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

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. 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. 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. 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.

Weng LH ，Ko JY ，Wang CJ ，Sun YC ，Wang FS ... -  《-》

Control of Dkk-1 ameliorates chondrocyte apoptosis, cartilage destruction, and subchondral bone deterioration in osteoarthritic knees.

Weng LH ，Wang CJ ，Ko JY ，Sun YC ，Wang FS ... -  《-》

Activation of matrix metalloproteinases 2, 9, and 13 by activated protein C in human osteoarthritic cartilage chondrocytes.

Levels of activated protein C (APC) are elevated in the synovial fluid of patients with osteoarthritis (OA), and increased APC levels are correlated with the levels of active matrix metalloproteinase 2 (MMP-2). This study sought to investigate whether APC is a relevant protein for activation of MMPs in the degradation of human OA cartilage, and to elucidate its mechanisms of action. Human articular cartilage was cultured with or without interleukin-1α (IL-1α), in the presence or absence of APC or protein C, and an MMP or serine proteinase inhibitor. Aggrecan and collagen release and chondrocyte gene expression levels were quantified. Aggrecanase and MMP cleavage of aggrecan was examined with neoepitope-specific antibodies, and MMP activity was measured using gelatin zymography and fluorogenic peptide assay. In human OA cartilage, APC induced aggrecan and collagen release, whereas in non-OA cartilage, costimulation with IL-1α was required. Inhibition of MMP activity reduced APC-induced cartilage proteolysis, and MMP-induced aggrecanolysis was confirmed by Western blotting. In cultures with APC alone, the activity of MMPs 2, 9, and 13 was significantly increased in OA cartilage, although APC could not directly activate MMPs 2 or 9. Expression of MMP1, MMP2, MMP9, MMP13, TIMP1, and TIMP3 was not altered by APC in OA cartilage. Human OA chondrocytes expressed messenger RNA for protein C, endothelial protein C receptor, thrombomodulin, and protease-activated receptor 1, but these were unaltered or down-regulated by APC. The induction of MMP activation and cartilage degradation by APC was dependent on its serine protease activity. APC is a physiologically relevant activator of MMPs and cartilage breakdown in human OA. The effects of APC are dependent on its proteolytic activity and as-yet-undefined cell and/or cartilage matrix factors, and inhibition of this pathway may provide a novel therapeutic target to halt the progression of cartilage damage in OA.

Jackson MT ，Moradi B ，Smith MM ，Jackson CJ ，Little CB ... -  《-》

Catabolic stress induces expression of hypoxia-inducible factor (HIF)-1 alpha in articular chondrocytes: involvement of HIF-1 alpha in the pathogenesis of osteoarthritis.

Yudoh K ，Nakamura H ，Masuko-Hongo K ，Kato T ，Nishioka K ... -  《-》

Chaperonin 60 regulation of SOX9 ubiquitination mitigates the development of knee osteoarthritis.

Ko JY ，Sun YC ，Li WC ，Wang FS ... -  《-》