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Cells. 2019 Oct 18;8(10). pii: E1273. doi: 10.3390/cells8101273.

Is NO the Answer? The Nitric Oxide Pathway Can Support Bone Morphogenetic Protein 2 Mediated Signaling.

Differ C1,2,3, Klatte-Schulz F4,5, Bormann N6,7, Minkwitz S8,9, Knaus P10,11, Wildemann B12,13,14,15.

Author information

1
Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany. christopher.differ@outlook.com.
2
Berlin-Brandenburg School for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. christopher.differ@outlook.com.
3
Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. christopher.differ@outlook.com.
4
Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany. franka.klatte@charite.de.
5
Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. franka.klatte@charite.de.
6
Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany. Nicole.bormann@charite.de.
7
Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. Nicole.bormann@charite.de.
8
Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany. susann.minkwitz@charite.de.
9
Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. susann.minkwitz@charite.de.
10
Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. petra.knaus@fu-berlin.de.
11
Institute of Chemistry and Biochemistry - Free University, 14195 Berlin, Germany. petra.knaus@fu-berlin.de.
12
Julius Wolff Institute, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany. britt.wildemann@charite.de.
13
Berlin-Brandenburg School for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. britt.wildemann@charite.de.
14
Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, 13353 Berlin, Germany. britt.wildemann@charite.de.
15
Experimentelle Unfallchirurgie - Universitätsklinikum Jena, 07747 Jena, Germany. britt.wildemann@charite.de.

Abstract

The growth factor bone morphogenetic protein 2 (BMP2) plays an important role in bone development and repair. Despite the positive effects of BMP2 in fracture healing, its use is associated with negative side effects and poor cost effectiveness, partly due to the large amounts of BMP2 applied. Therefore, reduction of BMP2 amounts while maintaining efficacy is of clinical importance. As nitric oxide (NO) signaling plays a role in bone fracture healing and an association with the BMP2 pathway has been indicated, this study aimed to investigate the relationship of BMP2 and NO pathways and whether NO can enhance BMP2-induced signaling and osteogenic abilities in vitro. To achieve this, the stable BMP reporter cell line C2C12BRELuc was used to quantify BMP signaling, and alkaline phosphatase (ALP) activity and gene expression were used to quantify osteogenic potency. C2C12BRELuc cells were treated with recombinant BMP2 in combination with NO donors and substrate (Deta NONOate, SNAP & L-Arginine), NOS inhibitor (LNAME), soluble guanylyl cyclase (sGC) inhibitor (LY83583) and activator (YC-1), BMP type-I receptor inhibitor (LDN-193189), or protein kinase A (PKA) inhibitor (H89). It was found that the NOS enzyme, direct NO application, and sGC enhanced BMP2 signaling and improved BMP2 induced osteogenic activity. The application of a PKA inhibitor demonstrated that BMP2 signaling is enhanced by the NO pathway via PKA, underlining the capability of BMP2 in activating the NO pathway. Collectively, this study proves the ability of the NO pathway to enhance BMP2 signaling.

KEYWORDS:

BMP2; C2C12; crosstalk; nitric oxide; signaling

PMID:
31635347
DOI:
10.3390/cells8101273
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