Roles of PKR in differentiation and apoptosis of bone-related cells.

Double-stranded RNA-dependent protein kinase (PKR) is a serine/threonine protein kinase which is activated by double-stranded RNAs and related to several signal transduction pathways. To examine the effects of PKR on bone metabolism, we established PKR-K/R mutant cells in which amino acid lysine at 296 is substituted with arginine. PKR regulated apoptosis in osteoblastic cells via nuclear factor kappa-B (NF-κB) cascade. MC3T3-E1 cells cultured with osteoblast differentiation medium differentiated into osteoblasts, while the mutant cells did not differentiate into osteoblasts. RAW246.7 cells triggered with receptor activator of NF-κB ligand (RANKL) formed tartrate-resistant acid phosphatase-positive multinucleated giant cells, whereas PKR-K/R mutant RAW cells did not. Differentiation of osteoblasts and osteoclasts was caused by NF-κB activation and signal transducer and activator of transcription 1 (STAT1) ubiquitination and degradation. We also demonstrated involvement of PKR in chondrocyte differentiation. PKR prevented tumor necrosis factor-α- and interleukin 1α-induced bone resorption in calvaria and artificially induced periodontal disease in rat. Our findings indicate that PKR regulates bone metabolism in vitro and in vivo.