Peroxiredoxin II negatively regulates BMP2-induced osteoblast differentiation and bone formation via PP2A Cα-mediated Smad1/5/9 dephosphorylation

Abstract

Peroxiredoxin II (Prx II), an antioxidant enzyme in the Prx family, reduces oxidative stress by decreasing the intracellular ROS levels. Osteoblast differentiation is promoted by bone morphogenetic protein 2 (BMP2), which upregulates the expression of osteoblast differentiation marker genes, through Smad1/5/9 phosphorylation. We found that Prx II expression was increased by a high dose of lipopolysaccharide (LPS) but was not increased by a low dose of LPS. Prx II itself caused a decrease in the osteogenic gene expression, alkaline phosphatase (ALP) activity, and Smad1/5/9 phosphorylation induced by BMP2. In addition, BMP2-induced osteogenic gene expression and ALP activity were higher in Prx II knockout (KO) cells than they were in wild-type (WT) cells. These inhibitory effects were mediated by protein phosphatase 2A Cα (PP2A Cα), which was increased and is known to induce the dephosphorylation of Smad1/5/9. The overexpression of Prx II increased the expression of PP2A Cα, and PP2A Cα was not expressed in Prx II KO cells. Moreover, PP2A Cα reduced the level of BMP2-induced osteogenic gene expression and Smad1/5/9 phosphorylation. LPS inhibited BMP2-induced Smad1/5/9 phosphorylation and the suppressed phosphorylation was restored by the PP2A inhibitor okadaic acid (OA). Bone phenotype analyses using microcomputed tomography (μCT) revealed that the Prx II KO mice had higher levels of bone mass than the levels of the WT mice. We hypothesize that Prx II has a negative role in osteoblast differentiation through the PP2A-dependent dephosphorylation of Smad1/5/9.

RETRACTED ARTICLE: Schnurri-3 regulates BMP9-induced osteogenic differentiation and angiogenesis of human amniotic mesenchymal stem cells through Runx2 and VEGF

“…BMPs belong to the TGF-β super-family, which are recognized as playing critical roles in regulating bone formation and proliferation 50,51 , as well as in angiogenesis 52,53 . However, some members of BMPs can commit MSCs to osteoblast lineages, such BMP2, BMP4, BMP6, and BMP7 54,55 . In a recent study, we reported that BMP9 (also termed as growth differentiation factor 2) is one of the most potent BMPs among the 14 types of BMPs in the induction of osteogenic differentiation 19,56 .…”

Knockout Mouse Models for Peroxiredoxins

“…PRDX2 is expressed in all cell types and is the third most abundant protein in erythrocytes [44]. Three PRDX isoforms (PRDX1, PRDX2, and PRDX6) are expressed in mature erythrocytes and PRDX2 is the most abundant protein among them [45]. The role of PRDX2 in protecting erythrocytes against oxidative stress has been verified by several studies using the same Prdx2-knockout mouse model [46][47][48][49][50][51][52][53][54][55].…”

“…Prdx2 −/− have higher levels of bone mass than those of wild-type mice because PRDX2 is a negative regulator of BMP2-induced osteoblast differentiation [45]. PRDX2 also functions as a negative regulator of LPS-induced osteoclastogenesis and bone loss, which are induced by ROS-mediated JNK and STAT3 activation [71].…”

N-myc Downstream-Regulated Gene 2 (NDRG2) Promotes Bone Morphogenetic Protein 2 (BMP2)-Induced Osteoblastic Differentiation and Calcification by Janus Kinase 3 (JAK3)/Signal Transducer and Activator of Transcription 3 (STAT3) Signaling Pathway

“…BMP2 is the only growth factor inducing the mesenchymal cells to differentiate into bone tissues. In the early stage of bone formation, BMP2 can not only recruit undifferentiated mesenchymal cells into bone formation to differentiate into bone cells, but also reverse the differentiation of fibroblast myoblasts and bone marrow basal cells into bone cells [14].…”