PMID- 22736200
OWN - NLM
STAT- MEDLINE
DCOM- 20130116
LR  - 20121001
IS  - 1529-0131 (Electronic)
IS  - 0004-3591 (Linking)
VI  - 64
IP  - 10
DP  - 2012 Oct
TI  - Dkk-1 promotes angiogenic responses and cartilage matrix proteinase secretion in 
      synovial fibroblasts from osteoarthritic joints.
PG  - 3267-77
LID - 10.1002/art.34602 [doi]
AB  - 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-1beta (IL-1beta), 
      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-1beta induction of Dkk-1 increased expression of 
      hypoxia-inducible factor 1alpha (HIF-1alpha), angiogenic factors, ADAMTS-5, and MMP-3 in 
      synovial fibroblasts and promoted angiogenesis in vascular endothelial cells. 
      Knockdown of HIF-1alpha decreased Dkk-1 enhancement of angiogenic factor expression. 
      Stabilization of glycogen synthase kinase 3beta phosphorylated at Ser(9) , 
      beta-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.
CI  - Copyright (c) 2012 by the American College of Rheumatology.
FAU - Weng, Lin-Hsiu
AU  - Weng LH
AD  - Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of 
      Medicine, Kaohsiung, Taiwan.
FAU - Ko, Jih-Yang
AU  - Ko JY
FAU - Wang, Ching-Jen
AU  - Wang CJ
FAU - Sun, Yi-Chih
AU  - Sun YC
FAU - Wang, Feng-Sheng
AU  - Wang FS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Angiogenesis Inducing Agents)
RN  - 0 (CXCL12 protein, human)
RN  - 0 (Chemokine CXCL12)
RN  - 0 (DKK1 protein, human)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Interleukin-1beta)
RN  - 81627-83-0 (Macrophage Colony-Stimulating Factor)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Angiogenesis Inducing Agents/pharmacology
MH  - Cartilage, Articular/drug effects/*metabolism/pathology
MH  - Chemokine CXCL12/genetics/metabolism
MH  - Chondrocytes/drug effects/metabolism/pathology
MH  - Female
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/genetics/*metabolism/pharmacology
MH  - Interleukin-1beta/pharmacology
MH  - Knee Joint/drug effects/*metabolism/pathology
MH  - Macrophage Colony-Stimulating Factor/genetics/metabolism
MH  - Male
MH  - Matrix Metalloproteinase 3/genetics/metabolism
MH  - Neovascularization, Physiologic/*drug effects/physiology
MH  - Osteoarthritis, Knee/genetics/*metabolism/pathology
MH  - Synovial Fluid/drug effects/metabolism
MH  - Synovial Membrane/drug effects/*metabolism/pathology
EDAT- 2012/06/28 06:00
MHDA- 2013/01/17 06:00
CRDT- 2012/06/28 06:00
PHST- 2012/06/28 06:00 [entrez]
PHST- 2012/06/28 06:00 [pubmed]
PHST- 2013/01/17 06:00 [medline]
AID - 10.1002/art.34602 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2012 Oct;64(10):3267-77. doi: 10.1002/art.34602.