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Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2.
J Cell Biochem. 2007 Mar 01; 100(4):1056-69.JC

Abstract

Methylglyoxal (MG) is a reactive dicarbonyl compound endogenously produced mainly from glycolytic intermediates. MG is cytotoxic through induction of cell death, and elevated MG levels in diabetes patients are believed to contribute to diabetic complications. In this report, we show for the first time that MG treatment triggers apoptosis in human osteoblasts. We further show that MG-induced apoptosis of osteoblasts involves specific apoptotic biochemical changes, including oxidative stress, c-Jun N-terminal kinase (JNK) activation, mitochondrial membrane potential changes, cytochrome C release, increased Bax/Bcl-2 protein ratios, and activation of caspases (caspase-9, caspase-3) and p21-activated protein kinase 2 (PAK2). Treatment of osteoblasts with SP600125, a JNK-specific inhibitor, led to a reduction in MG-induced apoptosis and decreased activation of caspase-3 and PAK2, indicating that JNK activity is upstream of these events. Experiments using anti-sense oligonucleotides against PAK2 further showed that PAK2 activation is required for MG-induced apoptosis in osteoblasts. Interestingly, we also found that MG treatment triggered nuclear translocation of NF-kappaB, although the precise regulatory role of NF-kappaB activation in MG-induced apoptosis remains unclear. Lastly, we examined the effect of MG on osteoblasts in vivo, and found that exposure of rats to dietary water containing 100-200 microM MG caused bone mineral density (BMD) loss. Collectively, these results reveal for the first time that MG treatment triggers apoptosis in osteoblasts via specific apoptotic signaling, and causes BMD loss in vivo.

Authors+Show Affiliations

Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Chung Li, Taiwan. whchan@cycu.edu.twNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17131386

Citation

Chan, Wen-Hsiung, et al. "Apoptotic Signaling in Methylglyoxal-treated Human Osteoblasts Involves Oxidative Stress, c-Jun N-terminal Kinase, Caspase-3, and P21-activated Kinase 2." Journal of Cellular Biochemistry, vol. 100, no. 4, 2007, pp. 1056-69.
Chan WH, Wu HJ, Shiao NH. Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2. J Cell Biochem. 2007;100(4):1056-69.
Chan, W. H., Wu, H. J., & Shiao, N. H. (2007). Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2. Journal of Cellular Biochemistry, 100(4), 1056-69.
Chan WH, Wu HJ, Shiao NH. Apoptotic Signaling in Methylglyoxal-treated Human Osteoblasts Involves Oxidative Stress, c-Jun N-terminal Kinase, Caspase-3, and P21-activated Kinase 2. J Cell Biochem. 2007 Mar 1;100(4):1056-69. PubMed PMID: 17131386.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Apoptotic signaling in methylglyoxal-treated human osteoblasts involves oxidative stress, c-Jun N-terminal kinase, caspase-3, and p21-activated kinase 2. AU - Chan,Wen-Hsiung, AU - Wu,Hsin-Jung, AU - Shiao,Nion-Heng, PY - 2006/11/30/pubmed PY - 2007/4/17/medline PY - 2006/11/30/entrez SP - 1056 EP - 69 JF - Journal of cellular biochemistry JO - J Cell Biochem VL - 100 IS - 4 N2 - Methylglyoxal (MG) is a reactive dicarbonyl compound endogenously produced mainly from glycolytic intermediates. MG is cytotoxic through induction of cell death, and elevated MG levels in diabetes patients are believed to contribute to diabetic complications. In this report, we show for the first time that MG treatment triggers apoptosis in human osteoblasts. We further show that MG-induced apoptosis of osteoblasts involves specific apoptotic biochemical changes, including oxidative stress, c-Jun N-terminal kinase (JNK) activation, mitochondrial membrane potential changes, cytochrome C release, increased Bax/Bcl-2 protein ratios, and activation of caspases (caspase-9, caspase-3) and p21-activated protein kinase 2 (PAK2). Treatment of osteoblasts with SP600125, a JNK-specific inhibitor, led to a reduction in MG-induced apoptosis and decreased activation of caspase-3 and PAK2, indicating that JNK activity is upstream of these events. Experiments using anti-sense oligonucleotides against PAK2 further showed that PAK2 activation is required for MG-induced apoptosis in osteoblasts. Interestingly, we also found that MG treatment triggered nuclear translocation of NF-kappaB, although the precise regulatory role of NF-kappaB activation in MG-induced apoptosis remains unclear. Lastly, we examined the effect of MG on osteoblasts in vivo, and found that exposure of rats to dietary water containing 100-200 microM MG caused bone mineral density (BMD) loss. Collectively, these results reveal for the first time that MG treatment triggers apoptosis in osteoblasts via specific apoptotic signaling, and causes BMD loss in vivo. SN - 0730-2312 UR - https://www.unboundmedicine.com/medline/citation/17131386/Apoptotic_signaling_in_methylglyoxal_treated_human_osteoblasts_involves_oxidative_stress_c_Jun_N_terminal_kinase_caspase_3_and_p21_activated_kinase_2_ L2 - https://doi.org/10.1002/jcb.21114 DB - PRIME DP - Unbound Medicine ER -