摘要：SummaryAlthough angiogenesis-osteogenesis coupling is important in ankylosing spondylitis (AS), therapeutic agents targeting the vasculature remain elusive. Here, we identified activating transcription factor 6 (ATF6) as an important regulator of angiogenesis in the pathogenesis of AS. First, we found that ATF6 and fibroblast growth factor 2 (FGF2) levels were higher in SKG mice and in cartilage of pateints with AS1. The proangiogenic activity of human chondrocytes was enhanced by the activation of the ATF6-FGF2 axis following 7 days of stimulation with inflammatory factors, e.g., tumor necrosis factor alpha (TNF-α), interferon-γ (IFN-γ) or interleukin-17 (IL-17). Mechanistically, ATF6 interacted with theFGF2promotor and promoted its transcription. Treatment with the ATF6 inhibitor Ceapin-A7 inhibited angiogenesisin vitroand angiogenesis-osteogenesis couplingin vivo. ATF6 may aggravate angiogenesis-osteogenesis coupling during AS by mediating FGF2 transcription in chondrocytes, implying that ATF6 represents a promising therapeutic target for AS.Graphical abstractFGF2 is an effective factor that promotes angiogenesis-osteogenesis coupling and plays an important role in AS. Chondrocytes stimulated for 7 days with proinflammatory cytokines undergo chronic ERS with ATF6 pathway activation. By directly binding to theFGF2promoter, ATF6 increases FGF2 expression. Treatment of chondrocytes with the ATF6 inhibitor Ceapin-A7 effectively inhibits FGF2 expression.Display OmittedHighlights•Prolonged inflammatory stimulation triggers ERS in human chondrocytes•ERS upregulated FGF2 through ATF6 pathway, thereby promoting angiogenesis•Ceapin-A7 decreases the number of vessels and osteophytes in the AS mouse model•ATF6 may be a promising therapeutic target for ASBiological sciences; Physiology; Molecular biology
