The Role of Double-stranded RNA-dependent Protein Kinase in Osteoblasts

Double-stranded RNA-dependent protein kinase (PKR) is interferon ON) -inducible, doublestranded RNA (dsRNA)-activated serine/threonine protein kinase. PKR is known to have an anti-viral function and mediate transcriptional activation. However, there are few reports concerning the role of PKR in bone metabolism. We established cells that stably expressed the PKR catalytic mutant gene (PKR-K/R) to investigate the role of PKR in osteoblast differentiation. The PKR-K/R mutant cells exhibited up-regulated cell proliferation and low alkaline phosphatase (ALP) activity. The PKR-K/R mutant cells were not able to form bone nodules in vitro. In the PKR-K/R mutant cells, runt-related gene 2 (Runx2) -mediated transcription decreased compared to the level in control cells. The expression of STAT1α protein increased, and the protein was translocated to the nucleus in PKR-K/R mutant cells. When the expression of STAT1α protein in PKR mutant cells was suppressed using RNAi, the activity of Runx2-mediated transcription recovered to the control level. These results indicate that PKR is a stimulator of Runx2 transcription and a negative modulator of STAT1α expression. Our findings also suggest that PKR plays an important role in the differentiation of osteoblasts and calcification of bone matrix by modulating STAT1α and/or Runx2 expression.