A heterodimer formed by bone morphogenetic protein 9 (BMP9) and BMP10 provides most BMP biological activity in plasma
Abstract
Bone morphogenetic protein 9 (BMP9) and BMP10 are the
two high-affinity ligands for the endothelial receptor activin
receptor-like kinase 1 (ALK1) and are key regulators of vascular
remodeling. They are both present in the blood, but
their respective biological activities are still a matter of
debate. The aim of the present work was to characterize their
circulating forms to better understand how their activities
are regulated in vivo. First, by cotransfecting BMP9 and
BMP10, we found that both can form a disulfide-bonded heterodimer
in vitro and that this heterodimer is functional on
endothelial cells via ALK1. Next, we developed an ELISA that
could specifically recognize the BMP9–BMP10 heterodimer
and which indicated its presence in both human and mouse
plasma. In addition to using available Bmp9-KO mice,
we generated a conditional Bmp10-KO mouse strain. The
plasma from Bmp10-KO mice, similarly to that of Bmp9-KO
mice, completely lacked the ability to activate ALK1-transfected
3T3 cells or phospho-Smad1–5 on endothelial cells,
indicating that the circulating BMP activity is mostly due to
the BMP9–BMP10 heterodimeric form. This result was confirmed
in human plasma that had undergone affinity chromatography
to remove BMP9 homodimer. Finally, we provide
evidence that hepatic stellate cells in the liver could be the
source of the BMP9–BMP10 heterodimer. Together, our
findings demonstrate that BMP9 and BMP10 can heterodimerize
and that this heterodimer is responsible for most
of the biological BMP activity found in plasma.
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