PDZRN3 negatively regulates BMP-2-induced osteoblast differentiation through inhibition of Wnt signaling.
PDZRN3 is a member of the PDZ domain-containing RING finger family of proteins. We previously showed that PDZRN3 is essential for the differentiation of C2C12 mouse mesenchymal progenitor cells into myotubes. Mesenchymal progenitor cells differentiate into osteoblasts, chondrocytes, and adipocytes in addition to myotubes, and we have now examined the potential role of PDZRN3 in the differentiation of C2C12 cells into osteoblasts. The abundance of PDZRN3 in C2C12 cells was increased after the induction of osteoblast differentiation by exposure to bone morphogenetic protein (BMP)-2 in low-serum medium. Depletion of PDZRN3 in C2C12 cells by RNA interference resulted in marked enhancement of the BMP-2-induced up-regulation of alkaline phosphatase (ALP) activity. Dkk1, an inhibitor of Wnt signaling, markedly attenuated the enhancement of the BMP-2-induced increase in ALP activity by PDZRN3 depletion. The up-regulation of ALP activity by Wnta3a was also promoted by depletion of PDZRN3. Furthermore, the expression and Wnt3a-induced phosphorylation of LRP6 as well as the increase in the cytosolic abundance of β-catenin induced by Wnt3a were potentiated in PDZRN3-depleted cells. These results indicate that PDZRN3 plays an important role in negative feedback control of BMP-2-induced osteoblast differentiation in C2C12 cells through inhibition of Wnt-β-catenin signaling.
Honda
Takeshi
T
Department of Pharmacology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi 755-8505, Japan.
Yamamoto
Hisato
H
Ishii
Aiko
A
Inui
Makoto
M
D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D055396:Bone Morphogenetic Protein 2; D002352:Carrier Proteins; D050659:Core Binding Factor Alpha 1 Subunit; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; C485992:PDZRN3 protein, human; D044767:Ubiquitin-Protein Ligases; D000469:Alkaline Phosphatase