PKC signaling inhibits osteogenic differentiation through the regulation of Msx2 function.
Protein kinase C (PKC) signaling regulates osteoblast differentiation, but little is known about its downstream effectors. We examined the effect of modulating PKC activity on osteogenic transcription factors and found that the protein level of Msx2 is affected. Msx2 is induced by osteogenic signals such as BMPs and it plays critical roles in bone formation and osteoblast differentiation. Here, we examined the role of PKC signaling in regulating the function of Msx2. We found that the inhibition of PKC signaling enhances osteogenic differentiation in BMP2-stimulated C2C12 cells. Treatment with inhibitors of PKC activity or overexpression of kinase-defective (KD), dominant-negative mutant PKC isoforms strongly reduced the level of Msx2 protein. Several PKC isoforms (α, β, δ, and ζ) interacted with Msx2, and PKCβ phosphorylated Msx2 at Thr135 and Thr141. Msx2 repressed the transcriptional activity of the osteogenic transcription factor Runx2, and this repression was relieved by inhibition of PKC activity or overexpression of the KD mutant PKC isoforms. In addition, PKC prolonged the half-life of Msx2 protein. These results suggest that PKC signaling modulates osteoblast differentiation, at least in part, through the regulation of Msx2.
Chonnam National University, Gwangju, Republic of Korea.
Hyung Min
HM
Jeong
Yun-Hye
YH
Jin
You Hee
YH
Choi
Jinah
J
Yum
Joong-Kook
JK
Choi
Chang-Yeol
CY
Yeo
Kwang-Youl
KY
Lee
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000502:physiology; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D015870:Gene Expression; D006207:Half-Life; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D010012:Osteogenesis; D010766:Phosphorylation; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D064546:Protein Kinase C beta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D015398:Signal Transduction; D015533:Transcriptional Activation; D054875:Ubiquitination
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D018398:Homeodomain Proteins; C084119:MSX2 protein; D047428:Protein Kinase Inhibitors; C493709:RUNX2 protein, human; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D000469:Alkaline Phosphatase