Dkk‐1 promotes angiogenic responses and cartilage matrix proteinase secretion in synovial fibroblasts from osteoarthritic joints

OBJECTIVE: Synovial hypervascularity is a prominent pathologic feature in osteoarthritic (OA) joints. Wnt inhibitor Dkk-1 contributes to joint remodeling. We undertook this study to investigate whether Dkk-1 regulates cartilage destruction activities in OA synovial fibroblasts. METHODS: Synovial tissues were harvested from knees of patients with OA and from injured knees of non-OA patients who underwent arthroscopy. Expression of Dkk-1, angiogenic factors (stromal cell-derived factor 1 and colony-stimulating factor 1), and cartilage proteinases (ADAMTS-5 and matrix metalloproteinase 3 [MMP-3]) as well as vascularity in synovium and synovial fluid were quantified using enzyme-linked immunosorbent assay, reverse transcription-polymerase chain reaction, and histomorphometry. Synovial fibroblasts were treated with interleukin-1β (IL-1β), anti-Dkk-1 antibody, and RNA interference to characterize their angiogenic activity. Rats with OA knees were administered Dkk-1 antisense oligonucleotide to verify synovial angiogenesis and cartilage integrity. RESULTS: OA synovium exhibited increased vascularity and expression of angiogenic factors and proteinases in association with up-regulated Dkk-1 levels. Neutralizing Dkk-1 reduced the inhibitory effects of OA synovial fluid on aggrecan expression in chondrocyte cultures. IL-1β induction of Dkk-1 increased expression of hypoxia-inducible factor 1α (HIF-1α), angiogenic factors, ADAMTS-5, and MMP-3 in synovial fibroblasts and promoted angiogenesis in vascular endothelial cells. Knockdown of HIF-1α decreased Dkk-1 enhancement of angiogenic factor expression. Stabilization of glycogen synthase kinase 3β phosphorylated at Ser(9) , β-catenin, T cell factor 4, and ERK signaling attenuated Dkk-1 up-regulation of angiogenic factor and proteinase expression in synovial fibroblasts. In vivo, Dkk-1 interference reduced the expression of angiogenic factors and proteinases and ameliorated synovial vascularity and cartilage deterioration in knees of rats with OA. CONCLUSION: Dkk-1 promoted angiogenic and cartilage degradation activities in synovial fibroblasts, which accelerated synovial angiogenesis and cartilage destruction. Dkk-1 blockade has therapeutic potential for reducing OA-induced synovitis and joint deterioration.