TY - JOUR
T1 - Peroxiredoxin II negatively regulates lipopolysaccharide-induced osteoclast formation and bone loss via JNK and STAT3
AU - Park, Hyojung
AU - Noh, A. Long Sae Mi
AU - Kang, Ju Hee
AU - Sim, Jung Sun
AU - Lee, Dong Seok
AU - Yim, Mijung
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Aims: Lipopolysaccharide (LPS) is considered a prominent pathogenic factor in inflammatory bone diseases. LPS challenge contributes to the production of reactive oxygen species (ROS) in diverse inflammatory diseases. However, its mechanism remains to be clarified in bone. Thus, we investigated the critical mechanism of ROS in LPS-induced osteoclastogenesis and bone loss.Results: Antioxidant prevented LPS-induced osteoclast formation via inhibition of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and c-Fos expression in preosteoclasts. Moreover, LPS-induced osteoclast formation via ROS was attenuated by treatment with c-Jun N-terminal protein kinase (JNK) inhibitor. Interestingly, LPS also activated signal transducer and activator of transcription 3 (STAT3), which is suppressed by antioxidants. We found that knockdown of STAT3 or use of a STAT3 inhibitor resulted in a significant reduction in interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) production, followed by decreased osteoclast formation by LPS. Peroxiredoxin II (PrxII) is a member of the antioxidant enzyme family, and it plays a protective role against oxidative damage caused by ROS. In our study, ROS production and osteoclast formation by LPS was significantly enhanced in PrxII-/- cells. Moreover, JNK-mediated c-Fos and NFATc1 expression was promoted in PrxII-/- cells. Furthermore, STAT3 activation and accompanying IL-1β, IL-6, and NO production was also increased in PrxII-/- cells. Consistent with the in vitro result, PrxII-deficient mice showed increased osteoclast formation and bone loss by LPS challenge compared with wild-type mice. Innovation: For the first time, we showed that LPS-induced ROS signaling is dependent on the coordinated mechanism of JNK and STAT3 during osteoclastogenesis, which is negatively regulated by PrxII.Conclusion: We suggest that PrxII could be useful in the development of a novel target for inflammatory bone loss. Antioxid. Redox Signal. 22, 63-77.
AB - Aims: Lipopolysaccharide (LPS) is considered a prominent pathogenic factor in inflammatory bone diseases. LPS challenge contributes to the production of reactive oxygen species (ROS) in diverse inflammatory diseases. However, its mechanism remains to be clarified in bone. Thus, we investigated the critical mechanism of ROS in LPS-induced osteoclastogenesis and bone loss.Results: Antioxidant prevented LPS-induced osteoclast formation via inhibition of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) and c-Fos expression in preosteoclasts. Moreover, LPS-induced osteoclast formation via ROS was attenuated by treatment with c-Jun N-terminal protein kinase (JNK) inhibitor. Interestingly, LPS also activated signal transducer and activator of transcription 3 (STAT3), which is suppressed by antioxidants. We found that knockdown of STAT3 or use of a STAT3 inhibitor resulted in a significant reduction in interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and nitric oxide (NO) production, followed by decreased osteoclast formation by LPS. Peroxiredoxin II (PrxII) is a member of the antioxidant enzyme family, and it plays a protective role against oxidative damage caused by ROS. In our study, ROS production and osteoclast formation by LPS was significantly enhanced in PrxII-/- cells. Moreover, JNK-mediated c-Fos and NFATc1 expression was promoted in PrxII-/- cells. Furthermore, STAT3 activation and accompanying IL-1β, IL-6, and NO production was also increased in PrxII-/- cells. Consistent with the in vitro result, PrxII-deficient mice showed increased osteoclast formation and bone loss by LPS challenge compared with wild-type mice. Innovation: For the first time, we showed that LPS-induced ROS signaling is dependent on the coordinated mechanism of JNK and STAT3 during osteoclastogenesis, which is negatively regulated by PrxII.Conclusion: We suggest that PrxII could be useful in the development of a novel target for inflammatory bone loss. Antioxid. Redox Signal. 22, 63-77.
UR - http://www.scopus.com/inward/record.url?scp=84919372335&partnerID=8YFLogxK
U2 - 10.1089/ars.2013.5748
DO - 10.1089/ars.2013.5748
M3 - Article
C2 - 25074339
AN - SCOPUS:84919372335
SN - 1523-0864
VL - 22
SP - 63
EP - 77
JO - Antioxidants and Redox Signaling
JF - Antioxidants and Redox Signaling
IS - 1
ER -