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Open AccessArticle

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

Julius Wolff Institute, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany
Berlin-Brandenburg School for Regenerative Therapies, Charité – Universitätsmedizin Berlin, 13353 Berlin, Germany
Berlin-Brandenburg Center for Regenerative Therapies, Charité – Universitätsmedizin Berlin, 13353 Berlin, Germany
Institute of Chemistry and Biochemistry – Free University, 14195 Berlin, Germany
Experimentelle Unfallchirurgie – Universitätsklinikum Jena, 07747 Jena, Germany
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(10), 1273;
Received: 15 July 2019 / Revised: 14 October 2019 / Accepted: 16 October 2019 / Published: 18 October 2019
(This article belongs to the Special Issue TGF-beta/BMP Signaling Pathway)
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. View Full-Text
Keywords: C2C12; BMP2; nitric oxide; signaling; crosstalk C2C12; BMP2; nitric oxide; signaling; crosstalk
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Differ, C.; Klatte-Schulz, F.; Bormann, N.; Minkwitz, S.; Knaus, P.; Wildemann, B. Is NO the Answer? The Nitric Oxide Pathway Can Support Bone Morphogenetic Protein 2 Mediated Signaling. Cells 2019, 8, 1273.

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