The JNK-dependent CaMK pathway restrains the reversion of committed cells during osteoclast differentiation

Chang, Eunmi; Ha, Jung Min; Huang, Hao; Kim, Hyung Joon; Woo, Jung Hoon; Lee, Youngkyun; Lee, Zang Hee; Kim, Ju Han; Kim, Hong Hee

doi:10.1242/jcs.028217

Cited by 59 publications

(49 citation statements)

References 44 publications

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“…Several intracellular signals are essential for osteoclast formation, including NF-jB, JNK, ERK, and p38 MAPK. JNK activity, in particular, is required to maintain the committed status during osteoclastogenesis (9). We found that ROS mediate LPS-induced osteoclast formation via JNK (Fig.…”

mentioning

confidence: 62%

Peroxiredoxin II Negatively Regulates Lipopolysaccharide-Induced Osteoclast Formation and Bone LossviaJNK and STAT3

Park

Noh

Kang

et al. 2015

Antioxidants & Redox Signaling

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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-1b), 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-1b, 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][64][65][66][67][68][69][70][71][72][73][74][75][76][77]

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confidence: 62%

Peroxiredoxin II Negatively Regulates Lipopolysaccharide-Induced Osteoclast Formation and Bone LossviaJNK and STAT3

Park

Noh

Kang

et al. 2015

Antioxidants & Redox Signaling

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“…Mouse TLT-1-To discover new molecules that regulate osteoclast differentiation, we monitored gene expression profiles during osteoclast differentiation of human peripheral blood mononuclear cells (18). Microarray analysis revealed that the TLT-1 mRNA level negatively correlated with osteoclastogenesis.…”

Section: Cloning and Characterization Of The Alternative Transcript Ofmentioning

confidence: 99%

TLT-1s, Alternative Transcripts of Triggering Receptor Expressed on Myeloid Cell-like Transcript-1 (TLT-1), Inhibits the Triggering Receptor Expressed on Myeloid Cell-2 (TREM-2)-mediated Signaling Pathway during Osteoclastogenesis

Yoon

Lee

et al. 2012

Journal of Biological Chemistry

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Background:The triggering receptor expressed on myeloid cell (TREM)-mediated signaling is essential for osteoclastogenesis. Results: The alternative transcripts of triggering receptor expressed on myeloid cell-like transcript-1 (TLT-1s) inhibits osteoclast formation by counteracting the TREM-2 signaling pathway. Conclusion: TLT-1s is a negative regulator of osteoclastogenesis, by constitutively associating with SHP-1 and SHIP-1 phosphatases, abrogating the TREM-2 signaling upon RANKL stimulation. Significance: We discovered that an alternative transcript of TLT-1, namely TLT-1s, negatively regulates osteoclastogenesis.

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“…BMMs (5 3 10 5 cells per well in 6-well plates) were treated with M-CSF (20 ng/ml), RANKL (150 ng/ml), or M-CSF plus RANKL for 6 h. To detect CXCL2, 50 ml of the 1 ml culture supernatant was used for Western blotting (14). After treating BMMs with CXCL2 (50 ng/ml) in the absence or presence of M-CSF (10 ng/ml) for the indicated times, cell lysates were subjected to Western blotting to detect ERK and Akt phosphorylation.…”

Section: Western Blottingmentioning

confidence: 99%

CXC Chemokine Ligand 2 Induced by Receptor Activator of NF-κB Ligand Enhances Osteoclastogenesis

Choi

Lee

et al. 2010

The Journal of Immunology

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CXCL2 has been known to regulate immune functions mainly by chemo-attracting neutrophils. In this study, we show that CXCL2 can be induced by receptor activator of NF-κB ligand, the osteoclast (OC) differentiation factor, through JNK and NF-κB signaling pathways in OC precursor cells. CXCL2 in turn enhanced the proliferation of OC precursor cells of bone marrow-derived macrophages (BMMs) through the activation of ERK. Knockdown of CXCL2 inhibited both the proliferation of and the ERK activation in BMMs. During osteoclastogenesis CXCL2 stimulated the adhesion and the migration of BMMs. Moreover, the formation of OCs from BMMs was significantly increased on treatment with CXCL2. Conversely, the CXCL2 antagonist repertaxin and a CXCL2 neutralizing Ab potently reduced receptor activator of NF-κB ligand-induced osteoclastogenesis. Furthermore, CXCL2 evoked fulminant bone erosion in the in vivo mouse experiments. Finally, prominent upregulation of CXCL2 was detected in synovial fluids and sera from rheumatoid arthritis patients, suggesting a potential involvement of CXCL2-mediated osteoclastogenesis in rheumatoid arthritis-associated bone destruction. Thus, CXCL2 is a novel therapeutic target for inflammatory bone destructive diseases.

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The JNK-dependent CaMK pathway restrains the reversion of committed cells during osteoclast differentiation

Cited by 59 publications

References 44 publications

Peroxiredoxin II Negatively Regulates Lipopolysaccharide-Induced Osteoclast Formation and Bone LossviaJNK and STAT3

Peroxiredoxin II Negatively Regulates Lipopolysaccharide-Induced Osteoclast Formation and Bone LossviaJNK and STAT3

TLT-1s, Alternative Transcripts of Triggering Receptor Expressed on Myeloid Cell-like Transcript-1 (TLT-1), Inhibits the Triggering Receptor Expressed on Myeloid Cell-2 (TREM-2)-mediated Signaling Pathway during Osteoclastogenesis

CXC Chemokine Ligand 2 Induced by Receptor Activator of NF-κB Ligand Enhances Osteoclastogenesis

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