt10b was involved in the osteogenic differentiation induced by BMP9 in multiple progenitor cells, but the relationship between them is unknown
Polymerase Chain Reaction (PCR) results show the recombinant adenovirus vectors increase or decrease the mRNA level of PTEN or Wnt10b in C3H10T1/2 cells (Figure 1G). These results suggest that PTEN may coordinate to regulate the osteogenic potential of BMP9 in MSCs
Summary
As a member of the bone morphogenetic protein (BMP) family, BMP9 exhibits more efficacious osteogenic potential than that of BMP2 and/or BMP7 in mesenchymal stem cells (MSCs) (Kang et al, 2004; McKie et al, 2014; Xie and Bu, 2019) It initializes the osteogenic differentiation through BMP/Smad and/or noncanonical BMP/Smad signaling, such as p38 MAPK and PI3K/Akt (Xie and Bu, 2019). Wnt10b may be associated with regulating bone mass and maintaining the progenitor activity of bone marrow stem cells (Stevens et al, 2010). It may function as a switcher between adipogenesis and osteogenesis. The molecular mechanism about how BMP9 promotes the expression of Wnt10b remains unclear
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