Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair

Sivakumar Ramadoss^#^{1

2

3

4

5

6}, Juan Qin^#^{1

2

3

4

5

6}, Bo Tao^{1

2

3

4

5

6}, Nathan E Thomas^{7

8}, Edward Cao^{1

2

3

4

5

6}, Rimao Wu^{1

2

3

4

5

6}, Daniel R Sandoval⁷, Ann Piermatteo⁷, Kaare V Grunddal⁷, Feiyang Ma⁹, Shen Li^{1

2

3

4

5

6}, Baiming Sun^{1

2

3

4

5

6}, Yonggang Zhou^{1

2

3

4

5

6}, Jijun Wan^{1

2

3

4

5

6}, Matteo Pellegrini^{3

4

5

6}, Birgitte Holst¹⁰, Aldons J Lusis^{1

11}, Philip L S M Gordts^{7

8}, Arjun Deb^{12

13

14

15

16

17}

Affiliations

¹ Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
² UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
³ Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California-Los Angeles, Los Angeles, CA, USA.
⁴ Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California-Los Angeles, Los Angeles, CA, USA.
⁵ Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA, USA.
⁶ California Nanosystems Institute, University of California-Los Angeles, Los Angeles, CA, USA.
⁷ Department of Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA, USA.
⁸ Glycobiology Research and Training Center, University of California-San Diego, La Jolla, CA, USA.
⁹ Department of Cell and Development Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁰ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹¹ Department of Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
¹² Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹³ UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹⁴ Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹⁵ Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹⁶ Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹⁷ California Nanosystems Institute, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.

^# Contributed equally.

PMID: 39455836
DOI: 10.1038/s44161-024-00555-4

Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair

Sivakumar Ramadoss et al. Nat Cardiovasc Res. 2024 Nov.

. 2024 Nov;3(11):1356-1373.

doi: 10.1038/s44161-024-00555-4. Epub 2024 Oct 25.

Authors

Affiliations

¹ Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
² UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
³ Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California-Los Angeles, Los Angeles, CA, USA.
⁴ Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California-Los Angeles, Los Angeles, CA, USA.
⁵ Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA, USA.
⁶ California Nanosystems Institute, University of California-Los Angeles, Los Angeles, CA, USA.
⁷ Department of Cellular and Molecular Medicine, University of California-San Diego, La Jolla, CA, USA.
⁸ Glycobiology Research and Training Center, University of California-San Diego, La Jolla, CA, USA.
⁹ Department of Cell and Development Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹⁰ Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
¹¹ Department of Genetics, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
¹² Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹³ UCLA Cardiovascular Theme, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹⁴ Department of Molecular, Cell and Developmental Biology, College of Letters and Sciences, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹⁵ Eli & Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹⁶ Molecular Biology Institute, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.
¹⁷ California Nanosystems Institute, University of California-Los Angeles, Los Angeles, CA, USA. adeb@mednet.ucla.edu.

^# Contributed equally.

PMID: 39455836
DOI: 10.1038/s44161-024-00555-4

Abstract

Glycoprotein nonmetastatic melanoma protein B (GPNMB) is a type I transmembrane protein initially identified in nonmetastatic melanomas and has been associated with human heart failure; however, its role in cardiac injury and function remains unclear. Here we show that GPNMB expression is elevated in failing human and mouse hearts after myocardial infarction (MI). Lineage tracing and bone-marrow transplantation reveal that bone-marrow-derived macrophages are the main source of GPNMB in injured hearts. Using genetic loss-of-function models, we demonstrate that GPNMB deficiency leads to increased mortality, cardiac rupture and rapid post-MI left ventricular dysfunction. Conversely, increasing circulating GPNMB levels through viral delivery improves heart function after MI. Single-cell transcriptomics show that GPNMB enhances myocyte contraction and reduces fibroblast activation. Additionally, we identified GPR39 as a receptor for circulating GPNMB, with its absence negating the beneficial effects. These findings highlight a pivotal role of macrophage-derived GPNMBs in post-MI cardiac repair through GPR39 signaling.

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Conflict of interest statement

Competing interests The authors declare no competing interests.

References

1. Frangogiannis, N. G. Pathophysiology of myocardial infarction. Compr. Physiol. 5, 1841–1875 (2015). - DOI - PubMed
1. Frangogiannis, N. G. Emerging roles for macrophages in cardiac injury: cytoprotection, repair, and regeneration. J. Clin. Invest. 125, 2927–2930 (2015). - DOI - PubMed - PMC
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Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair

Affiliations

Bone-marrow macrophage-derived GPNMB protein binds to orphan receptor GPR39 and plays a critical role in cardiac repair

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources