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

Cells ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 1273 ◽  
Author(s):  
Christopher Differ ◽  
Franka Klatte-Schulz ◽  
Nicole Bormann ◽  
Susann Minkwitz ◽  
Petra Knaus ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Fracture Healing ◽  
Bone Morphogenetic Protein ◽  
Clinical Importance ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Positive Effects ◽  
Morphogenetic Protein

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.

Bone Morphogenetic Protein-2 Inhibits Differentiation and Mineralization of Cementoblasts in vitro

2003 ◽  
Vol 82 (1) ◽  
pp. 23-27 ◽  
Author(s):  
M. Zhao ◽  
J.E. Berry ◽  
M.J. Somerman
Keyword(s):  
Bone Morphogenetic Protein ◽  
Type I Collagen ◽  
Bone Morphogenetic Protein 2 ◽  
Nodule Formation ◽  
Type I ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Morphogenetic Protein ◽  
Regenerative Therapies

As an approach for improving the outcome and predictability of periodontal regenerative therapies, we have focused on determining the responses of cells within the local environment to putative regenerative factors. This study examined the effects of bone morphogenetic protein-2 (BMP-2) on murine cementoblasts in vitro. Northern blot analysis indicated that BMP-2 decreased mRNA levels of bone sialoprotein and type I collagen dose-dependently (10–300 ng/mL). At low doses, up to 100 ng/mL, BMP-2 had no effect on transcripts for osteocalcin and osteopontin, whereas at 300 ng/mL, BMP-2 greatly increased expression of these two genes. BMP-2 also inhibited cementoblast-mediated mineral nodule formation in a dose-dependent manner (inhibition was noted at 10 ng/mL). Noggin reversed the effects of BMP-2 on gene expression and on mineralization. These findings reflect the diverse responses of periodontal cells to BMP-2 and highlight the need to consider the complexity of factors involved in designing predictable regenerative therapies.

scholarly journals Bone morphogenetic protein 2 inhibits growth differentiation factor 8-induced cell signaling via upregulation of gremlin2 expression in human granulosa-lutein cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaoyan Luo ◽  
Hsun-Ming Chang ◽  
Yuyin Yi ◽  
Yingpu Sun ◽  
Peter C. K. Leung
Keyword(s):  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Differentiation Factor ◽  
Morphogenetic Protein

Abstract Background Bone morphogenetic protein 2 (BMP2), growth differentiation factor 8 (GDF8) and their functional receptors are expressed in human ovarian follicles, and these two intrafollicular factors play essential roles in regulating follicle development and luteal function. As BMP antagonists, gremlin1 (GREM1) and gremlin2 (GREM2) suppress BMP signaling through blockage of ligand-receptor binding. However, whether BMP2 regulates the expression of GREM1 and GREM2 in follicular development remains to be determined. Methods In the present study, we investigated the effect of BMP2 on the expression of GREM1 and GREM2 and the underlying mechanisms in human granulosa-lutein (hGL) cells. An established immortalized human granulosa cell line (SVOG) and primary hGL cells were used as study models. The expression of GREM1 and GREM2 were examined following cell incubation with BMP2 at different concentrations and time courses. The TGF-β type I inhibitors (dorsomorphin, DMH-1 and SB431542) and small interfering RNAs targeting ALK2, ALK3, SMAD2/3, SMAD1/5/8 and SMAD4 were used to investigate the involvement of the SMAD-dependent pathway. Results Our results showed that BMP2 significantly increased the expression of GREM2 (but not GREM1) in a dose- and time-dependent manner. Using a dual inhibition approach combining kinase inhibitors and siRNA-mediated knockdown, we found that the BMP2-induced upregulation of GREM2 expression was mediated by the ALK2/3-SMAD1/5-SMAD4 signaling pathway. Moreover, we demonstrated that BMP2 pretreatment significantly attenuated the GDF8-induced phosphorylation of SMAD2 and SMAD3, and this suppressive effect was reversed by knocking down GREM2 expression. Conclusions Our findings provide new insight into the molecular mechanisms by which BMP2 modulates the cellular activity induced by GDF8 through the upregulated expression of their antagonist (GREM2).

scholarly journals Connective Tissue Growth Factor Mediates Bone Morphogenetic Protein 2-Induced Increase in Hyaluronan Production in Luteinized Human Granulosa Cells

2021 ◽  
Author(s):  
Long Bai ◽  
Hsun-Ming Chang ◽  
Yi-Min Zhu ◽  
Peter CK Leung
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Bone Morphogenetic Protein ◽  
Molecular Mechanism ◽  
Granulosa Cells ◽  
Tissue Growth ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Human Granulosa Cells ◽  
Morphogenetic Protein

Abstract Background: Hyaluronan is the main component of the cumulus-oocyte complex (COC) matrix and it maintains the basic structure of the COC during ovulation. As a member of the transforming growth factor β (TGF-β) superfamily, bone morphogenetic protein 2 (BMP2) has been identified as a critical regulator of mammalian folliculogenesis and ovulation. However, whether BMP2 can regulate the production of hyaluronan in human granulosa cells has never been elucidated.Methods: In the present study, we investigated the effect of BMP2 on the production of hyaluronan and the underlying molecular mechanism using both immortalized (SVOG) and primary human granulosa-lutein (hGL) cells. The expression of three hyaluronan synthases (including HAS1, HAS2 and HAS3) were examined following cell incubation with BMP2 at different concentrations. The concentrations of the hyaluronan cell culture medium were determined by enzyme-linked immunosorbent assay (ELISA). The TGF-β type I receptor inhibitors (dorsomorphin and DMH-1) and small interfering RNAs targeting ALK2, ALK3, ALK6 and SMAD4 were used to investigate the involvement of TGF-β type I receptor and SMAD-dependent pathway.Results: Our results showed that BMP2 treatment significantly increased the production of hyaluronan by upregulating the expression of hyaluronan synthase 2 (HAS2). In addition, BMP2 upregulates the expression of connective tissue growth factor (CTGF), which subsequently mediates the BMP2-induced increases in HAS2 expression and hyaluronan production because overexpression of CTGF enhances, whereas knockdown of CTGF reverses, these effects. Notably, using kinase inhibitor- and siRNA-mediated knockdown approaches, we demonstrated that the inductive effect of BMP2 on the upregulation of CTGF is mediated by the ALK2/ALK3-mediated SMAD-dependent signaling pathway.Conclusions: Our findings provide new insight into the molecular mechanism by which BMP2 promotes the production of hyaluronan in human granulosa cells.

The Effect of Bone Morphogenetic Protein-2 on Rat Intervertebral Disc Cells in Vitro

Spine ◽  
2003 ◽  
Vol 28 (16) ◽  
pp. 1773-1780 ◽  
Author(s):  
S. Tim Yoon ◽  
Keun Su Kim ◽  
Jun Li ◽  
Jin Soo Park ◽  
Tomoyuki Akamaru ◽  
...  
Keyword(s):  
Intervertebral Disc ◽  
Bone Morphogenetic Protein ◽  
Bone Morphogenetic Protein 2 ◽  
Morphogenetic Protein ◽  
Disc Cells
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