Focus on the p38 MAPK signaling pathway in bone development and maintenance

Advanced oxidation protein products (AOPPs) are recognized as novel markers of oxidative stress and contribute to various medical conditions, which are associated with secondary osteoporosis. However, little is currently known regarding the role of AOPPs in the development of secondary osteoporosis. As the commander cells of bone remodeling, osteocytes are involved in the pathogenesis of osteoporosis. The present study aimed to determine the cytotoxic mechanisms of AOPPs on osteocytic MLO-Y4 cells. The results demonstrated that treatment with AOPPs significantly triggered apoptosis of MLO-Y4 cells, in a dose- and time-dependent manner. Furthermore, exposure to AOPPs induced phosphorylation of c-Jun N-terminal kinases (JNK) and p38 mitogen-activated protein kinases (MAPK). Conversely, N-acetylcysteine inhibited the activation of JNK and p38 MAPK, thus suggesting that the AOPPs-induced activation of JNK/p38 MAPK is reactive oxygen species (ROS)-dependent. In addition, SB203580 and SP600125 suppressed apoptosis, but did not affect ROS production, following AOPPs treatment. Notably, AOPPs also induced a significant upregulation in the expression levels of sclerostin and receptor activator of nuclear factor kappa-B ligand (RANKL) in a JNK/p38 MAPK-dependent manner. These findings provide novel insights into the molecular mechanisms underlying AOPPs-mediated cell death, and suggest that modulation of apoptotic pathways via the MAPK signaling cascade may be considered a therapeutic strategy for the prevention and treatment of secondary osteoporosis.

show abstract

“…The extent and duration of MAPK activation serves a key role in regulating cell functions (17,18). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Advanced oxidation protein products induce apoptosis, and upregulate sclerostin and RANKL expression, in osteocytic MLO-Y4 cells via JNK/p38 MAPK activation

Huang

Wang

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

show abstract

“…In the MSC-osteoblast lineage, p38 MAPKs are found to promote MSC osteogenic commitment and osteoblast maturation by suppressing the NF-κB pathway and phosphorylating Runx2203746. In addition, p38 MAPKs in Prx1-labeled MSCs appear to regulate the expression of OPG, which regulates bone mass accrual under physiological and pathological conditions23.…”

Section: Discussionmentioning

confidence: 99%

p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner

Qian

Jia

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α−/− cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.

show abstract

“…(8,9,12) Inhibition of p38 MAPK was reported to fully diminish RANKL and TNF-α-induced osteoclast formation. (15) In the present study, RANKL and TNF-α induced formation of TRAP + PNCs, meanwhile pretreatment of caffeic acid could diminish the formation of RANKL and TNF-α-induced TRAP + PNCs. The upregulated phosphorylation of p38 MAPK was clearly observed in RANKL and TNF-α-induced RAW-D cell, meanwhile pretreatment of caffeic acid could diminish the phosphorylation of p38 MAPK.…”

Section: Discussionmentioning

confidence: 86%

Caffeic Acid Inhibits RANKL and TNF-α-induced Phosphorylation of p38 Mitogen-activated Protein Kinase in RAW-D Cells

Sandra

Ketherin

2018

Indones Biomed J

View full text Add to dashboard Cite

B ACKGROUND:Caffeic acid inhibits osteoclastogenesis by downregulating expression of Cathepsin K and Nuclear Factor of Activated T cells (NFATc)1, as well as inhibiting activity of Nuclear Factor kB (NFkB). Meanwhile TNF Receptor-associated Factor (TRAF)6 was not influenced by caffeic acid. In order to investigate further caffeic acid's mechanism in inhibiting osteoclastogenesis, regulation of caffeic acid on p38 Mitogen-activated Protein Kinase (MAPK) was investigated.METHODS: RAW-D cells were pretreated with/without caffeic acid and treated with/without 20 ng/mL RANKL and 1 ng/mL TNFα for 0.2, 1, 6, and 12 hour. Tartrate Resistant Acid Phosphatase (TRAP) staining was performed. Then, western blot analysis was performed to detect p38 MAPK and phosphorylated-p38 MAPK. Resulted protein bands were quantified and statistically analyzed. RESULTS:Under induction of 20 ng/mL RANKL and 1 ng/ mL TNF-α, RAW-D cells were successfully differentiated into TRAP + osteoclast-like polynuclear cells. Under treatment of 20 ng/mL of RANKL and 1 ng/mL of TNF-α for 0.2 or 1 hour, significant (p=0,000, T test) increment of phosphorylated p38 MAPK was observed as compared with control. Pretreatment of 10 µg/mL caffeic acid significantly (p=0.000, T test) suppressed the 20 ng/mL of RANKL and 1 ng/mL of TNF-α-induced phosphorylation of p38 MAPK.

show abstract

Focus on the p38 MAPK signaling pathway in bone development and maintenance

Cited by 126 publications

References 59 publications

Advanced oxidation protein products induce apoptosis, and upregulate sclerostin and RANKL expression, in osteocytic MLO-Y4 cells via JNK/p38 MAPK activation

Advanced oxidation protein products induce apoptosis, and upregulate sclerostin and RANKL expression, in osteocytic MLO-Y4 cells via JNK/p38 MAPK activation

p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner

Caffeic Acid Inhibits RANKL and TNF-α-induced Phosphorylation of p38 Mitogen-activated Protein Kinase in RAW-D Cells

Contact Info

Product

Resources

About