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

Sivakumar Ramadoss; Juan Qin; Bo Tao; Nathan E Thomas; Edward Cao; Rimao Wu; Daniel R Sandoval; Ann Piermatteo; Kaare V Grunddal; Feiyang Ma; Shen Li; Baiming Sun; Yonggang Zhou; Jijun Wan; Matteo Pellegrini; Birgitte Holst; Aldons J Lusis; Philip L S M Gordts; Arjun Deb

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

Nat Cardiovasc Res. 2024 Nov;3(11):1356-1373. doi: 10.1038/s44161-024-00555-4. Epub 2024 Oct 25.

Authors

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

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.

MeSH terms

Animals
Bone Marrow Transplantation
Cells, Cultured
Disease Models, Animal*
Eye Proteins
Female
Heart Failure / genetics
Heart Failure / metabolism
Humans
Macrophages* / metabolism
Male
Membrane Glycoproteins* / genetics
Membrane Glycoproteins* / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout*
Myocardial Infarction* / genetics
Myocardial Infarction* / metabolism
Myocytes, Cardiac* / metabolism
Protein Binding
Receptors, G-Protein-Coupled* / genetics
Receptors, G-Protein-Coupled* / metabolism
Regeneration
Signal Transduction
Ventricular Dysfunction, Left / genetics
Ventricular Dysfunction, Left / metabolism
Ventricular Function, Left

Substances

GPNMB protein, human
Receptors, G-Protein-Coupled
Membrane Glycoproteins
Gpnmb protein, mouse
Eye Proteins

Grants and funding

HL149658/National Heart and Lung Institute (NHLI)