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.


CONCLUSIONS
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.
Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
Lin-Hsiu
LH
Weng
Jih-Yang
JY
Ko
Ching-Jen
CJ
Wang
Yi-Chih
YC
Sun
Feng-Sheng
FS
Wang
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D007719:Knee Joint / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013582:Synovial Fluid / Q000187:drug effects / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology
D043925:Angiogenesis Inducing Agents; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053583:Interleukin-1beta; D016173:Macrophage Colony-Stimulating Factor; D019278:Matrix Metalloproteinase 3