Gene expression of matrix metalloproteinases 1, 3, and 9 by chondrocytes in osteoarthritic human knee articular cartilage is zone and grade specific

Freemont, A. J.; Hampson, V; Tilman, R; Goupille, Philippe; Taiwo, Yetunde O.; Hoyland, Judith A.

doi:10.1136/ard.56.9.542

Cited by 181 publications

(144 citation statements)

References 37 publications

(16 reference statements)

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“…Taken together, these results and the results of previous studies (9,24,25) suggest that MMP-9 activity may be more damaging to cartilage matrix when it is protected by NGAL against autodegradation. The detection of the NGAL-MMP-9 complex in OA SF suggests that protection of MMP-9 also occurs in vivo.…”

Section: Discussionsupporting

confidence: 79%

“…Although HMW MMP-9 enzymatic activity has been recognized in OA SF in earlier studies (30), the 125-kd MMP activity (24,25) has not previously been characterized. Since the apparent size of the HMW synovial fluid MMP activity noted in these and other studies was similar to the size reported for the NGAL-MMP-9 complex purified from human neutrophils (31) and also shown to be present in breast cancer patients (15), we investigated the possibility that this HMW (ϳ125 kd) MMP activity in OA SF might represent an NGAL-MMP-9 complex.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies have documented the presence of HMW MMP activity in the SF of arthritis patients (9,24,25), but these HMW gelatinases were not characterized. The NGAL-MMP-9 complex detected in OA SF may be from joint-infiltrating cells, or possibly from cytokine-stimulated chondrocytes and synovial cells.…”

Section: Discussionmentioning

confidence: 99%

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Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

Gupta¹,

Shukla²,

Cowland³

et al. 2007

Arthritis & Rheumatism

120

119

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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 ϳ125-130-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.The developed world's aging population has experienced a dramatic increase in the incidence of joint dysfunction and osteoarthritis (OA), leading to a compromised quality of life. Aging, biomechanical stress, and oxidative stress, in addition to genetic factors and trauma, all appear to be associated with degenerative and progressive cartilage and bone changes in OA, particularly in the weight-bearing joints. Although OA is not considered an inflammatory disease by traditional standards, elevated levels of proinflammatory cytokines, such as interleukin-1␤ (IL-1␤) and tumor necrosis factor ␣, have been observed in OA synovial fluid (SF), supporting the notion that there is an inflammatory component associated with the pathogenesis of OA (for review, see refs. 1-3).The only cell type present in articular cartilage is the chondrocyte, which is embedded within an extracellular matrix (ECM) primarily composed of type II collagen and aggrecan. Chondrocytes arise from a mesenchymal progenitor cell and are responsible for the biosynthesis of ECM proteins and their transport into the space occupied by the ECM. Chondrocytes play an important role in cartilage homeostasis by maintaining the proper balance between anabolic pathways, which Supported in part by the NIH...

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Section: Discussionsupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

Gupta¹,

Shukla²,

Cowland³

et al. 2007

Arthritis & Rheumatism

120

119

View full text Add to dashboard Cite

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“…Osteoarthritic cartilage exhibits a differential expression of MMPs 1,3, and 9, depending on the degenerative state of the cartilage and the region of tissue analyzed. MMP-9 expression is increased in degenerated cartilage (51), especially in the mid-deep layers (24). Because MMP-9 can degrade various cartilage matrix components, including denatured collagen, type-XI collagen, aggrecan, and link protein (22,34,54,55), it likely contributes to the progressive erosion of cartilage in osteoarthritis.…”

Section: Discussionmentioning

confidence: 99%

Biomechanical regulation of matrix metalloproteinase‐9 in cultured chondrocytes

Jin

Sah

et al. 2000

Journal Orthopaedic Research

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Summary:Abnormal mechanical loading of joints may induce degeneration of articular cartilage. Shear stress is one mode of mechanical loading that may regulate chondrocyte metabolism. We investigated the mechanism by which shear stress induccs the gene encoding matrix metalloproteinase-9, a mediator of the progressive degradation of articular cartilage in ostcoarthritis. In vifro experiments using passaged rabbit chondrocytes in monolayer culture subjected to a shear stress of 16 dynicn? (1.6 Pa) in a flow channel showed increased expression of the matrix mctalloproteinase-9 gcne. The induction of matrix metalloproteinase-9 appeared to depend on a region in the 5' promoter of the gcnc that contains a 12-0-tetradecanoylphorbol 13-acetateresponsive element. Transfection experiments using a construct containing a luciferase reporter driven by a 12-0-tetradecanoylphorbol 13-acetate-responsive clement indicated that shear stress activated a 12-0-tetradecanoylphorbol 13-acetate-responsive element-mediated transcription in chondrocytes. Similar experiments showed that shear stress induced a matrix metalloproteinase-9 promoter construct (matrix metalloproteinase-9-luciferase). Shear stress activated c-Jun NH1-terniinal kinasc, cxtraccllular signal-regulated kinase. and p3X. 'Transfection of matrix inetalloproteinase-9-lucifcrase together with thc dominant negative mutant of c-.Tun NH,-terminal kinase. hut not with that of cxtraccllular signal-regulated kinase or p38. attenuated the shearinduced matrix metalloproteinasc-9 promoter activity. In addition. transfection of constructs encoding dominant negative mutants o C Ras. Rac. and Cdc42 attenuated the induction of c-Jun transcriptional activity by shear stress. Thus. shear stimulation of chondrocytes stimulates Kas, Rac, and Cdc42, which subsequcntly activate c-Jun NH?-terminal kinasc to induce a 12-0-tetradecanoylphorhol 13-acetate-responsive clementmcdiatcd expression of matrix metalloproteinase-9. ~The metabolic activity of chondrocytes is regulated by mechanical factors (28). Such biomechanical regulation map affect the balance between anabolic and catabolic processes in articular cartilage. In osteoarthritis, a metabolic imbalance results in lie1 matrix degradation and the degeneration of articular cartilage (59). Many in vivo and in vitro studies have examined the effect of biomechanical stimuli on the synthesis of matrix proteins by chondrocytes (28). However. relatively few studies have analyzed the extracellular or cellular mechanisms by which mechanical stimuli may alter cartilage matrix degradationincluding the modulation of matrix protcinascs and their inhibitors (68)-and thereby contribute to the initiation or progression of osteoarthritis.In osteoarthritis, the synthesis of matrix metalloprotcinascs (MMPs) by chondrocytes is incrcased (20) and the balancc betwcen proteases and protease

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“…MMPs are considered to be important in the chondrolytic processes that contribute to the degenerative changes in OA cartilage (2)(3)(4). Recent studies have identified the messenger RNA (mRNA) for some MMPs, such as MMP-1, MMP-3, MMP-9, and MMP-13, in human OA cartilage (4,5), and other investigators have reported specific MMP proteins and collagenasemediated type II collagen degradation products (6,7). There is a consensus that these enzymes play a critical role in intrinsic chondrocyte-mediated degenerative changes of the cartilage matrix in OA.…”

mentioning

confidence: 99%

Inhibition of interleukin‐1β‐stimulated production of matrix metalloproteinases by hyaluronan via CD44 in human articular cartilage

Julovi

Yasuda

Shimizu

et al. 2004

Arthritis & Rheumatism

156

122

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Objective. To investigate the mechanism of the inhibitory action of hyaluronan (HA) on interleukin-1␤ (IL-1␤)-stimulated production of matrix metalloproteinases (MMPs) in human articular cartilage.Methods. IL-1␤ 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-1␤-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-1␤-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-1␤-stimulated MMPs, reversed the inhibitory effect of HA on MMP production that was induced by IL-1␤ in normal and OA cartilage.Conclusion. This study demonstrates that HA effectively inhibits IL-1␤-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-1␤ may involve direct interaction between HA and CD44 on chondrocytes.Osteoarthritis (OA) is the most prevalent disease of articular joints and is the major cause of disability in the elderly. Pathophysiologic changes occur in OA cartilage due to the excessive expression of cartilagedegrading proteinases, the resultant progressive breakdown of collagen fibers, and the degradation of proteoglycan, mainly aggrecan (1).Matrix metalloproteinases (MMPs) are zinccontaining, calcium-dependent proteinases, which collectively degrade all components of the extracellular matrix. MMPs are considered to be important in the chondrolytic processes that contribute to the degenerative changes in OA cartilage (2-4). Recent studies have identified the messenger RNA (mRNA) for some MMPs, such as MMP-1, in human OA cartilage (4,5), and other investigators have reported specific MMP proteins and collagenasemediated type II collagen degradation products (6,7). There is a consensus that these enzymes play a critical role in intrinsic chondrocyte-mediated degenerative changes of the cartilage matrix in OA. Proinflammatory cytokines such as interleukin-1 (IL-1) strongly stimulate the expression of MMPs by chondrocytes in arthritis (8).Hyaluronan (HA) is a major component of synovial fluid and cartilage matrix, and it play...

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Gene expression of matrix metalloproteinases 1, 3, and 9 by chondrocytes in osteoarthritic human knee articular cartilage is zone and grade specific

Cited by 181 publications

References 37 publications

Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

Neutrophil gelatinase–associated lipocalin is expressed in osteoarthritis and forms a complex with matrix metalloproteinase 9

Biomechanical regulation of matrix metalloproteinase‐9 in cultured chondrocytes

Inhibition of interleukin‐1β‐stimulated production of matrix metalloproteinases by hyaluronan via CD44 in human articular cartilage

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