Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7

Rachel H. Church; Arjun Krishnakumar; Annika Urbanek; Stefan  Geschwinder; Julie Meneely; Alessandro Bianchi; Barbro Basta; Sean  Monaghan; Christopher Elliott; Maria Stromstedt; Neil Ferguson; Finian Martin; Derek P. Brazil

doi:10.1042/BJ20140771

Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7

Rachel H. Church, Arjun Krishnakumar, Annika Urbanek, Stefan Geschwinder, Julie Meneely, Alessandro Bianchi, Barbro Basta, Sean Monaghan, Christopher Elliott, Maria Stromstedt, Neil Ferguson, Finian Martin, Derek P. Brazil

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Abstract

Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis-associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during DN has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. Here we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readout, Grem1 consistently demonstrated a higher affinity for BMP-2>4>7. Cell-associated Grem1 did not inhibit BMP-2 or BMP-4 mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.

Original language	English
Pages (from-to)	55-68
Number of pages	14
Journal	Biochemical Journal
Volume	466
Issue number	1
Early online date	07 Nov 2014
DOIs	https://doi.org/10.1042/BJ20140771
Publication status	Published - 15 Feb 2015

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10.1042/BJ20140771

Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7
The final version of record is available at http://www.biochemj.org/bj/imps/abs/BJ20140771.htm
Accepted author manuscript, 1.2 MB

Derek Brazil
- d.brazilqub.acuk
- School of Medicine, Dentistry and Biomedical Sciences - Reader
- Wellcome Wolfson Institute for Experimental Medicine
Person: Academic

Cite this

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title = "Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7",

abstract = "Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis-associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during DN has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. Here we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readout, Grem1 consistently demonstrated a higher affinity for BMP-2>4>7. Cell-associated Grem1 did not inhibit BMP-2 or BMP-4 mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.",

author = "Church, {Rachel H.} and Arjun Krishnakumar and Annika Urbanek and Stefan Geschwinder and Julie Meneely and Alessandro Bianchi and Barbro Basta and Sean Monaghan and Christopher Elliott and Maria Stromstedt and Neil Ferguson and Finian Martin and Brazil, {Derek P.}",

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T1 - Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7

AU - Church, Rachel H.

AU - Krishnakumar, Arjun

AU - Urbanek, Annika

AU - Geschwinder, Stefan

AU - Meneely, Julie

AU - Bianchi, Alessandro

AU - Basta, Barbro

AU - Monaghan, Sean

AU - Elliott, Christopher

AU - Stromstedt, Maria

AU - Ferguson, Neil

AU - Martin, Finian

AU - Brazil, Derek P.

PY - 2015/2/15

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N2 - Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis-associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during DN has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. Here we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readout, Grem1 consistently demonstrated a higher affinity for BMP-2>4>7. Cell-associated Grem1 did not inhibit BMP-2 or BMP-4 mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.

AB - Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis-associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during DN has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. Here we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readout, Grem1 consistently demonstrated a higher affinity for BMP-2>4>7. Cell-associated Grem1 did not inhibit BMP-2 or BMP-4 mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.

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DO - 10.1042/BJ20140771

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SN - 0264-6021

VL - 466

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JO - Biochemical Journal

JF - Biochemical Journal

IS - 1

ER -

Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7

Abstract

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