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Quinoline compound KM11073 enhances BMP-2-dependent osteogenic differentiation of C2C12 cells via activation of p38 signaling and exhibits in vivo bone forming activity.

Baek SH, Choi SW, Park SJ, Lee SH, Chun HS, Kim SH - PLoS ONE (2015)

Bottom Line: In addition, a pharmacological inhibition study suggested the involvement of p38 activation in the osteogenic action of KM11073 accompanied by enhanced expression of BMP-2, -6, and -7 mRNA.In conclusion, the combination of rhBMP-2 with osteogenic small molecules could reduce the use of expensive rhBMP-2, mitigating the undesirable side effects of its supra-physiological dose for therapeutic efficacy.Moreover, due to their inherent physical properties, small molecules could represent the next generation of regenerative medicine.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Translational Therapeutics, Pharmacology Research Center, Korea Research Institute of Chemical Technology, Daejeon, 305-600, Republic of Korea; Department of Food Science & Biotechnology, Kyungpook National University, Daegu, 702-701, Republic of Korea.

ABSTRACT
Recombinant human bone morphogenetic protein (rhBMP)-2 has been approved by the FDA for clinical application, but its use is limited due to high cost and a supra-physiological dose for therapeutic efficacy. Therefore, recent studies have focused on the generation of new therapeutic small molecules to induce bone formation or potentiate the osteogenic activity of BMP-2. Here, we show that [4-(7-chloroquinolin-4-yl) piperazino][1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (KM11073) strongly enhances the BMP-2-stimulated induction of alkaline phosphatase (ALP), an early phase biomarker of osteoblast differentiation, in bi-potential mesenchymal progenitor C2C12 cells. The KM11073-mediated ALP induction was inhibited by the BMP antagonist noggin, suggesting that its osteogenic activity occurs via BMP signaling. In addition, a pharmacological inhibition study suggested the involvement of p38 activation in the osteogenic action of KM11073 accompanied by enhanced expression of BMP-2, -6, and -7 mRNA. Furthermore, the in vivo osteogenic activity of KM11073 was confirmed in zebrafish and mouse calvarial bone formation models, suggesting the possibility of its single use for bone formation. In conclusion, the combination of rhBMP-2 with osteogenic small molecules could reduce the use of expensive rhBMP-2, mitigating the undesirable side effects of its supra-physiological dose for therapeutic efficacy. Moreover, due to their inherent physical properties, small molecules could represent the next generation of regenerative medicine.

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Involvement of p38 in the KM11073-mediated enhancement of BMP-2-stimulated ALP induction.In a 96-well plate, cells (4 × 103 cells/well) were treated with each inhibitor for 2 h and then treated with BMP-2 and KM11073. After 3 days, the cells were treated with each inhibitor. On differentiation day 6, ALP staining (A) and its activity (B) were assayed. ###p < 0.001 compared to the BMP-2-treated group; * p < 0.05, ** p < 0.01, *** p < 0.001 compared to the group treated with BMP-2 and KM11073.
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pone.0120150.g003: Involvement of p38 in the KM11073-mediated enhancement of BMP-2-stimulated ALP induction.In a 96-well plate, cells (4 × 103 cells/well) were treated with each inhibitor for 2 h and then treated with BMP-2 and KM11073. After 3 days, the cells were treated with each inhibitor. On differentiation day 6, ALP staining (A) and its activity (B) were assayed. ###p < 0.001 compared to the BMP-2-treated group; * p < 0.05, ** p < 0.01, *** p < 0.001 compared to the group treated with BMP-2 and KM11073.

Mentions: Next, in order to investigate the underlying mechanism explaining the osteogenic activity of KM11073, a pharmacological inhibition study was performed. The KM11073-enhanced ALP induction in the presence of BMP-2 was strongly inhibited by p38 inhibitors, but not inhibitors of Ras, phosphatidylinositol 3-kinase (PI3K), or Akt (Fig. 3).


Quinoline compound KM11073 enhances BMP-2-dependent osteogenic differentiation of C2C12 cells via activation of p38 signaling and exhibits in vivo bone forming activity.

Baek SH, Choi SW, Park SJ, Lee SH, Chun HS, Kim SH - PLoS ONE (2015)

Involvement of p38 in the KM11073-mediated enhancement of BMP-2-stimulated ALP induction.In a 96-well plate, cells (4 × 103 cells/well) were treated with each inhibitor for 2 h and then treated with BMP-2 and KM11073. After 3 days, the cells were treated with each inhibitor. On differentiation day 6, ALP staining (A) and its activity (B) were assayed. ###p < 0.001 compared to the BMP-2-treated group; * p < 0.05, ** p < 0.01, *** p < 0.001 compared to the group treated with BMP-2 and KM11073.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4366212&req=5

pone.0120150.g003: Involvement of p38 in the KM11073-mediated enhancement of BMP-2-stimulated ALP induction.In a 96-well plate, cells (4 × 103 cells/well) were treated with each inhibitor for 2 h and then treated with BMP-2 and KM11073. After 3 days, the cells were treated with each inhibitor. On differentiation day 6, ALP staining (A) and its activity (B) were assayed. ###p < 0.001 compared to the BMP-2-treated group; * p < 0.05, ** p < 0.01, *** p < 0.001 compared to the group treated with BMP-2 and KM11073.
Mentions: Next, in order to investigate the underlying mechanism explaining the osteogenic activity of KM11073, a pharmacological inhibition study was performed. The KM11073-enhanced ALP induction in the presence of BMP-2 was strongly inhibited by p38 inhibitors, but not inhibitors of Ras, phosphatidylinositol 3-kinase (PI3K), or Akt (Fig. 3).

Bottom Line: In addition, a pharmacological inhibition study suggested the involvement of p38 activation in the osteogenic action of KM11073 accompanied by enhanced expression of BMP-2, -6, and -7 mRNA.In conclusion, the combination of rhBMP-2 with osteogenic small molecules could reduce the use of expensive rhBMP-2, mitigating the undesirable side effects of its supra-physiological dose for therapeutic efficacy.Moreover, due to their inherent physical properties, small molecules could represent the next generation of regenerative medicine.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Translational Therapeutics, Pharmacology Research Center, Korea Research Institute of Chemical Technology, Daejeon, 305-600, Republic of Korea; Department of Food Science & Biotechnology, Kyungpook National University, Daegu, 702-701, Republic of Korea.

ABSTRACT
Recombinant human bone morphogenetic protein (rhBMP)-2 has been approved by the FDA for clinical application, but its use is limited due to high cost and a supra-physiological dose for therapeutic efficacy. Therefore, recent studies have focused on the generation of new therapeutic small molecules to induce bone formation or potentiate the osteogenic activity of BMP-2. Here, we show that [4-(7-chloroquinolin-4-yl) piperazino][1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (KM11073) strongly enhances the BMP-2-stimulated induction of alkaline phosphatase (ALP), an early phase biomarker of osteoblast differentiation, in bi-potential mesenchymal progenitor C2C12 cells. The KM11073-mediated ALP induction was inhibited by the BMP antagonist noggin, suggesting that its osteogenic activity occurs via BMP signaling. In addition, a pharmacological inhibition study suggested the involvement of p38 activation in the osteogenic action of KM11073 accompanied by enhanced expression of BMP-2, -6, and -7 mRNA. Furthermore, the in vivo osteogenic activity of KM11073 was confirmed in zebrafish and mouse calvarial bone formation models, suggesting the possibility of its single use for bone formation. In conclusion, the combination of rhBMP-2 with osteogenic small molecules could reduce the use of expensive rhBMP-2, mitigating the undesirable side effects of its supra-physiological dose for therapeutic efficacy. Moreover, due to their inherent physical properties, small molecules could represent the next generation of regenerative medicine.

Show MeSH