Evidence map›Paper›PMID 24743742›Full record

ArticleCell death & disease2014

Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation.

R-L Huang, Y Yuan, J Tu, G-M Zou, Q Li

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell death & disease, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 90 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
90citing papers in PubMed, 1 pooled it
4.7field-weighted citation impact, top 4% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

90 citing papers in PubMed, 1 synthesis or guideline pooled it, 184 citations in OpenAlex.

  1. Pooled it
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  13. Nrf2 signaling pathway: focus on oxidative stress in osteoporosis.Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA · 2025
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  15. Paeonol fromFood science and biotechnology · 2025
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  19. Frontiers in veterinary science · 2025
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30 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

5 authors at 2 institutions in 1 country.

R-L Huang1] Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China [2] Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Y Yuan1] Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China [2] Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
J Tu1] Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China [2] Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
G-M ZouShanghai Cancer Institute, Shanghai Jiao Tong University, Shanghai 200240, China.
Q LiDepartment of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Shanghai Jiao Tong University · CNShanghai Cancer Institute · CN

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

In patients who were treated with exogenous BMP-2 to repair bone fractures or defects, the levels of the inflammatory cytokines such as TNF-α and IL-1β in sera are significantly elevated, which may affect the outcome of bone regeneration. Mitogen-activated protein kinase (MAPK) cascades such as extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and c-Jun NH2-terminal kinase 1/2 (JNK1/2) have a crucial role in osteogenic differentiation and are activated by both BMP-2 and TNF-α/IL-1β. However, previous studies suggested that the effects of BMP-2 and TNF-α/IL-1β in osteoblastic differentiation are opposite. Here, we investigated the exact role of MAPKs in a BMP-2 and TNF-α/IL-1β co-existed condition. Treatment with TNF-α/IL-1β inhibited BMP-2-induced alkaline phosphatase activity, calcium deposition, osteogenic transcriptional factor Runx2, and the expression of osteogenic markers in C2C12 and MC3T3-E1 cells. This inhibitory effect was independent of the canonical BMP/Smad pathway, suggesting the presence of an alternate regulatory pathway for BMP-2-induced Runx2 activity and subsequent osteoblastic differentiation. We then confirmed that BMP-2, TNF-α, and IL-1β alone can activate p38, ERK1/2, and JNK1/2, respectively. However, only inhibition of p38 and ERK1/2 signaling were required to modulate BMP-2-induced Runx2 expression. Finally, we determined that TNF-α/IL-1β decreased BMP-2-induced Runx2 expression through the activation of p38 and ERK1/2 signaling. Furthermore, strong activation of p38 and ERK1/2 signaling by transfection with CA-MKK3 or CA-MEK1 inhibited BMP-2-induced Runx2 expression and osteoblastic differentiation in C2C12 and MC3T3-E1 cells. Based on these results, we conclude that TNF-α/IL-1β- and BMP-2-activated p38 and ERK1/2 signaling have opposing roles that converge on Runx2 to regulate osteoblastic differentiation. The elucidation of these mechanisms may hasten the development of new strategies and improve the osteoinductive efficacy of BMP-2 in the clinic to enhance osteoblastic differentiation and bone formation.

Indexed as

AnimalsBone Morphogenetic Protein 2Cell DifferentiationCell LineCore Binding Factor Alpha 1 SubunitEnzyme ActivationExtracellular Signal-Regulated MAP KinasesHumansInterleukin-1betaMAP Kinase Signaling SystemMiceModels, BiologicalOsteoblastsp38 Mitogen-Activated Protein KinasesSmad ProteinsTumor Necrosis Factor-alphaBone Morphogenetic Protein 2Core Binding Factor Alpha 1 SubunitExtracellular Signal-Regulated MAP KinasesInterleukin-1betap38 Mitogen-Activated Protein KinasesSmad ProteinsTumor Necrosis Factor-alpha

Identifiers

PMID24743742
PMCPMC4001295
OpenAlexW2066371393

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-SA
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.