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1.
Mark G. Chambers Lucy Cox Lisa Chong Nida Suri Patricia Cover Michael T. Bayliss Roger M. Mason 《Arthritis \u0026amp; Rheumatology》2001,44(6):1455-1465
Objective
To map aggrecan cleavage by matrix metalloproteinases (MMPs) and aggrecanases in normal murine tibial articular cartilage (CBA strain) and in the development of spontaneous osteoarthritis (OA) in the STR/ort mouse and to assess the influence of sex hormone status on these conditions in gonadectomized STR/ort mice.Methods
The distributions of neoepitopes of aggrecan generated by MMP (VDIPEN) and aggrecanase (NITEGE) cleavage were investigated by immunohistochemistry.Results
VDIPEN neoepitope was detected mainly in the pericellular matrix of deep‐zone chondrocytes in normal tibial cartilage from STR/ort and CBA mice. In early OA, VDIPEN immunostaining also localized to the pericellular matrix of chondrocytes at the site of the lesion. With increasing severity of OA lesions, VDIPEN immunostaining was also detected in the interterritorial matrix, close to the site of the lesion. In contrast, NITEGE mapped most strongly to the pericellular matrix of upper‐zone chondrocytes in normal tibial cartilage. As with VDIPEN, NITEGE was strongly expressed in the pericellular matrix at the site of early OA lesions. With advancing OA, NITEGE colocalized with VDIPEN in both the pericellular and interterritorial matrices of chondrocytes adjacent to OA lesions and in those of the deep zones. Hormone status did not appear to influence the development of OA or the distribution of aggrecan neoepitopes in STR/ort mice.Conclusion
MMP‐ and aggrecanase‐generated neoepitopes map predominantly to different regions in normal murine tibial cartilage. However, both groups of enzymes generate increased amounts of neoepitopes in pericellular and interterritorial matrix adjacent to histopathologic lesions of OA. Aggrecan degradation and the development of OA appear to be independent of sex hormone status in this model.2.
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Jennifer M. Milner Amit Patel Rose K. Davidson Tracey E. Swingler Antoine Desilets David A. Young Elizabeth B. Kelso Simon T. Donell Tim E. Cawston Ian M. Clark William R. Ferrell Robin Plevin John C. Lockhart Richard Leduc Andrew D. Rowan 《Arthritis \u0026amp; Rheumatology》2010,62(7):1955-1966
Objective
Increasing evidence implicates serine proteinases in pathologic tissue turnover. The aim of this study was to assess the role of the transmembrane serine proteinase matriptase in cartilage destruction in osteoarthritis (OA).Methods
Serine proteinase gene expression in femoral head cartilage obtained from either patients with hip OA or patients with fracture to the neck of the femur (NOF) was assessed using a low‐density array. The effect of matriptase on collagen breakdown was determined in cartilage degradation models, while the effect on matrix metalloproteinase (MMP) expression was analyzed by real‐time polymerase chain reaction. ProMMP processing was determined using sodium dodecyl sulfate–polyacrylamide gel electrophoresis/N‐terminal sequencing, while its ability to activate proteinase‐activated receptor 2 (PAR‐2) was determined using a synovial perfusion assay in mice.Results
Matriptase gene expression was significantly elevated in OA cartilage compared with NOF cartilage, and matriptase was immunolocalized to OA chondrocytes. We showed that matriptase activated proMMP‐1 and processed proMMP‐3 to its fully active form. Exogenous matriptase significantly enhanced cytokine‐stimulated cartilage collagenolysis, while matriptase alone caused significant collagenolysis from OA cartilage, which was metalloproteinase‐dependent. Matriptase also induced MMP‐1, MMP‐3, and MMP‐13 gene expression. Synovial perfusion data confirmed that matriptase activates PAR‐2, and we demonstrated that matriptase‐dependent enhancement of collagenolysis from OA cartilage is blocked by PAR‐2 inhibition.Conclusion
Elevated matriptase expression in OA and the ability of matriptase to activate selective proMMPs as well as induce collagenase expression make this serine proteinase a key initiator and inducer of cartilage destruction in OA. We propose that the indirect effects of matriptase are mediated by PAR‐2, and a more detailed understanding of these mechanisms may highlight important new therapeutic targets for OA treatment.5.
K. C. A. M. Nabbe P. Boross A. E. M. Holthuysen A. W. Sloëtjes J. K. Kolls S. Verbeek P. L. E. M. Van Lent W. B. Van Den Berg 《Arthritis \u0026amp; Rheumatology》2005,52(3):967-974
Objective
It has previously been shown that the onset and the degree of joint inflammation during immune complex (IC)–mediated arthritis depend on Fcγ receptor type III (FcγRIII). Local adenoviral overexpression of interferon‐γ (IFNγ) in the knee joint prior to onset of IC‐mediated arthritis aggravated severe cartilage destruction. In FcγRI−/− mice, however, chondrocyte death was not enhanced by IFNγ, whereas matrix metalloproteinase (MMP)–mediated aggrecan breakdown was markedly elevated, suggesting a role for the activating FcγRIII in the latter process. We undertook this study to determine the role of FcγRIII in joint inflammation and severe cartilage destruction in IFNγ‐stimulated IC‐mediated arthritis, using FcγRIII−/− mice.Methods
FcγRIII−/− and wild‐type (WT) mice were injected in the knee joint with recombinant adenovirus encoding murine IFNγ (AdIFNγ) or with adenovirus encoding enhanced green fluorescent protein 1 day prior to induction of IC‐mediated arthritis. Histologic sections were obtained 3 days after arthritis onset to study inflammation and cartilage damage. MMP‐mediated expression of the VDIPEN neoepitope was detected by immunolocalization. Chemokine and FcγR expression levels were determined in synovial washouts and synovium, respectively.Results
Injection of AdIFNγ in naive knee joints markedly increased levels of messenger RNA for FcγRI, FcγRII, and FcγRIII. Upon IFNγ overexpression prior to induction of IC‐mediated arthritis, joint inflammation was similar in FcγRIII−/− and WT mice. The percentage of macrophages in the knee joint was increased, which correlated with high concentrations of the macrophage attractant macrophage inflammatory protein 1α. Furthermore, IFNγ induced 2‐fold and 3‐fold increases in chondrocyte death in WT controls and FcγRIII−/− mice, respectively. Notably, VDIPEN expression also remained high in FcγRIII−/− mice.Conclusion
IFNγ bypasses the dependence on FcγRIII in the development of IC‐mediated arthritis. Furthermore, both FcγRI and FcγRIII can mediate MMP‐dependent cartilage matrix destruction.6.
Kalpana Gupta Meenakshi Shukla Jack B. Cowland Charles J. Malemud Tariq M. Haqqi 《Arthritis \u0026amp; Rheumatology》2007,56(10):3326-3335
Objective
Expression of matrix metalloproteinase 9 (MMP‐9) is up‐regulated in osteoarthritis (OA) and usually presents as multiple bands when synovial fluid (SF) from OA patients is analyzed by zymography. Among these bands is an ∼125–130–kd band for high molecular weight (HMW) gelatinase, which has not been characterized. This study was undertaken to characterize the HMW MMP activity in OA SF.Methods
MMP activity in OA SF was determined by gelatin zymography. Recombinant MMPs were used to identify MMP activity on the zymogram. Western immunoblotting, immunoprecipitation, and immunodepletion analyses were performed using antibodies specific for human MMP‐9 and human neutrophil gelatinase–associated lipocalin (NGAL). Human cartilage matrix degradation was determined by dimethylmethylene blue assay.Results
Zymographic analysis showed that the HMW gelatinase in OA SF comigrated with a purified NGAL–MMP‐9 complex. Results of Western immunoblotting showed that the HMW gelatinase was also recognized by antibodies specific for human NGAL or human MMP‐9. These same antibodies also immunoprecipitated the HMW gelatinase activity from OA SF. The NGAL–MMP‐9 complex was reconstituted in vitro in gelatinase buffer. In the presence of NGAL, MMP‐9 activity was stabilized; in the absence of NGAL, rapid loss of MMP‐9 activity occurred. MMP‐9–mediated release of cartilage matrix proteoglycans was significantly higher in the presence of NGAL (P < 0.05).Conclusion
Our findings demonstrate that the HMW gelatinase activity in OA SF represents a complex of NGAL and MMP‐9. The ability of NGAL to protect MMP‐9 activity is relevant to cartilage matrix degradation in OA and may represent an important mechanism by which NGAL may contribute to the loss of cartilage matrix proteins in OA.7.
Kristen M. Clements Joanne S. Price Mark G. Chambers Denise M. Visco A. Robin Poole Roger M. Mason 《Arthritis \u0026amp; Rheumatology》2003,48(12):3452-3463
Objective
To investigate the development of osteoarthritis (OA) after transection of the medial collateral ligament and partial medial meniscectomy in mice in which genes encoding either interleukin‐1β (IL‐1β), IL‐1β–converting enzyme (ICE), stromelysin 1, or inducible nitric oxide synthase (iNOS) were deleted.Methods
Sectioning of the medial collateral ligament and partial medial meniscectomy were performed on right knee joints of wild‐type and knockout mice. Left joints served as unoperated controls. Serial histologic sections were obtained from throughout the whole joint of both knees 4 days or 1, 2, 3, or 4 weeks after surgery. Sections were graded for OA lesions on a scale of 0–6 and were assessed for breakdown of tibial cartilage matrix proteoglycan (aggrecan) and type II collagen by matrix metalloproteinases (MMPs) and aggrecanases with immunohistochemistry studies using anti‐VDIPEN, anti‐NITEGE, and Col2‐3/4Cshort neoepitope antibodies. Proteoglycan depletion was assessed by Alcian blue staining and chondrocyte cell death, with the TUNEL technique.Results
All knockout mice showed accelerated development of OA lesions in the medial tibial cartilage after surgery, compared with wild‐type mice. ICE‐, iNOS‐, and particularly IL‐1β–knockout mice developed OA lesions in the lateral cartilage of unoperated limbs. Development of focal histopathologic lesions was accompanied by increased levels of MMP‐, aggrecanase‐, and collagenase‐generated cleavage neoepitopes in areas around lesions, while nonlesional areas showed no change in immunostaining. Extensive cell death was also detected by TUNEL staining in focal areas around lesions.Conclusion
We postulate that deletion of each of these genes, which encode molecules capable of producing degenerative changes in cartilage, leads to changes in the homeostatic controls regulating the balance between anabolism and catabolism, favoring accelerated cartilage degeneration. These observations suggest that these genes may play important regulatory roles in maintaining normal homeostasis in articular cartilage matrix turnover.8.
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Arjen B. Blom Sarah M. Brockbank Peter L. van Lent Henk M. van Beuningen Jeroen Geurts Nozomi Takahashi Peter M. van der Kraan Fons A. van de Loo B. Wim Schreurs Kristen Clements Peter Newham Wim B. van den Berg 《Arthritis \u0026amp; Rheumatology》2009,60(2):501-512
Objective
Wnt signaling pathway proteins are involved in embryonic development of cartilage and bone, and, interestingly, developmental processes appear to be recapitulated in osteoarthritic (OA) cartilage. The present study was undertaken to characterize the expression pattern of Wnt and Fz genes during experimental OA and to determine the function of selected genes in experimental and human OA.Methods
Longitudinal expression analysis was performed in 2 models of OA. Levels of messenger RNA for genes from the Wnt/β‐catenin pathway were determined in synovium and cartilage, and the results were validated using immunohistochemistry. Effects of selected genes were assessed in vitro using recombinant protein, and in vivo by adenoviral overexpression.Results
Wnt‐induced signaling protein 1 (WISP‐1) expression was strongly increased in the synovium and cartilage of mice with experimental OA. Wnt‐16 and Wnt‐2B were also markedly up‐regulated during the course of disease. Interestingly, increased WISP‐1 expression was also found in human OA cartilage and synovium. Stimulation of macrophages and chondrocytes with recombinant WISP‐1 resulted in interleukin‐1–independent induction of several matrix metalloproteinases (MMPs) and aggrecanase. Adenoviral overexpression of WISP‐1 in murine knee joints induced MMP and aggrecanase expression and resulted in cartilage damage.Conclusion
This study included a comprehensive characterization of Wnt and Frizzled gene expression in experimental and human OA articular joint tissue. The data demonstrate, for the first time, that WISP‐1 expression is a feature of experimental and human OA and that WISP‐1 regulates chondrocyte and macrophage MMP and aggrecanase expression and is capable of inducing articular cartilage damage in models of OA.10.
Objective
To investigate the in vivo effect of an imbalance between metalloproteinases and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs), in mouse articular cartilage.Methods
Hind joints of Timp3−/− and wild‐type mice were examined by routine staining and by immunohistochemical analysis using antibodies specific for type X collagen and for the neoepitopes produced on proteolytic cleavage of aggrecan (… VDIPEN and … NVTEGE) and type II collagen. The neoepitope generated on cleavage of type II collagen by collagenases was quantitated in sera by enzyme‐linked immunosorbent assay.Results
Articular cartilage from Timp3‐knockout animals (ages ≥6 months) showed reduced Safranin O staining and an increase in …VDIPEN content compared with cartilage from heterozygous and wild‐type animals. There was also a slight increase in … NVTEGE content in articular cartilage and menisci of Timp3−/− animals. Chondrocytes showed strong pericellular staining for type II collagen cleavage neoepitopes, particularly in the superficial layer, in knockout mice. Also, there was more type X collagen expression in the superficial zone of articular cartilage, especially around clusters of proliferating chondrocytes, in the knockout mice. More type II collagen cleavage product was found in the serum of Timp3−/− mice compared with wild‐type animals. This increase was significant in 15‐month‐old animals.Conclusion
These results indicate that TIMP‐3 deficiency results in mild cartilage degradation similar to changes seen in patients with osteoarthritis, suggesting that an imbalance between metalloproteinases and TIMP‐3 may play a pathophysiologic role in the development of this disease.11.
K. C. A. M. Nabbe A. B. Blom A. E. M. Holthuysen P. Boross J. Roth S. Verbeek P. L. E. M. Van Lent W. B. Van Den Berg 《Arthritis \u0026amp; Rheumatology》2003,48(1):255-265
Objective
To study the role of the activating Fcγ receptor types I and III (FcγRI and FcγRIII, respectively) and the inhibiting Fcγ receptor II (FcγRII) in inflammation and in various aspects of cartilage destruction during arthritis that is solely induced by immune complexes.Methods
Immune complex–mediated arthritis (ICA) was passively induced by lysozyme–antilysozyme complexes in FcγRI‐, FcγRIII‐, and FcγRII‐knockout mice and their wild‐type controls. Total knee joints were isolated to study inflammation and cartilage destruction (loss of proteoglycans [PGs], chondrocyte death, matrix metalloproteinase [MMP]–mediated neoepitope [VDIPEN] expression, and erosion). The presence of an active phenotype of macrophages was studied by detection of myeloid‐related proteins 8 and 14 (MRP8 and MRP14, respectively).Results
Influx and activation of inflammatory cells (MRP expression) during ICA was decreased in FcγRIII‐deficient mice and enhanced in mice lacking FcγRII. Mild cartilage destruction reflected by loss of PGs was consistent with the degree of inflammation. Mice lacking FcγRIII showed almost no PG depletion, whereas in FcγRII−/− mice, PG depletion was increased 3–7‐fold in various cartilage areas. Initiation of erosive cartilage destruction, as reflected by MMP‐mediated VDIPEN expression, was reduced in FcγRIII−/− and FcγRI−/− mice, directing the two different critical steps of cellular influx and subsequent activation. These aspects were enhanced in FcγRII−/− mice. In FcγRI−/− and FcγRIII−/− mice, VDIPEN expression was 90–99% lower, whereas in FcγRII−/− mice, VDIPEN expression was increased 4‐fold. Chondrocyte death was reduced in FcγRIII−/− mice (68% lower) and enhanced in FcγRII−/− mice (6–12‐fold higher). Progression of arthritis and erosion of the cartilage surface were markedly elevated in FcγRII−/− arthritic joints.Conclusion
During ICA, FcγRIII is the dominant activating receptor mediating joint inflammation, whereas both FcγRI and FcγRIII are involved in cartilage destruction. FcγRII inhibits both joint inflammation and severe cartilage destruction during ICA.12.
Marije I. Koenders Erik Lubberts Birgitte Oppers‐Walgreen Liduine van den Bersselaar Monique M. Helsen Jay K. Kolls Leo A. B. Joosten Wim B. van den Berg 《Arthritis \u0026amp; Rheumatology》2005,52(3):975-983
Objective
To examine the capacity of T cell interleukin‐17A (IL‐17A; referred to hereinafter as IL‐17) to induce cartilage damage during experimental arthritis in the absence of IL‐1.Methods
Local IL‐17 gene transfer was performed in the knee joint of IL‐1–deficient mice and wild‐type controls during streptococcal cell wall (SCW)–induced arthritis. Knee joints were isolated at various time points for histologic analysis of cartilage proteoglycan (PG) depletion. Expression of messenger RNA for inducible nitric oxide synthase, matrix metalloproteinases (MMPs) 3, 9, and 13, and ADAMTS‐4 was determined by quantitative polymerase chain reaction analysis. VDIPEN staining was analyzed to study MMP‐mediated cartilage damage. In addition, systemic anti–IL‐1α/β antibody treatment was performed in mice immunized with type II collagen and injected locally with an adenoviral vector expressing IL‐17 or with control adenovirus. Knee joints were isolated and analyzed for cartilage PG depletion, chondrocyte death, and cartilage surface erosion.Results
During SCW‐induced arthritis, local T cell IL‐17 gene transfer turned this acute, macrophage‐driven joint inflammation into a severe, chronic arthritis accompanied by aggravated cartilage damage. Of high interest, the IL‐1 dependency of cartilage PG depletion was fully abrogated when IL‐17 was locally overexpressed in the joint. Moreover, local IL‐17 gene transfer increased MMP expression without the need for IL‐1, although IL‐1 remained essential for part of the cartilage VDIPEN expression. Furthermore, when IL‐17 was overexpressed in the knee joints of mice with collagen‐induced arthritis, anti–IL‐1 treatment did not reduce the degree of chondrocyte death or cartilage surface erosion.Conclusion
These data show the capacity of IL‐17 to replace the catabolic function of IL‐1 in cartilage damage during experimental arthritis.13.
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Steven Settle Lillian Vickery Olga Nemirovskiy Tom Vidmar Alison Bendele Dean Messing Peter Ruminski Mark Schnute Teresa Sunyer 《Arthritis \u0026amp; Rheumatology》2010,62(10):3006-3015
Objective
To demonstrate that the novel highly selective matrix metalloproteinase 13 (MMP‐13) inhibitor PF152 reduces joint lesions in adult dogs with osteoarthritis (OA) and decreases biomarkers of cartilage degradation.Methods
The potency and selectivity of PF152 were evaluated in vitro using 16 MMPs, TACE, and ADAMTS‐4 and ADAMTS‐5, as well as ex vivo in human cartilage explants. In vivo effects were evaluated at 3 concentrations in mature beagles with partial medial meniscectomy. Gross and histologic changes in the femorotibial joints were evaluated using various measures of cartilage degeneration. Biomarkers of cartilage turnover were examined in serum, urine, or synovial fluid. Results were analyzed individually and in combination using multivariate analysis.Results
The potent and selective MMP‐13 inhibitor PF152 decreased human cartilage degradation ex vivo in a dose‐dependent manner. PF152 treatment of dogs with OA reduced cartilage lesions and decreased biomarkers of type II collagen (type II collagen neoepitope) and aggrecan (peptides ending in ARGN or AGEG) degradation. The dose required for significant inhibition varied with the measure used, but multivariate analysis of 6 gross and histologic measures indicated that all doses differed significantly from vehicle but not from each other. Combined analysis of cartilage degradation markers showed similar results.Conclusion
This highly selective MMP‐13 inhibitor exhibits chondroprotective effects in mature animals. Biomarkers of cartilage degradation, when evaluated in combination, parallel the joint structural changes induced by the MMP‐13 inhibitor. These data support the potential therapeutic value of selective MMP‐13 inhibitors and the use of a set of appropriate biomarkers to predict efficacy in OA clinical trials.16.
Mary‐Clare Miller Hugh B. Manning Abhilash Jain Linda Troeberg Jayesh Dudhia David Essex Ann Sandison Motoharu Seiki Jagdeep Nanchahal Hideaki Nagase Yoshifumi Itoh 《Arthritis \u0026amp; Rheumatology》2009,60(3):686-697
Objective
A hallmark of rheumatoid arthritis (RA) is invasion of the synovial pannus into cartilage, and this process requires degradation of the collagen matrix. The aim of this study was to explore the role of one of the collagen‐degrading matrix metalloproteinases (MMPs), membrane type 1 MMP (MT1‐MMP), in synovial pannus invasiveness.Methods
The expression and localization of MT1‐MMP in human RA pannus were investigated by Western blot analysis of primary synovial cells and immunohistochemical analysis of RA joint specimens. The functional role of MT1‐MMP was analyzed by 3‐dimensional (3‐D) collagen invasion assays and a cartilage invasion assay in the presence or absence of tissue inhibitor of metalloproteinases 1 (TIMP‐1), TIMP‐2, or GM6001. The effect of adenoviral expression of a dominant‐negative MT1‐MMP construct lacking a catalytic domain was also examined.Results
MT1‐MMP was highly expressed at the pannus–cartilage junction in RA joints. Freshly isolated rheumatoid synovial tissue and isolated RA synovial fibroblasts invaded into a 3‐D collagen matrix in an MT1‐MMP–dependent manner. Invasion was blocked by TIMP‐2 and GM6001 but not by TIMP‐1. Invasion was also inhibited by the overexpression of a dominant‐negative MT1‐MMP, which inhibits collagenolytic activity and proMMP‐2 activation by MT1‐MMP on the cell surface. Synovial fibroblasts also invaded into cartilage in an MT1‐MMP–dependent manner. This process was further enhanced by removing aggrecan from the cartilage matrix.Conclusion
MT1‐MMP serves as an essential collagen‐degrading proteinase during pannus invasion in human RA. Specific inhibition of MT1‐MMP–dependent invasion may represent a novel therapeutic strategy for RA.17.
Michihisa Zemmyo E. John Meharra Klaus Kühn Lilo Creighton‐Achermann Martin Lotz 《Arthritis \u0026amp; Rheumatology》2003,48(10):2873-2880
Objective
Cell–matrix interactions regulate chondrocyte differentiation and survival. The α1β1 integrin is a major collagen receptor that is expressed on chondrocytes. Mice with targeted inactivation of the integrin α1 gene (α1‐KO mice) provide a model that can be used to address the role of cell–matrix interactions in cartilage homeostasis and osteoarthritis (OA) pathogenesis.Methods
Knee joints from α1‐KO and wild‐type (WT) BALB/c mice were harvested at ages 4–15 months. Knee joint sections were examined for inflammation, cartilage degradation, and loss of glycosaminoglycans (by Safranin O staining). Immunohistochemistry was performed to detect the distribution of α1 integrin, matrix metalloproteinases (MMPs), and chondrocyte apoptosis.Results
In WT mice, the α1 integrin subunit was detected in hypertrophic chondrocytes in the growth plate and in a subpopulation of cells in the deep zone of articular cartilage. There was a marked increase in α1‐positive chondrocytes in the superficial and upper mid‐zones in OA‐affected areas in joints from old WT mice. The α1‐KO mice showed more severe cartilage degradation, glycosaminoglycan depletion, and synovial hyperplasia as compared with the WT mice. MMP‐2 and MMP‐3 expression was increased in the OA‐affected areas. In cartilage from α1‐KO mice, the cellularity was reduced and the frequency of apoptotic cells was increased. These results suggest that the α1 integrin subunit is involved in the early remodeling process in OA cartilage.Conclusion
Deficiency in the α1 integrin subunit is associated with an earlier deregulation of cartilage homeostasis and an accelerated, aging‐dependent development of OA.18.
Sohel M. Julovi Tadashi Yasuda Makoto Shimizu Teruko Hiramitsu Takashi Nakamura 《Arthritis \u0026amp; Rheumatology》2004,50(2):516-525
Objective
To investigate the mechanism of the inhibitory action of hyaluronan (HA) on interleukin‐1β (IL‐1β)‐stimulated production of matrix metalloproteinases (MMPs) in human articular cartilage.Methods
IL‐1β was added to normal and osteoarthritic (OA) human articular cartilage in explant culture to stimulate MMP production. Articular cartilage was incubated or preincubated with a clinically used form of 800‐kd HA to assess its effect on IL‐1β‐induced MMPs. Levels of secreted MMPs 1, 3, and 13 in conditioned media were detected by immunoblotting; intracellular MMP synthesis in chondrocytes was evaluated by immunofluorescence microscopy. Penetration of HA into cartilage tissue and its binding to CD44 were analyzed by fluorescence microscopy using fluoresceinated HA. Blocking experiments with anti‐CD44 antibody were performed to investigate the mechanism of action of HA.Results
Treatment and pretreatment with 800‐kd HA at 1 mg/ml resulted in significant suppression of IL‐1β‐stimulated production of MMPs 1, 3, and 13 in normal and OA cartilage explant culture. Fluorescence histocytochemistry revealed that HA penetrated cartilage tissue and localized in the pericellular matrix around chondrocytes. HA‐binding blocking experiments using anti‐CD44 antibody demonstrated that the association of HA with chondrocytes was mediated by CD44. Preincubation with anti‐CD44 antibody, which suppressed IL‐1β‐stimulated MMPs, reversed the inhibitory effect of HA on MMP production that was induced by IL‐1β in normal and OA cartilage.Conclusion
This study demonstrates that HA effectively inhibits IL‐1β‐stimulated production of MMP‐1, MMP‐3, and MMP‐13, which supports the clinical use of HA in the treatment of OA. The action of HA on IL‐1β may involve direct interaction between HA and CD44 on chondrocytes.19.
Menno ter Huurne Rik Schelbergen Roxane Blattes Arjen Blom Wouter de Munter Lilyanne C. Grevers Jannik Jeanson Danile Noël Louis Casteilla Christian Jorgensen Wim van den Berg Peter L. E. M. van Lent 《Arthritis \u0026amp; Rheumatology》2012,64(11):3604-3613