Matrix Gla protein maintains normal and malignant hematopoietic progenitor cells by interacting with bone morphogenetic protein-4

Abstract

Matrix Gla protein (MGP), a modulator of the BMP-SMAD signals, inhibits arterial calcification in a Glu γ-carboxylation dependent manner but the role of MGP highly expressed in a subset of bone marrow (BM) mesenchymal stem/stromal cells is unknown. Here we provide evidence that MGP might be a niche factor for both normal and malignant myelopoiesis. When mouse BM hematopoietic cells were cocultured with mitomycin Ctreated BM stromal cells in the presence of anti-MGP antibody, growth of hematopoietic cells was reduced by half, and maintenance of long-term culture-initiating cells (LTC-ICs) was profoundly attenuated. Antibody-mediated blockage of MGP also inhibited growth (by a fifth) and cobblestone formation (by half) of stroma-dependent MB-1 myeloblastoma cells. MGP was undetectable in normal hematopoietic cells but was expressed in various mesenchymal cells and was aberrantly high in MB-1 cells. MGP and bone morphogenetic protein (BMP)-4 were co-induced in stromal cells cocultured with both normal hematopoietic cells and MB-1 myeloblastoma cells in an oscillating several days-periodic manner. BMP-2 was also induced in stromal cells cocultured with normal hematopoietic cells but was barely expressed when cocultured with MB-1 cells. GST-pulldown and luciferase reporter assays showed that uncarboxylated MGP interacted with BMP-4 and that anti-MGP antibody abolished this interaction. LDN-193189, a selective BMP signaling inhibitor, inhibited growth and cobblestone formation of MB-1 cells. The addition of warfarin, a selective inhibitor of vitamin K-dependent Glu γ-carboxylation, did not affect MB-1 cell growth, suggesting that uncarboxylated MGP has a biological effect in niche. These results indicate that MGP may maintain normal and malignant hematopoietic progenitor cells, possibly by modulating BMP signals independently of Glu γ-carboxylation. Aberrant MGP by leukemic cells and selective induction of BMP-4 relative to BMP-2 in stromal cells might specify malignant niche.

p57Kip2 regulates embryonic haematopoietic stem cell numbers by controlling the size of the sympathoadrenal progenitor pool

“…The detection of HSC regulators prompted us to mine our dataset for other polarised factors, searching for genes significantly differentially expressed between ventrally and dorsally derived Ngfr+ cells. Amongst the genes upregulated in the ventral cells were known HSC regulators, such as Mgp 47 , Ntf3 48 and Tgfbi 49 , some of which have previously been shown to be expressed in the ventral mesenchyme, such as Bmper 23 and Bmp4 17,25 ( Figure 7G ). The expression of the majority of the ventrally upregulated genes was restricted to cluster 3 cells ( Figure 7H ), demonstrating that they are the strongest contributor to the polarised expression of genes within the Ngfr+ populations and may represent an important subset of HSC niche cells.…”

p57Kip2 regulates embryonic blood stem cells by controlling sympathoadrenal progenitor expansion

“…The detection of HSC regulators prompted us to mine our data set for other polarized factors, differentially expressed between ventrally and dorsally derived Ngfr + cells. Among the genes upregulated in the ventral cells were known HSC regulators such as Mgp , 65 Ntf3, 66 and Tgfbi , 67 some of which have been shown to be expressed in the ventral mesenchyme, such as Bmper 17 and Bmp4 16,19 ( Figure 7L ). The expression of the majority of the ventrally upregulated genes was restricted to cluster 3 ( Figure 7M ), showing that they are the strongest contributor to the polarized expression of genes within the Ngfr + populations and may represent an important subset of HSC niche cells.…”

Matrix-GLA-Protein and Vascular Calcification: Can Diet Influence the Consequences of Matrix GLA Protein Inactivation? A Review

“…The binding and affinity of matrix GLA protein to BMP-2 are directly dependent on the concentration of free calcium ions and carboxylation state of matrix GLA protein [34,35] .…”