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1.
Temporospatial expression of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases in mouse antigen-induced arthritis 总被引:1,自引:1,他引:0
Several lines of evidence speak for an important role of matrix metalloproteinases (MMPs) in the development of progressive
joint destruction. To better understand the role of MMPs and their tissue inhibitors (TIMPs) in this process, we have used
the antigen-induced arthritis model to study the temporospatial expression of several MMPs and TIMPs during the progression
of arthritis. Arthritis was induced by a single intra-articular injection of methylated bovine serum albumin (mBSA) into one
or both knee joints of adult mice previously immunised against mBSA. Samples were collected at 3, 7, 21 and 42 days after
induction of arthritis for histology and RNA extraction, and analysed by Northern hybridisation, histochemistry and immunohistochemistry
for production of several MMPs and TIMPs −1, −2 and −3. A systematic analysis of MMP and TIMP mRNA levels in mouse knee joints
demonstrated a general upregulation of both MMPs and TIMPs during progression of arthritis. Upregulation of MMP-9, −13 and
−14 coincided with the advancement of cartilage degeneration, but the expression patterns of MMP-9 and −13 also followed the
course of synovial inflammation. TIMPs were steadily upregulated throughout the examination period. Immunohistochemical localisation
of MMPs and TIMPs suggested the synovium to be the major source of MMP and TIMP production in arthritis, although articular
cartilage chondrocytes also showed an increased production of both MMPs and TIMPs. 相似文献
2.
We demonstrated previously that local, intra-articular injection of an adenoviral vector expressing human tumor necrosis factor-related
apoptosis-inducing ligand (TRAIL) in a rabbit knee model of inflammatory arthritis stimulated synovial apoptosis and reduced
inflammation. To examine whether intra-articular injection of recombinant chimeric human TRAIL protein (rTRAIL) also induces
apoptosis of proliferating rabbit synovium and reduces inflammation, we used an experimental rabbit arthritis model of rheumatoid
arthritis, induced by intra-articular introduction of allogeneic fibroblasts genetically engineered to secrete human IL-1β.
Analysis of synovium isolated from the rabbits treated with intra-articular injection of rTRAIL, relative to saline control,
showed areas of extensive acellular debris and large fibrous regions devoid of intact cells, similar to adenoviral mediated
TRAIL gene transfer. Extensive apoptosis of the synovial lining was demonstrated using TUNEL analysis of the sections, corresponding
to the microscopic findings in hematoxylin and eosin staining. In addition, leukocyte infiltration into the synovial fluid
of the inflamed knee joints following rTRAIL treatment was reduced more than 50% compared with the saline control. Analysis
of the glycosaminoglycan synthetic rate by cultured cartilage using radiolabeled sulfur and cartilage histology demonstrated
that rTRAIL did not adversely affect cartilage metabolism and structure. Analysis of serum alanine aminotransferase showed
that intra-articular injection of rTRAIL did not have adverse effects on hepatic function. These results demonstrate that
intra-articular injection of rTRAIL could be therapeutic for treating pathologies associated with rheumatoid arthritis. 相似文献
3.
Judith van Holten Kris Reedquist Pascale Sattonet-Roche Tom JM Smeets Christine Plater-Zyberk Margriet J Vervoordeldonk Paul P Tak 《Arthritis research & therapy》2004,6(3):R239
We investigated the therapeutic potential and mechanism of action of IFN-β protein for the treatment of rheumatoid arthritis
(RA). Collagen-induced arthritis was induced in DBA/1 mice. At the first clinical sign of disease, mice were given daily injections
of recombinant mouse IFN-β or saline for 7 days. Disease progression was monitored by visual clinical scoring and measurement
of paw swelling. Inflammation and joint destruction were assessed histologically 8 days after the onset of arthritis. Proteoglycan
depletion was determined by safranin O staining. Expression of cytokines, receptor activator of NF-κB ligand, and c-Fos was
evaluated immunohistochemically. The IL-1-induced expression of IL-6, IL-8, and granulocyte/macrophage-colony-stimulating
factor (GM-CSF) was studied by ELISA in supernatant of RA and osteoarthritis fibroblast-like synoviocytes incubated with IFN-β.
We also examined the effect of IFN-β on NF-κB activity. IFN-β, at 0.25 μg/injection and higher, significantly reduced disease
severity in two experiments, each using 8–10 mice per treatment group. IFN-β-treated animals displayed significantly less
cartilage and bone destruction than controls, paralleled by a decreased number of positive cells of two gene products required
for osteoclastogenesis, receptor activator of NF-κB ligand and c-Fos. Tumor necrosis factor α and IL-6 expression were significantly
reduced, while IL-10 production was increased after IFN-β treatment. IFN-β reduced expression of IL-6, IL-8, and GM-CSF in
RA and osteoarthritis fibroblast-like synoviocytes, correlating with reduced NF-κB activity. The data support the view that
IFN-β is a potential therapy for RA that might help to diminish both joint inflammation and destruction by cytokine modulation. 相似文献
4.
5.
6.
Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction. 总被引:7,自引:0,他引:7
E Lubberts L A Joosten L van Den Bersselaar M M Helsen A C Bakker J B van Meurs F L Graham C D Richards W B van Den Berg 《Journal of immunology (Baltimore, Md. : 1950)》1999,163(8):4546-4556
Rheumatoid arthritis is a chronic inflammatory joint disease, leading to cartilage and bone destruction. In this study, we investigated the effects of local IL-4 application, introduced by a recombinant human type 5 adenovirus vector, in the knee joint of mice with collagen-induced arthritis. One intraarticular injection with an IL-4-expressing virus caused overexpression of IL-4 in the mouse knee joint. Enhanced onset and aggravation of the synovial inflammation were found in the IL-4 group. However, despite ongoing inflammation, histologic analysis showed impressive prevention of chondrocyte death and cartilage erosion. In line with this, chondrocyte proteoglycan synthesis was enhanced in the articular cartilage. This was quantified with ex vivo 35S-sulfate incorporation in patellar cartilage and confirmed by autoradiography on whole knee joint sections. Reduction of cartilage erosion was further substantiated by lack of expression of the stromelysin-dependent cartilage proteoglycan breakdown neoepitope VDIPEN in the Ad5E1 mIL-4-treated knee joint. Reduced metalloproteinase activity was also supported by markedly diminished mRNA expression of stromelysin-3 in the synovial tissue. Histologic analysis revealed marked reduction of polymorphonuclear cells in the synovial joint space in the IL-4-treated joints. This was confirmed by immunolocalization studies on knee joint sections using NIMP-R14 staining and diminished mRNA expression of macrophage-inflammatory protein-2 in the synovium tissue. mRNA levels of TNF-alpha and IL-1beta were suppressed as well, and IL-1beta and nitric oxide production by arthritic synovial tissue were strongly reduced. Our data show an impressive cartilage-protective effect of local IL-4 and underline the feasibility of local gene therapy with this cytokine in arthritis. 相似文献
7.
Esmeralda N Blaney Davidson Elly L Vitters Wim B van den Berg Peter M van der Kraan 《Arthritis research & therapy》2006,8(3):R65-8
Cartilage damage in osteoarthritis (OA) is considered an imbalance between catabolic and anabolic factors, favoring the catabolic
side. We assessed whether adenoviral overexpression of transforming growth factor-β (TGFβ) enhanced cartilage repair and whether
TGFβ-induced fibrosis was blocked by local expression of the intracellular TGFβ inhibitor Smad7. We inflicted cartilage damage
by injection of interleukin-1 (IL-1) into murine knee joints. After 2 days, we injected an adenovirus encoding TGFβ. On day
4, we measured proteoglycan (PG) synthesis and content. To examine whether we could block TGFβ-induced fibrosis and stimulate
cartilage repair simultaneously, we injected Ad-TGFβ and Ad-Smad7. This was performed both after IL-1-induced damage and in
a model of primary OA. In addition to PG in cartilage, synovial fibrosis was measured by determining the synovial width and
the number of procollagen I-expressing cells. Adenoviral overexpression of TGFβ restored the IL-1-induced reduction in PG
content and increased PG synthesis. TGFβ-induced an elevation in PG content in cartilage of the OA model. TGFβ-induced synovial
fibrosis was strongly diminished by simultaneous synovial overexpression of Smad7 in the synovial lining. Of great interest,
overexpression of Smad7 did not reduce the repair-stimulating effect of TGFβ on cartilage. Adenoviral overexpression of TGFβ
stimulated repair of IL-1- and OA-damaged cartilage. TGFβ-induced synovial fibrosis was blocked by locally inhibiting TGFβ
signaling in the synovial lining by simultaneously transfecting it with an adenovirus overexpressing Smad7. 相似文献
8.
Blaney Davidson EN Vitters EL van Lent PL van de Loo FA van den Berg WB van der Kraan PM 《Arthritis research & therapy》2007,9(5):R102
Bone morphogenetic protein-2 (BMP-2) has been proposed as a tool for cartilage repair and as a stimulant of chondrogenesis.
In healthy cartilage, BMP-2 is hardly present, whereas it is highly expressed during osteoarthritis. To assess its function
in cartilage, BMP-2 was overexpressed in healthy murine knee joints and the effects on proteoglycan (PG) synthesis and degradation
were evaluated. Moreover, the contribution of BMP in repairing damage induced by interleukin-1 (IL-1) was investigated. Ad-BMP-2
was injected intra-articularly into murine knee joints, which were isolated 3, 7, and 21 days after injection for histology,
immunohistochemistry, and autoradiography. In addition, patellar and tibial cartilage was isolated for RNA isolation or measurement
of PG synthesis by means of 35SO4
2- incorporation. To investigate the role for BMP-2 in cartilage repair, cartilage damage was induced by intra-articular injection
of IL-1. After 2 days, Ad-BMP-2, Ad-BMP-2 + Ad-gremlin, Ad-gremlin, or a control virus was injected. Whole knee joints were
isolated for histology at day 4 or patellae were isolated to measure 35SO4
2- incorporation. BMP-2 stimulated PG synthesis in patellar cartilage on all days and in tibial cartilage on day 21. Aggrecan
mRNA expression had increased on all days in patellar cartilage, with the highest increase on day 7. Collagen type II expression
showed a similar expression pattern. In tibial cartilage, collagen type II and aggrecan mRNA expression had increased on days
7 and 21. BMP-2 overexpression also induced increased aggrecan degradation in cartilage. VDIPEN staining (indicating matrix
metalloproteinase activity) was elevated on day 3 in tibial cartilage and on days 3 and 7 in patellar cartilage, but no longer
was by day 21. Increased NITEGE staining (indicating aggrecanase activity) was found on days 7 and 21. In IL-1-damaged patellar
cartilage, BMP-2 boosted PG synthesis. Blocking of BMP activity resulted in a decreased PG synthesis compared with IL-1 alone.
This decreased PG synthesis was associated with PG depletion in the cartilage. These data show that BMP-2 boosts matrix turnover
in intact and IL-damaged cartilage. Moreover, BMP contributes to the intrinsic repair capacity of damaged cartilage. Increased
matrix turnover might be functional in replacing matrix molecules in the repair of a damaged cartilage matrix. 相似文献
9.
Nabbe KC van Lent PL Holthuysen AE Sloëtjes AW Koch AE Radstake TR van den Berg WB 《Arthritis research & therapy》2005,7(2):R392-R401
During immune-complex-mediated arthritis (ICA), severe cartilage destruction is mediated by Fcγ receptors (FcγRs) (mainly
FcγRI), cytokines (e.g. IL-1), and enzymes (matrix metalloproteinases (MMPs)). IL-13, a T helper 2 (Th2) cytokine abundantly
found in synovial fluid of patients with rheumatoid arthritis, has been shown to reduce joint inflammation and bone destruction
during experimental arthritis. However, the effect on severe cartilage destruction has not been studied in detail. We have
now investigated the role of IL-13 in chondrocyte death and MMP-mediated cartilage damage during ICA. IL-13 was locally overexpressed
in knee joints after injection of an adenovirus encoding IL-13 (AxCAhIL-13), 1 day before the onset of arthritis; injection
of AxCANI (an empty adenoviral construct) was used as a control. IL-13 significantly increased the amount of inflammatory
cells in the synovial lining and the joint cavity, by 30% to 60% at day 3 after the onset of ICA. Despite the enhanced inflammatory
response, chondrocyte death was diminished by two-thirds at days 3 and 7. The mRNA level of FcγRI, a receptor shown to be
crucial in the induction of chondrocyte death, was significantly down-regulated in synovium. Furthermore, MMP-mediated cartilage
damage, measured as neoepitope (VDIPEN) expression using immunolocalization, was halved. In contrast, mRNA levels of MMP-3,
-9, -12, and -13 were significantly higher and IL-1 protein, which induces production of latent MMPs, was increased fivefold
by IL-13. This study demonstrates that IL-13 overexpression during ICA diminished both chondrocyte death and MMP-mediated
VDIPEN expression, even though joint inflammation was enhanced. 相似文献
10.
Gihan Hashem Qin Zhang Takayuki Hayami Jean Chen Wei Wang Sunil Kapila 《Arthritis research & therapy》2006,8(4):R98-9
Relaxin, a 6-kDa polypeptide hormone, is a potent mediator of matrix turnover and contributes to the loss of collagen and
glycosaminoglycans (GAGs) from reproductive tissues, including the fibrocartilaginous pubic symphysis of several species.
This effect is often potentiated by β-estradiol. We postulated that relaxin and β-estradiol might similarly contribute to
the enhanced degradation of matrices in fibrocartilaginous tissues from synovial joints, which may help explain the preponderance
of diseases of specific fibrocartilaginous joints in women of reproductive age. The objective of this study was to compare
the in vivo effects of relaxin, β-estradiol, and progesterone alone or in various combinations on GAG and collagen content of the rabbit
temporomandibular joint (TMJ) disc fibrocartilage, knee meniscus fibrocartilage, knee articular cartilage, and the pubic symphysis.
Sham-operated or ovariectomized female rabbits were administered β-estradiol (20 ng/kg body weight), progesterone (5 mg/kg),
or saline intramuscularly. This was repeated 2 days later and followed by subcutaneous implantation of osmotic pumps containing
relaxin (23.3 μg/kg) or saline. Tissues were retrieved 4 days later and analyzed for GAG and collagen. Serum relaxin levels
were assayed using enzyme-linked immunosorbent assay. Relaxin administration resulted in a 30-fold significant (p < 0.0001) increase in median levels (range, approximately 38 to 58 pg/ml) of systemic relaxin. β-estradiol, relaxin, or β-estradiol
+ relaxin caused a significant loss of GAGs and collagen from the pubic symphysis and TMJ disc and of collagen from articular
cartilage but not from the knee meniscus. Progesterone prevented relaxin- or β-estradiol-mediated loss of these molecules.
The loss of GAGs and collagen caused by β-estradiol, relaxin, or β-estradiol + relaxin varied between tissues and was most
prominent in pubic symphysis and TMJ disc fibrocartilages. The findings suggest that this targeted modulation of matrix loss
by hormones may contribute selectively to degeneration of specific synovial joints. 相似文献
11.
12.
Interleukin-34 (IL-34), recently identified as a novel inflammatory cytokine and the second ligand for colony-stimulating factor-1 receptor, is known to play regulatory roles in the development, maintenance, and function of mononuclear phagocyte lineage cells – especially osteoclasts. Regarding its primary effect on osteoclasts, IL-34 has been shown to stimulate formation and activation of osteoclasts, which in turn magnifies osteoclasts-resorbing activity. In addition to its role in osteoclastogenesis, IL-34 has been implicated in inflammation of synovium via augmenting production of inflammatory mediators, in which altered IL-34 expression is regulated by pro-inflammatory cytokines responsible for cartilage degradation. Indeed, IL-34 has been documented to be highly expressed in inflamed synovium of rheumatoid arthritis (RA) and knee osteoarthritis (OA) patients, which are recognized as inflammatory arthritis. Furthermore, a number of clinical studies demonstrated that IL-34 levels were significantly increased in the circulation and synovial fluid of patients with RA and knee OA. Its levels were also found to be positively associated with disease severity – especially radiographic severity of both RA and knee OA patients. Interestingly, emerging evidence has accumulated that functional blockage of IL-34 with specific antibody can alleviate the severity of inflammatory arthritis. It is therefore reasonable to speculate that IL-34 may be developed as a potential biomarker and a new therapeutic candidate for inflammatory arthritis. To date, there are numerous studies showing IL-34 involvement and association with many aspects of inflammatory arthritis. Herein, this review aimed to summarize the recent findings regarding regulatory role of IL-34 in synovial inflammation-mediated cartilage destruction and update the current comprehensive knowledge on usefulness of IL-34-based treatment in inflammatory arthritis – particularly RA and knee OA. 相似文献
13.
Rowan S Hardy Andrew Filer Mark S Cooper Greg Parsonage Karim Raza Debbie L Hardie Elizabeth H Rabbitt Paul M Stewart Christopher D Buckley Martin Hewison 《Arthritis research & therapy》2006,8(4):R108-10
Stromal cells such as fibroblasts play an important role in defining tissue-specific responses during the resolution of inflammation.
We hypothesized that this involves tissue-specific regulation of glucocorticoids, mediated via differential regulation of
the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Expression, activity and function of 11β-HSD1 was assessed
in matched fibroblasts derived from various tissues (synovium, bone marrow and skin) obtained from patients with rheumatoid
arthritis or osteoarthritis. 11β-HSD1 was expressed in fibroblasts from all tissues but mRNA levels and enzyme activity were
higher in synovial fibroblasts (2-fold and 13-fold higher mRNA levels in dermal and synovial fibroblasts, respectively, relative
to bone marrow). Expression and activity of the enzyme increased in all fibroblasts following treatment with tumour necrosis
factor-α or IL-1β (bone marrow: 8-fold and 37-fold, respectively, compared to vehicle; dermal fibroblasts: 4-fold and 14-fold;
synovial fibroblasts: 7-fold and 31-fold; all P < 0.01 compared with vehicle). Treatment with IL-4 or interferon-γ was without effect, and there was no difference in 11β-HSD1
expression between fibroblasts (from any site) obtained from patients with rheumatoid arthritis or osteoarthritis. In the
presence of 100 nmol/l cortisone, IL-6 production – a characteristic feature of synovial derived fibroblasts – was significantly
reduced in synovial but not dermal or bone marrow fibroblasts. This was prevented by co-treatment with an 11β-HSD inhibitor,
emphasizing the potential for autocrine activation of glucocorticoids in synovial fibroblasts. These data indicate that differences
in fibroblast-derived glucocorticoid production (via the enzyme 11β-HSD1) between cells from distinct anatomical locations
may play a key role in the predeliction of certain tissues to develop persistent inflammation. 相似文献
14.
15.
Wähämaa H Schierbeck H Hreggvidsdottir HS Palmblad K Aveberger AC Andersson U Harris HE 《Arthritis research & therapy》2011,13(4):R136
Introduction
In addition to its direct proinflammatory activity, extracellular high mobility group box protein 1 (HMGB1) can strongly enhance the cytokine response evoked by other proinflammatory molecules, such as lipopolysaccharide (LPS), CpG-DNA and IL-1β, through the formation of complexes. Extracellular HMGB1 is abundant in arthritic joint tissue where it is suggested to promote inflammation as intra-articular injections of HMGB1 induce synovitis in mice and HMGB1 neutralizing therapy suppresses development of experimental arthritis. The aim of this study was to determine whether HMGB1 in complex with LPS, interleukin (IL)-1α or IL-1β has enhancing effects on the production of proinflammatory mediators by rheumatoid arthritis synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF). Furthermore, we examined the toll-like receptor (TLR) 4 and IL-1RI requirement for the cytokine-enhancing effects of the investigated HMGB1-ligand complexes. 相似文献16.
Sander W Tas Margriet J Vervoordeldonk Najat Hajji Michael J May Sankar Ghosh Paul P Tak 《Arthritis research & therapy》2006,8(4):R86-9
Nuclear factor (NF)-κB is a key regulator of synovial inflammation. We investigated the effect of local NF-κB inhibition in
rat adjuvant arthritis (AA), using the specific IκB kinase (IKK)-β blocking NF-κB essential modulator-binding domain (NBD)
peptide. The effects of the NBD peptide on human fibroblast-like synoviocytes (FLS) and macrophages, as well as rheumatoid
arthritis (RA) whole-tissue biopsies, were also evaluated. First, we investigated the effects of the NBD peptide on RA FLS
in vitro. Subsequently, NBD peptides were administered intra-articularly into the right ankle joint of rats at the onset of disease.
The severity of arthritis was monitored over time, rats were sacrificed on day 20, and tissue specimens were collected for
routine histology and x-rays of the ankle joints. Human macrophages or RA synovial tissues were cultured ex vivo in the presence or absence of NBD peptides, and cytokine production was measured in the supernatant by enzyme-linked immunosorbent
assay. The NBD peptide blocked interleukin (IL)-1-β-induced IκBα phosphorylation and IL-6 production in RA FLS. Intra-articular
injection of the NBD peptide led to significantly reduced severity of arthritis (p < 0.0001) and reduced radiological damage (p = 0.04). This was associated with decreased synovial cellularity and reduced expression of tumor necrosis factor (TNF)-α
and IL-1-β in the synovium. Incubation of human macrophages with NBD peptides resulted in 50% inhibition of IL-1-β-induced
TNF-α production in the supernatant (p < 0.01). In addition, the NBD peptide decreased TNF-α-induced IL-6 production by human RA synovial tissue biopsies by approximately
42% (p < 0.01). Specific NF-κB blockade using a small peptide inhibitor of IKK-β has anti-inflammatory effects in AA and human RA
synovial tissue as well as in two important cell types in the pathogenesis of RA: macrophages and FLS. These results indicate
that IKK-β-targeted NF-κB blockade using the NBD peptide could offer a new approach for the local treatment of arthritis. 相似文献
17.
Spectroscopic study of ALA-induced endogenous porphyrins in arthritic knee tissues: targeting rheumatoid arthritis PDT. 总被引:1,自引:0,他引:1
Saulius Bagdonas Gailute Kirdaite Giedre Streckyte Vida Graziene Laima Leonaviciene Ruta Bradunaite Algirdas Venalis Ricardas Rotomskis 《Photochemical & photobiological sciences》2005,4(7):497-502
The inflamed synovium of rheumatoid arthritis exhibits many features typical for neoplastic tissue implying that the photodynamic therapy might be an efficient modality for chronic poliarthritis. The accumulation of endogenously produced porphyrins after administration of exogenous 5-aminolevulinic acid (ALA) in a rabbit model of rheumatoid arthritis was evaluated by fluorescence spectroscopy. Independent of the way, intravenously or intra-articularly, in which ALA was administered to the experimental animals, the highest fluorescence intensity of endogenously produced porphyrins was detected in the tissues of the inflamed joints. Besides, the application of ALA had a systemic sensitising effect on the whole organism of rabbits. The highest amount of endogenously produced porphyrins in the inflamed joints measured from the surface of the skin above the synovium tissues was detected 1-3 h after the administration of ALA. Fluorescence measurements performed on the tissue specimens ex vivo showed the predominant accumulation of porphyrins in the synovium of the inflamed joints. The fluorescence of porphyrins was also observed in the cartilage tissues taken from knee joints. However, the fluorescence spectra features indicated that the composition of porphyrins detected in the cartilage tissues was different than that in the synovial tissues. The selective accumulation of porphyrins in the inflamed synovial tissues stands up for the application of photodynamic therapy in the treatment of rheumatoid arthritis and implies the possibility to use optical non-invasive methods based on fluorescence detection of endogenously produced porphyrins for diagnostics of inflamed tissues. 相似文献
18.
Campo GM Avenoso A Campo S Ferlazzo AM Altavilla D Calatroni A 《Arthritis research & therapy》2003,5(3):R122-R131
To evaluate the antioxidant activity of the glycosaminoglycans hyaluronic acid (HYA) and chondroitin-4-sulphate (C4S), we
used a rat model of collagen-induced arthritis (CIA). Arthritis was induced in Lewis rats by multiple intradermal injections
of 250 μl of emulsion containing bovine type II collagen in complete Freund's adjuvant at the base of the tail and into three
to five other sites on the back. Rats were challenged again with the same antigen preparation 7 days later. Disease developed
about 11 days after the second immunization. The effects of treatment in the rats were monitored by biochemical parameters
and by macroscopic and histological evaluations in blood, synovial tissue and articular cartilage. Arthritis produced the
following symptoms: severe periarticular erythema, edema and inflammation in the hindpaws; membrane peroxidation in the cartilage
of the joints; endogenous antioxidant wasting; high tumour necrosis factor-α (TNF-α) plasma levels; and synovial neutrophil
accumulation. Treatment with HYA and C4S, starting at the onset of arthritis for 10 days, limited the erosive action of the
disease in the articular joints of knee and paw, reduced lipid peroxidation, restored the endogenous antioxidants reduced
glutathione (GSH) and superoxide dismutase, decreased plasma TNF-α levels, and limited synovial neutrophil infiltration. These
data confirm that erosive destruction of the joint cartilage in CIA is due at least in part to free radicals released by activated
neutrophils and produced by other biochemical pathways. The beneficial effects obtained with the treatment suggest that HYA
and C4S could be considered natural endogenous macromolecules to limit erosive damage in CIA or as a useful tool with which
to study the involvement of free radicals in rheumatoid arthritis. 相似文献
19.
Itthiarbha A Phitak T Sanyacharernkul S Pothacharoen P Pompimon W Kongtawelert P 《In vitro cellular & developmental biology. Animal》2012,48(1):43-53
Interleukin-1β (IL-1β) induces the expression of matrix metalloproteinases (MMPs) implicated in cartilage and joint degradation
in osteoarthritis (OA) and rheumatoid arthritis (RA). Polyoxypregnane glycoside (PPG), active compound was identified from
Dregea volubilis extract by chemical analysis, shown to exert chondroprotective effects in cartilage explant models. However, no studies have
been undertaken for the molecular investigation of whether PPG constituents protect the human articular chondrocyte (HAC).
In the present studies, HAC was co-treated with IL-1β and PPG. The expression of MMPs, type II collagen, phosphorylation of
mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathway were determined by Western immunoblotting. PPG (6.25–25 μM)
decreased the IL-1β-induced HA release from chondrocyte to culture medium. The mode of action of PPG was likely mediated through
inhibiting expression of MMP-1, -3 and -13 in the medium, which was associated with the inhibition of mRNA expression. PPG
had no effect on IL-1β-induced phosphorylation of MAPK pathway. Conversely, PPG decreased phosphorylation of IκB kinase and
IκBα degradation. Taken together, these results indicate that PPG may inhibit cartilage degradation in OA and may also be
used as nutritional supplement for maintaining joint integrity and function. 相似文献
20.
Danielle M Gerlag Eric Borges Paul P Tak H Michael Ellerby Dale E Bredesen Renata Pasqualini Erkki Ruoslahti Gary S Firestein 《Arthritis research & therapy》2001,3(6):357-5
Because angiogenesis plays a major role in the perpetuation of inflammatory arthritis, we explored a method for selectively
targeting and destroying new synovial blood vessels. Mice with collagen-induced arthritis were injected intravenously with
phage expressing an RGD motif. In addition, the RGD peptide (RGD-4C) was covalently linked to a proapoptotic heptapeptide
dimer, D(KLAKLAK)2, and was systemically administered to mice with collagen-induced arthritis. A phage displaying an RGD-containing cyclic peptide
(RGD-4C) that binds selectively to the αvβ3 and αvβ5 integrins accumulated in inflamed synovium but not in normal synovium.
Homing of RGD-4C phage to inflamed synovium was inhibited by co-administration of soluble RGD-4C. Intravenous injections of
the RGD-4C–D(KLAKLAK)2 chimeric peptide significantly decreased clinical arthritis and increased apoptosis of synovial blood vessels, whereas treatment
with vehicle or uncoupled mixture of the RGD-4C and the untargeted proapoptotic peptide had no effect. Targeted apoptosis
of synovial neovasculature can induce apoptosis and suppress clinical arthritis. This form of therapy has potential utility
in the treatment of inflammatory arthritis. 相似文献