Abstract
The hypoxia-inducible factors (HIFα) are the critical factors that couple angiogenesis and osteogenesis by activating transcription of VEGF in osteoblasts. Mice lacking von Hippel–Lindau gene (Vhl), thus overexpressing HIFα in osteoblasts develop extremely dense and highly vascularized long bones. Here we provide evidence that osteoblasts lacking Vhl overexpress and secrete high levels of VEGF, which subsequently promotes the proliferation and osteogenic differentiation of bone marrow stromal cells (BMSC) by promoting expression of Heme oxygenase-1 (HO-1) in BMSC. Conditioned medium from osteoblasts Vhl (CM-CRE) promoted the proliferation and osteogenic differentiation of BMSC, in comparison with conditioned medium derived from normal osteoblasts (CM-GFP). Recombinant VEGF stimulated the proliferation and osteogenic differentiation of BMSC culturing in CM-GFP. By contrast, VEGF-neutralizing antibody inhibited the proliferation and osteogenic differentiation of BMSC culturing in CM-CRE. Treatment with a HO-1 inhibitor, SnPP, significantly inhibited VEGF-induced BMSC proliferation and osteogenic differentiation. On the contrary, activation of HO-1 with CoPP reversed the suppressing of VEGF-antibody on the proliferation and osteogesis of BMSC culturing in CM-CRE. These studies suggest that osteoblasts promote the proliferation and osteogenic differentiation of BMCS by VEGF/HO-1 pathway.
Highlights
The proper development and maintenance of bone size, shape, and integrity are based on communication among cells within the bone marrow microenvironment, such as osteoblasts, chondrocytes, osteocytes, osteoblasts and bone marrow mesenchymal stromal cells (BMSCs)
Quantitative analysis revealed the bone mineral density (BMD) of femoral distal metaphyseal trabecular bone was significantly increased at 3 weeks (p = 0.0292) and 6 weeks (p,0.0001) of age compared with the control mice (Fig. S1B)
The BMD of middle femur cortical bone was decreased at 3 weeks (p = 0.0012) and 6 weeks (p = 0.0380) of age compared with the control mice (Fig. S1C)
Summary
The proper development and maintenance of bone size, shape, and integrity are based on communication among cells within the bone marrow microenvironment, such as osteoblasts, chondrocytes, osteocytes, osteoblasts and bone marrow mesenchymal stromal cells (BMSCs). BMSCs comprise a clonogenic, nonhematopoietic stem cell population that reside within the bone marrow stroma and is capable of differentiation into mesodermlineage cells e.g. osteoblasts, adipocytes and chondrocytes [1,2]. BMSCs suppress osteoblast proliferation and transiently retard osteoblast differentiation by downregulating Runx2 [3]. Mice overexpressing HIFa in osteoblasts through selective deletion of the von Hippel-Lindau gene (Vhl) expressed high levels of VEGF and developed extremely dense, heavily vascularized long bones. Loss of Vhl and upregulation of HIFa in osteoblasts have minimal effects on in vitro osteoblast proliferation, survival, and differentiation [5]
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