Adiponectin may contribute to synovitis and joint destruction in rheumatoid arthritis by stimulating vascular endothelial growth factor, matrix metalloproteinase-1, and matrix metalloproteinase-13 expression in fibroblast-like synoviocytes more than proinflammatory mediators
© Choi et al.; licensee BioMed Central Ltd. 2009
Received: 19 June 2009
Accepted: 2 November 2009
Published: 2 November 2009
The role of adiponectin in the pathogenesis of arthritis is still controversial. This study was performed to examine whether adiponectin is involved in joint inflammation and destruction in rheumatoid arthritis (RA) in relation to the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs).
Synovial cells from RA patients were treated with adiponectin or interleukin (IL)-1β for 24 hours. The culture supernatant was collected and analyzed for the levels of IL-6, IL-8, prostaglandin E2 (PGE2), VEGF, and MMPs by enzyme-linked immunosorbent assay. The levels of adiponectin, VEGF, MMP-1, and MMP-13 in the joint fluids from 30 RA or osteoarthritis (OA) patients were also measured.
Adiponectin at the concentration of 10 μg/mL stimulated the production of IL-6, IL-8, and PGE2 in RA fibroblast-like synoviocytes (FLSs), although the level of these was much lower than with 1 ng/mL IL-1β. However, adiponectin stimulated the production of VEGF, MMP-1, and MMP-13 at the same level as IL-1β. In addition, the level of adiponectin and MMP-1 in the joint fluid of RA patients was significantly higher than in OA patients. Adiponectin was positively correlated with VEGF in RA patients but not in OA patients, while the level of MMPs in joint fluid was not correlated with adiponectin in either RA or OA patients.
Adiponectin may play a significant role in the pathogenesis of RA by stimulating the production of VEGF and MMPs in FLSs, leading to joint inflammation and destruction, respectively.
Adipose tissue, once viewed as simply a storage and release depot for lipids, is now considered an endocrine tissue [1, 2] that secretes various substances (adipokines), including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, leptin, adiponectin, resistin, visfatin, and omenetin [3, 4]. Among these adipokines, much attention has been paid to adiponectin's relationship with insulin sensitivity and glucose and lipid metabolism in the past 10 years. In addition, adiponectin is known to exhibit potent anti-inflammatory , atheroprotective , and antidiabetic  effects.
Recent findings suggest that adiponectin may be involved in the pathogenesis of rheumatoid arthritis (RA). Levels of adiponectin in synovial fluid and sera were elevated in patients with RA [8, 9]. Adiponectin also induces the production of proinflammatory cytokines, IL-6, matrix metalloproteinase (MMP)-1, and IL-8 from RA synovial fibroblasts in vitro [10, 11]. Thus, it was suggested that adiponectin can also exert significant proinflammatory and matrix-degrading effects. However, the role of adiponectin in the pathogenesis of RA is still controversial because of conflicting reports about its function [10, 12–15]. In particular, adiponectin seems to play an anti-inflammatory role because it significantly inhibited IL-1β-stimulated synovial cell proliferation in collagen-induced arthritic mice, despite increased IL-6 expression . In contrast, high-grade inflammation in RA patients was negatively correlated with circulating adiponectin concentrations . Rather, it was suggested that circulating adiponectin may be involved in cardiovascular disease in RA patients. Although this contradiction was partly explained by the induction of tolerance to inflammatory stimuli by adiponectin , the pro- or anti-inflammatory effects of adiponectin on the pathogenesis of RA remain unknown.
With regard to adiponectin's proinflammatory effects, we wondered whether adiponectin might stimulate the production of vascular endothelial growth factor (VEGF) and MMPs as well as proinflammatory mediators like IL-1β and TNF-α do. In this study, we investigated the stimulatory effect of adiponectin on the production of IL-6, IL-8, prostaglandin E2 (PGE2), VEGF, and MMPs. In addition, the correlation between adiponectin and VEGF or MMPs was investigated by measuring the levels of these three proteins in the joint fluid of patients with RA or osteoarthritis (OA).
Materials and methods
All in vitro experiments were carried out with fibroblast-like synoviocytes (FLSs) derived from patients with RA. After informed consent was obtained, synovial tissues were collected from RA patients. They met the 1987 American College of Rheumatology criteria for the diagnosis of RA and had been treated with nonbiological disease-modifying antirheumatic drugs and had undergone therapeutic joint surgery. FLSs were isolated and grown in Dulbecco's modified essential medium (low glucose) (Gibco-BRL, now part of Invitrogen Corporation, Carlsbad, CA, USA) supplemented with 10% (vol/vol) fetal bovine serum (Invitrogen Corporation) and 1× Antibiotic-Antimycotic (Invitrogen Corporation) as described previously . After the cells had grown to confluence, they were split at a 1:4 ratio. FLS passages 3 to 6 from three patients were used for all experiments. Ethical permission was obtained from the Institutional Review Board for Human Research of Kyung Hee University, Neo-Medical Center.
Measurement of gene expression by enzyme-linked immunosorbent assay
Synovial cells (2.5 × 105 cells per 60-mm dish per 2 mL of serum-free media) were treated with recombinant adiponectin (1 or 10 μg/mL) or IL-1β (0.1 or 1 ng/mL) (ProSpec, Rehovot, Israel). Conditioned media was collected 24 hours later. Briefly, FLS cultures were centrifuged and the supernatants were collected and analyzed for IL-6, IL-8, PGE2, VEGF, MMP-1, and MMP-13 with an enzyme-linked immunosorbent assay (ELISA) kit (R&D Systems, Inc., Minneapolis, MN, USA). Three independent experiments were performed in quadruplicate. Each experiment was performed using synovial cells from different patients. For the assessment of MMP-1, MMP-13, VEGF, and adiponectin levels in joint fluid, the collected joint fluid from 30 patients with RA or OA was dispensed into 1-mL aliquots and treated with hyaluronadase at 50 μg/mL for 1 hour at room temperature. The joint fluid was diluted with diluent's buffer for the proper detection range with ELISA. The levels of proteins of interest in joint fluid were measured using a commercial ELISA kit from R&D Systems, Inc., as described above.
Real-time polymerase chain reaction
The sequence of polymerase chain reaction primers used in this experiment
5'-CCT AGC TAC ACC TTC AGT GG-3'
5'-GCC CAG TAC TTA TTC CCT TT-3'
5'-TTG AGG ATA CAG GCA AGA CT-3'
5'-TGG AAG TAT TAC CCC AAA TG-3'
5'-ACT TCA GGC TCT TCT CCT TT-3'
5'-TTC AGA CAA CCT GAG TCC TT-3'
5'-CTG GTC TTT TGG AGT TTG AG-3'
5'-TTT CTG ACC AGA AGA AGG AA-3'
5'-ACT TTC AGA GAC AGC AGA GC-3'
5'-GTG GTC CAC TCT CAA TCA CT-3'
5'-TTC AAA TGA GAT TGT GGG AAA ATT GCT-3'
5'-AGA TCA TCT CTG CCT GAG TAT CTT-3'
5'-TCA TGA GGT AGT CAG TCA GG-3'
5'-CTT CTA CAA TGA GCT GCG TG-3'
Western blot analysis
FLSs cultured (2.5 × 105 cells) in 60-mm dishes were serum-starved overnight and stimulated by adiponectin (1 or 10 μg/mL) or IL-1β (0.1 or 1 ng/mL) for 24 hours. The cells were subsequently washed twice in phosphate-buffered saline and treated with 50 μL of lysis buffer (20 mM Tris-Cl [pH 8.0], 150 mM NaCl, 1 mM EDTA [ethylenediaminetetraacetic acid], 1% Triton X-100, 20 μg/mL chymostatin, 2 mM PMSF [phenylmethylsulphonyl fluoride], 10 μM leupeptin, and 1 mM AEBSF [4-(2-aminoethyl)benzenesulfonyl fluoride]). The samples were separated using 12% SDS-PAGE and were then transferred to Hybond-ECL [enhanced chemiluminescence] membranes (Amersham, now part of GE Healthcare, Little Chalfont, Buckinghamshire, UK). The membranes were first blocked with 6% nonfat milk dissolved in TBST buffer (10 mM Tris-Cl [pH 8.0], 150 mM NaCl, 0.05% Tween 20). The blots were then probed with various rabbit polyclonal antibodies for COX-2 and β-actin (Cell Signaling Technology, Inc., Danvers, MA, USA) diluted 1:1,000 in Tris-buffered saline at 4°C overnight and incubated with 1:1,000 dilutions of goat anti-rabbit IgG secondary antibody coupled with horseradish peroxidase. The blots were developed using the ECL method (GE Healthcare). For re-probing, the blots were incubated in the stripping buffer (100 mM 2-mercaptoethanol, 2% SDS, 62.5 mM Tris-HCl [pH 6.7]) at 50°C for 30 minutes with occasional agitation.
The in vitro experimental data are expressed as the mean ± standard error of the mean of quadruplicate samples. Differences between groups were assessed by repeated analysis of variance followed by the Dunnett multiple comparison test. The level of MMPs, VEGF, and adiponectin in the joint fluid of RA and OA patients was compared between groups with the unpaired t test. To determine the degree of linearity between two variables, data were compared using the Pearson correlation test (two-tailed). Prism software 4 (GraphPad Software, Inc., San Diego, CA, USA) was used for statistical analysis and graphing. Differences were considered significant at a P value of less than 0.05.
Effect of adiponectin on the production of proinflammatory mediators in rheumatoid arthritis fibroblast-like synoviocytes
Effect of adiponectin on the production of vascular endothelial growth factor and matrix metalloproteinases in rheumatoid arthritis fibroblast-like synoviocytes
Correlation of matrix metalloproteinase levels with adiponectin in the joint fluid of patients
Adiponectin is known to play a significant role in the pathogenesis of RA, although whether adiponectin acts as an anti-inflammatory or proinflammatory mediator is controversial. Assuming that adiponectin plays a role in the pathogenesis of arthritis as a proinflammatory mediator, we tried to determine how significantly adiponectin contributes to joint inflammation and destruction compared with another proinflammatory cytokine, IL-1β. Thus, we evaluated the effect of adiponectin on the production of the proinflammatory mediators VEGF and MMPs and compared the result with that of IL-1β, one of the major proinflammatory cytokines in RA FLSs.
In this study, RA FLSs stimulated with 10 μg/mL adiponectin increased the production of IL-6, IL-8, and PGE2. However, the level of these proteins was low in comparison with that of RA FLSs stimulated with 1 ng/mL IL-1β. Adiponectin also greatly increased the mRNA and protein levels of collagenases (MMP-1 and MMP-13) and VEGF. MMPs and VEGF were elevated to a level comparable to that of IL-1β in RA FLSs. Interestingly, the mRNA and protein levels of gelatinases (MMP-2 and MMP-9) were not stimulated by either adiponectin or IL-1β. These results are consistent with some, but not all, previous results. Ehling and colleagues  reported that adiponectin increased the expression of pro-MMP-1 and IL-6 in RA FLSs, but not pro-MMP-13. In addition, adiponectin stimulated the expression of MMP-9, but not MMP-2, in cultured murine chondrocytes .
Next, we determined whether adiponectin affected the gene expression levels of the joint fluid in patients with arthritis in vitro by measuring the levels of adiponectin, MMPs, and VEGF in the joint fluid of patients with RA or OA, and we checked for a correlation between adiponectin and MMPs or VEGF. The level of adiponectin was not correlated with MMP levels in the joint fluid of either RA or OA patients. However, adiponectin was positively correlated with VEGF in the joint fluid of RA patients. Although the synovial adiponectin level was significantly higher in RA patients than in OA patients in our study (a result that is consistent with a previous report ), the elevated adiponectin may counteract the local inflammatory process since the adiponectin was negatively associated with local inflammatory factors in patients with RA. In addition, the level of adiponectin and VEGF in the joint fluids of RA or OA patients did not correlate with the level of C-reactive protein, suggesting that adiponectin may not be significantly involved in inflammation (data not shown). Furthermore, it was suggested that adiponectin may have a protective role in OA . Nevertheless, serum adiponectin concentrations correlate with the severity of RA evaluated by the extent of joint destruction, indirectly suggesting that adiponectin may be involved in joint destruction by stimulating the production of MMPs . In contrast, VEGF levels were positively correlated with adiponectin levels in RA joint fluid, but not in OA joint fluid, although a correlation does not necessarily imply a causal relationship given that the levels may be affected by various factors. Thus, we cannot explain why there are differences between the two groups, even though the VEGF level between the two groups was not significantly different. The relationship between adiponectin and VEGF has not been addressed previously. Inconsistent with our data, treatment with recombinant adiponectin in a mouse model of laser-induced choroidal neovascularization resulted in decreased levels of VEGF . Also, adiponectin did not regulate VEGF release in human airway smooth muscle cells whereas leptin did stimulate VEGF release . However, the concentration used in these treatments may not be the physiological concentrations. In our in vitro experiments, 1 to 10 μg/mL adiponectin was used to detect increased gene expression of various factors. At adiponectin concentrations of less than 1 μg/mL, the genes in RA FLSs were not activated. If its physiological concentration is taken into consideration, adiponectin should be used at a concentration of at least 1 μg/mL for in vitro experiments .
Pathological processes cannot be fully understood based on the change in expression of individual genes alone since various factors act in concert in the development of specific diseases in the body. Thus, systems biology can provide a novel conceptual framework for understanding a disease . Joint inflammation in arthritic patients is a complex immune reaction that is affected by various factors. Thus, joint inflammation should be understood as the integrated results of several factors, such as immune cell types infiltrating the joint cavity, cytokines, adipokines, hypoxia, and so on. In our study, the in vitro effect of adiponectin on MMP production was not demonstrated in the joint fluid of RA patients by evaluating the correlation between MMPs and adiponectin. The expression of MMPs also seems to be differentially regulated by various factors, including hypoxia (unpublished data) and nuclear factor-kappa-B inhibitors [28, 29]. In addition, MMP levels may be more significantly affected by the stage of disease than other factors, such as cytokines. MMP-9 level was increased more in early stages of arthritis than in later stages . Thus, the level of MMPs in the joint fluid of RA patients may not be affected by IL-1β or adiponectin alone. Rather, an integral effect of various unknown factors may impact the level of MMPs in joint fluid.
Factors that increase the expression of MMPs and VEGF have been suggested as potential therapeutic targets to delay or reduce the joint destruction that occurs in RA patients . Based on the in vitro effect of adiponectin on the expression of MMPs and VEGF, adiponectin may be a potential target to block MMP or VEGF expression. However, further studies should be performed to better understand factors that control the expression of MMPs and VEGF in the joint fluid of RA patients. This knowledge may open new doors to treatment and prevent the pathological processes of RA.
We show for the first time that adiponectin increases the level of VEGF and MMPs in RA FLSs as much as IL-1β but causes much smaller increases in IL-6, IL-8, and COX-2 compared with IL-1β. Furthermore, the level of adiponectin in the joint fluid of RA patients, but not OA patients, positively correlated with the level of VEGF. Although these data suggest a role for adiponectin in the perpetuation of synovitis in RA, no conclusions can be drawn from these results with regard to the relationship between adiponectin and inflammatory arthritis. Additional mechanistic and longitudinal studies in humans in the future might help to correlate our findings with clinical features.
enzyme-linked immunosorbent assay
polymerase chain reaction
tumor necrosis factor-alpha
vascular endothelial growth factor.
This work was supported by a research grant from the Korean Ministry of Health & Welfare (03-PJ9-PG6-SO01-002) and a grant from the Korea Science and Engineering Foundation (grant number R0809241). The authors thank Soo-Kon Lee of Yonsei University (Seoul, Korea) and William Sthol of the University of Southern California (Los Angeles, CA, USA) for their critical reading of the manuscript and their comments.
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