title: LPS-stimulated inflammation inhibits BMP-9-induced osteoblastic differentiation through crosstalk between BMP/MAPK and Smad signaling.
abstract: Inflammation is a common situation during bone healing and is recognized to inhibit osteogenic differentiation and bone formation. However, the effect of inflammation on BMP-9-induced osteoblastic differentiation remains unclear. In the present study, we found that an inflammatory environment triggered by lipopolysaccharide (LPS) in vitro suppressed BMP-9-induced osteogenic differentiation. In addition, LPS decreased BMP-9-induced phosphorylation of Smad1/5/8 and showed obvious inhibitory effects on BMP-9-induced Smad signaling. We then confirmed that LPS and BMP-9 can activate p38MAPK and ERK1/2 signaling, and that LPS stimulation reduces BMP-9-induced Runx2 expression through the activation of p38MAPK and ERK1/2 signaling. Finally, we determined that blockade of MAPK signaling by specific inhibitors reverses the inhibitory effect of LPS on BMP-9-induced osteogenic differentiation, and that MAPK acts as a mediator of the negative regulatory role of LPS in BMP-9-induced activation of Smad signaling. Based on these results, we conclude that the LPS-mediated inflammatory environment inhibits BMP-9-induced osteogenic differentiation, via crosstalk between BMP/MAPK and Smad signaling. The elucidation of these mechanisms may hasten the development of new strategies and improve the osteoinductive efficacy of BMP-9 in the clinic, resulting in enhanced osteoblastic differentiation and bone formation.
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Daigang
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Qu
authors.initials: Q
authors.lastname: Jining
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jinlai
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Wang
authors.initials: W
authors.lastname: Pengfei
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Sun
authors.initials: S
authors.lastname: Chuan
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Huang
authors.initials: H
authors.lastname: Liangku
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Ding
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhe
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhong
authors.affiliation: Xi'an Honghui Hospital, Affiliated to School of Medicine, Xi'an Jiaotong University, Xi'an 710054, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Kun
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D055427:Growth Differentiation Factor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C526108:Gdf2 protein, mouse; D055427:Growth Differentiation Factor 2; D008070:Lipopolysaccharides; D051785:Smad Proteins; D048051:p38 Mitogen-Activated Protein Kinases
keywords: BMP-9; LPS; Osteogenic differentiation