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

Levels of Glyco Protein Non-metastatic Melanoma protein B (GPNMB), a type I transmembrane protein, originally identified in non-metastatic melanomas has been shown to be strongly associated with human heart failure. However, the role of GPNMB in modulation of cardiac injury and cardiac function remains unclear. We analyzed human cardiac global gene expression data sets and observed increased GPNMB expression in failing hearts. In murine hearts after myocardial infarction (MI), we showed that GPNMB expression increased by an order of magnitude. Lineage tracing and bone marrow transplantation experiments demonstrated that bone marrow macrophages were the primary source of GPNMB in the injured heart. Using genetic loss of function approaches, we demonstrate that animals deficient in GPNMB exhibited significantly higher mortality, cardiac rupture and developed rapid post infarct LV dysfunction. Conversely gain of function approaches by increasing circulating GPNMB levels by viral delivery led to augmentation of post MI heart function. Single cell transcriptomics demonstrated pleiotropic effects of GPNMB on gene expression of myocytes and non-myocytes leading to enhanced myocyte contraction and decreased fibroblast activation. Using chemical cross-linking studies and immunoprecipitation studies, we identified the orphan receptor GPR39 as a receptor for circulating GPNMB. In animals deficient in GPR39, GPNMB failed to deliver beneficial effects on post infarct heart function. Taken together, these observations demonstrate that bone marrow macrophage derived GPNMB plays a pivotal role in cardiac repair following myocardial infarction, by mediating its pleiotropic effects in part via the orphan receptor GPR39