Abstract
Connective tissue growth factor (CTGF, a.k.a. CCN2) is inflammatory mediator and abundantly expressed in osteoarthritis (OA). Angiogenesis is essential for OA progression. Here, we investigated the role of CTGF in vascular endothelial growth factor (VEGF) production and angiogenesis in OA synovial fibroblasts (OASFs). We showed that expression of CTGF and VEGF in synovial fluid were higher in OA patients than in controls. Directly applying CTGF to OASFs increased VEGF production then promoted endothelial progenitor cells tube formation and migration. CTGF induced VEGF by raising miR-210 expression via PI3K, AKT, ERK, and nuclear factor-κB (NF-κB)/ELK1 pathways. CTGF-mediating miR-210 upregulation repressed glycerol-3-phosphate dehydrogenase 1-like (GPD1L) expression and PHD activity and subsequently promoted hypoxia-inducible factor (HIF)-1α-dependent VEGF expression. Knockdown of CTGF decreased VEGF expression and abolished OASF-conditional medium-mediated angiogenesis in vitro as well as angiogenesis in chick chorioallantoic membrane and Matrigel-plug nude mice model in vivo. Taken together, our results suggest CTGF activates PI3K, AKT, ERK, and NF-κB/ELK1 pathway, leading to the upregulation of miR-210, contributing to inhibit GPD1L expression and prolyl hydroxylases 2 activity, promoting HIF-1α-dependent VEGF expression and angiogenesis in human synovial fibroblasts.
Highlights
MRNA expression of Connective tissue growth factor (CTGF) has been upregulated adjacent to areas of cartilage surface damage, and present in chondroosteophytes.[11]
We found OA synovial fluid or OA synovial fibroblast (OASF) conditioned medium (CM) enhancing endothelial progenitor cell (EPC) tube formation and migration (Figures 1c and d), suggesting CTGF and vascular endothelial growth factor (VEGF) have key roles in OA angiogenesis and pathogenesis
CTGF is involved in OA pathogenesis;[12,14] its effect on VEGF expression and angiogenesis in human synovial fibroblasts is mostly unknown
Summary
MRNA expression of CTGF has been upregulated adjacent to areas of cartilage surface damage, and present in chondroosteophytes.[11]. CTGF enhancing IL-6 and MCP-1 expression and promoting inflammation in OASFs,[14,15] meaning CTGF contributes to pathogenesis of OA. The small, noncoding microRNAs (miRNAs) transcribed from DNA are 18–24 nucleotides in length, modulating targeted gene expression via either translational repression or mRNA cleavage.[16] It is recently reported that miRNA expression was associated with well-defined clinical pathological features and disease outcomes;[17,18] miRNAs have been linked with OA pathogenesis, especially for expression of genes encoding catabolic factors like matrix metalloproteinases and ADAMTS.[19] Many evidences indicated that. Received 23.5.14; revised 21.8.14; accepted 04.9.14; Edited by M Agostini miR-210 as angiogenic miRNA.[20,21,22] In addition, overexpression of miR-210 can stimulate formation of capillary-like structures in vitro when cells are cultured in Matrigel.[23] the exact etiological mechanism of miR-210 in angiogenesis and OA pathogenesis is largely unknown
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