PubMed · 15050236
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2004. Consultation section. Refractive surgical problem.. https://doi.org/10.1016/j.jcrs.2004.02.005
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It is well accepted, that there is communication between osteoblasts and endothelial cells. However, the influence of endothelial cells on the differentiation of bone precursors into mature osteoblasts is not yet well understood. We therefore studied the effect of human umbilical vein endothelial cells (HUVEC) on human bone marrow stromal cell (BMSC) differentiation towards an osteoblastic phenotype by culturing them in two different types of HUVEC-BMSC cultures (indirect contact, HUVEC-conditioned medium). Typical bone markers (45Ca incorporation, ALP activity, and gene expression of collagen 1 (COL1), osteonectin (ON), matrix metalloproteinase 13 (MMP-13), bone morphogenetic protein 2 (BMP-2)) and transcription factors (Runx2, osterix (OSX)) were evaluated at different time points. The effect of stimulating HUVEC with vascular endothelial growth factor (VEGF) before co-cultures with BMSC was also evaluated. As expected, BMSC in osteogenic medium (OM) (with dexamethasone) differentiated towards the osteoblastic phenotype, as measured by increased matrix mineralization, high ALP activity, and elevated expression of specific osteoblastic marker genes, when compared to BMSC in non-OM. HUVEC reversibly inhibited osteoblastic differentiation of BMSC in OM, independent of the co-culture type. When HUVEC were removed from the cultures, BMSC differentiated into osteoblasts, albeit at a faster rate than BMSC that were never co-cultured with HUVEC. Stimulation of HUVEC with VEGF before co-culture enhanced the inhibitory effect of HUVEC on BMSC differentiation. This inhibitory effect was connected to a reversible suppression of OSX gene expression and was specific to endothelial cells. We conclude that HUVEC can inhibit dexamethasone-induced BMSC differentiation into osteoblasts in vitro, by interfering with OSX expression, thereby arresting BMSC differentiation at a preosteoblastic stage.
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Central nervous system disorders are still a common complication of human immunodeficiency virus (HIV) infection and can lead to dementia and death. They are mostly the consequences of an inflammatory macrophagic activation and relate to glutamate-mediated excitotoxicity. However, recent studies also suggest neuroprotective aspects of macrophage activation through the expression of glutamate transporters and glutamine synthetase. We thus aimed to study whether HIV infection or activation of macrophages could modulate glutamate metabolism in these cells. We assessed the effect of HIV infection on glutamate transporter expression as well as on glutamate uptake by macrophages and showed that glutamate transport was partially decreased in the course of virus replication, whereas excitatory amino acid transporter-2 (EAAT-2) gene expression was dramatically increased. The consequences of HIV infection on glutamine synthetase were also measured and for the first time we show the functional expression of this key enzyme in macrophages. This expression was repressed during virus production. We then quantified EAAT-1 and EAAT-2 gene expression as well as glutamate uptake in differentially activated macrophages and show that the effects of HIV are not directly related to pro- or anti-inflammatory mediators. Finally, this study shows that glutamate transport by macrophages is less affected than what has been described in astrocytes. Macrophages may thus play a role in neuroprotection against glutamate in the infected brain, through their expression of both EAATs and glutamine synthetase. Because glutamate metabolism by activated macrophages is sensitive to both HIV infection and inflammation, it may thus be of potential interest as a therapeutic target in HIV encephalitis.