title: Pannexin 3 inhibits proliferation of osteoprogenitor cells by regulating Wnt and p21 signaling.
abstract: Canonical Wnt signaling and BMP promote the proliferation and differentiation of osteoprogenitors, respectively. However, the regulatory mechanism involved in the transition from proliferation to differentiation is unclear. Here, we show that Panx3 (pannexin 3) plays a key role in this transition by inhibiting the proliferation and promoting the cell cycle exit. Using primary calvarial cells and explants, C3H10T1/2 cells, and C2C12 cells, we found that Panx3 expression inhibited cell growth, whereas the inhibition of endogenous Panx3 expression increased it. We also found that the Panx3 hemichannel inhibited cell growth by promoting β-catenin degradation through GSK3β activation. Additionally, the Panx3 hemichannel inhibited cyclin D1 transcription and Rb phosphorylation through reduced cAMP/PKA/CREB signaling. Furthermore, the Panx3 endoplasmic reticulum Ca(2+) channel induced the transcription and phosphorylation of p21, through the calmodulin/Smad pathway, and resulted in the cell cycle exit. Our results reveal that Panx3 is a new regulator that promotes the switch from proliferation to differentiation of osteoprogenitors via multiple Panx3 signaling pathways.
authors: From the Laboratory of Cell and Developmental Biology, NIDCR, National Institutes of Health, Bethesda, Maryland 20892-4370.
authors: Masaki
authors: M
authors: Ishikawa
authors: Tsutomu
authors: T
authors: Iwamoto
authors: Satoshi
authors: S
authors: Fukumoto
authors: Yoshihiko
authors: Y
authors: Yamada
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009924:Organ Culture Techniques; D010011:Osteocytes / Q000166:cytology*; D012886:Skull / Q000166:cytology; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D017630:Connexins; D051176:beta Catenin; C528477:pannexin 3 protein, mouse; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D054462:p21-Activated Kinases; D038362:Glycogen Synthase Kinase 3; D002118:Calcium
keywords: ATP; Calcium Intracellular Release; Cell Proliferation; Hemichannel and ER Ca2+ Channel; Intracellular ATP and Ca2+ levels; Pannexin; Pannexin 3; Wnt Signaling; Wnt/β-Catenin Signaling; p21