Abstract
The higher level of Glucose-6-phosphate isomerase (G6PI) has been found in both synovial tissue and synovial fluid of rheumatoid arthritis (RA) patients, while the function of G6PI in RA remains unclear. Herein we found the enrichment of G6PI in microvascular endothelial cells of synovial tissue in RA patients, where a 3% O2 hypoxia environment has been identified. In order to determine the correlation between the high G6PI level and the low oxygen concentration in RA, a hypoxia condition (~3% O2) in vitro was applied to mimic the RA environment in vivo. Hypoxia promoted cellular proliferation of rheumatoid arthritis synovial fibroblasts (RASFs), and induced cell migration and angiogenic tube formation of human dermal microvascular endothelial cells (HDMECs), which were accompanied with the increased expression of G6PI and HIF-1α. Through application of G6PI loss-of-function assays, we confirmed the requirement of G6PI expression for those hypoxia-induced phenotype in RA. In addition, we demonstrated for the first time that G6PI plays key roles in regulating VEGF secretion from RASFs to regulate the hypoxia-induced angiogenesis in RA. Taken together, we demonstrated a novel pathway regulating hypoxia-induced angiogenesis in RA mediated by G6PI.
Highlights
Angiogenesis starts at the early phase of inflammation until the formation of new capillaries from the pre-existing vasculature
By gene loss-of-function assays, we demonstrated the hypoxia-induced angiogenesis is dependent on the Glucose-6-phosphate isomerase (G6PI) expression in human dermal microvascular endothelial cells (HDMECs) and vascular endothelial growth factor (VEGF) secretion from rheumatoid arthritis synovial fibroblasts (RASFs), the latter is regulated by G6PI
Strong G6PI signals were detected around the blood vessels and in the synovial fibroblasts (Fig. 1A), where the oxygen level is as low as 3% under hypoxia condition[13]
Summary
Angiogenesis starts at the early phase of inflammation until the formation of new capillaries from the pre-existing vasculature. The hypoxia level in inflamed joint is inversely correlated with the levels of vascularity, oxidative damage and synovial inflammation[14,15]. The upregulation of vascular endothelial growth factor (VEGF), angiopoietins, monocyte chemotactic protein 1, interleukin-8, CCL20 and matrix metalloproteinases (MMPs) and down-regulation of interleukin-10 have been reported in synovial cells under hypoxia condition[17]. All of these growth factors and chemokines can regulate angiogenesis. Literature shows that AMF induces angiogenesis in cancer by increasing the cell motility and the expression of vascular endothelial growth factor receptor (VEGFR) in endothelial cells[22,23,24]. By gene loss-of-function assays, we demonstrated the hypoxia-induced angiogenesis is dependent on the G6PI expression in HDMECs and VEGF secretion from RASFs, the latter is regulated by G6PI
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
