Biomedical subjects

J M Cloutier

Publications and source records attributed to J M Cloutier.

At least 37 records · Page 2Linked to original sources

PubMed1993

Regulation of human normal and osteoarthritic chondrocyte interleukin-1 receptor by antirheumatic drugs.

OBJECTIVE: To determine the effect of antirheumatic drugs and corticosteroids on interleukin-1 receptor (IL-1R) levels in, and IL-1-stimulated metalloprotease synthesis and expression by, normal and osteoarthritic (OA) human articular chondrocytes. METHODS: IL-1R affinity and density of human chondrocytes were determined using radioligand binding experiments. Collagenase and stromelysin synthesis activities were analyzed by 14C-labeled type I collagen and Azocoll assays, respectively. Their messenger RNA (mRNA) levels were determined by Northern blot analysis. IL-1 alpha, IL-1 beta, IL-1 receptor antagonist, and beta 2-microglobulin were measured using enzyme-linked immunosorbent assays. Protein synthesis was determined by 3H-leucine incorporation. RESULTS: Antirheumatic drugs reduced the IL-1R level in normal and OA chondrocytes in a dose-dependent manner. In normal chondrocytes, tenidap reduced the IL-1R level by 44% at 5 micrograms/ml to 88% at 100 micrograms/ml (50% inhibition constant [IC50] 10.1 micrograms/ml), indomethacin reduced IL-1R by 6% at 1.5 micrograms/ml to 43% at 60 micrograms/ml, and naproxen reduced IL-1R by 10% at 10 micrograms/ml to 41% at 300 micrograms/ml; the effects observed with indomethacin and naproxen occurred only when the drugs were used at levels above their therapeutic concentrations. In OA chondrocytes, the effect of indomethacin and naproxen on the IL-1R level was greatly reduced, whereas tenidap still had a marked effect (IC50 22.5 micrograms/ml). Dexamethasone and hydrocortisone had no consistent effect on the IL-1R level. At a therapeutic concentration (20 micrograms/ml), tenidap was found to reduce the IL-1R level in a time-dependent manner, with maximum inhibition (98%) by 48 hours. Tenidap was also found to markedly reduce collagenase and stromelysin synthesis and mRNA levels in IL-1-stimulated chondrocytes. CONCLUSION: The suppressive effects of tenidap on IL-1-stimulated metalloprotease synthesis and expression in OA and normal chondrocytes are likely related to a decrease in IL-1R levels. At therapeutic concentrations, tenidap has a greater effect on the IL-1R level than is seen with indomethacin or naproxen, and glucocorticoids have no effect on IL-1R.

Anti-Inflammatory Agents↗

PubMed1993

In vitro effects of NSAIDs and corticosteroids on the synthesis and secretion of interleukin 1 by human osteoarthritic synovial membranes.

The mechanism(s) of action of NSAIDs and corticosteroids in arthritic diseases has been the subject of intensive investigation in recent years. Although NSAIDs and corticosteroids have many effects, their possible ability to modify the disease course in patients has not been fully documented. In an attempt to characterize the mechanism(s) involved in the effect of some NSAIDs in joint diseases, we investigated the effect of three concentrations within the pharmacological (260 micrograms/ml) and therapeutic (26 and 2.6 micrograms/ml) ranges of tiaprofenic acid in the synthesis and release of interleukin (IL-1) alpha and beta in human OA synovial membranes. The effect of tiaprofenic acid was compared to the effect of two other NSAIDs, sodium salicylate (160 micrograms/ml) and indomethacin (1.5 micrograms/ml), and to a corticosteroid, hydrocortisone (0.725 and 7.25 micrograms/ml). This study was carried out using human OA synovium explants incubated in the presence or absence of LPS. In the absence of LPS and at therapeutic concentration, tiaprofenic acid decreased both the synthesis and release of IL-1 beta. A less marked effect of the drug was noted under LPS treatment, and inhibition of the production/secretion of IL-1 beta was found only at pharmacological concentration. Sodium salicylate and indomethacin did not share this action, and demonstrated either no effect or enhancement of IL-1 beta synthesis, respectively, in the presence of LPS. As expected, hydrocortisone demonstrated a marked decrease on IL-1 alpha and IL-1 beta, both in the presence and absence of LPS. These results bring forth new information on the action of these drugs and their effects on the OA pathophysiological process.

Adrenal Cortex Hormones↗

PubMed1993

Distinct expression pattern of early- and late-response genes in normal and osteoarthritic human synovial membranes.

The significance of activating proteins (AP-1), c-fos, c-jun and jun B relative to the AP-1 responsive metallothionein, collagenase and stromelysin gene expression in the pathophysiology of osteoarthritis (OA) was investigated. The 'early' c-fos, c-jun and jun-B mRNAs were ubiquitously expressed in normal and OA human knee synovial membranes. There was no strict correlation between expression of these and the AP-1 responsive, collagenase and stromelysin gene expression. Interestingly, the total metallothionein (MT) and the AP-1 responsive, MT-IIA gene-specific mRNAs were greatly diminished in OA compared with normal synovial membranes. The possible role of reduced expression of MT and trace metals in OA pathophysiology is discussed. Collectively, these data demonstrate a discoordinate expression of AP-1 encoding and their target genes in synovium.

Aged↗

PubMed1993

Reduced expression of glucocorticoid receptor levels in human osteoarthritic chondrocytes. Role in the suppression of metalloprotease synthesis.

Glucocorticoid occupancy of a large percentage of glucocorticoid receptor (GR) is necessary for the suppression of matrix metalloprotease synthesis by human articular chondrocytes. In this study, we evaluated the levels of GR binding, cellular GR protein, and messenger RNA expression in both normal and osteoarthritic (OA) human articular chondrocytes and compared the degree of suppression of collagenase synthesis by glucocorticoids in cultures of the two cell types in order to investigate whether or not the GR system played an important role in the pathophysiology of OA. By radioreceptor binding assay, we recorded 56,320 +/- 8,230 sites per cell (mean +/- SE, n = 9) in primary cultures of normal chondrocytes and 27,480 +/- 14,240 sites in OA cells (n = 10, P < 0.0001). Equilibrium dissociation constant (Kd) values did not vary between normal (12.4 +/- 1.4 nmol/L) and OA (13.0 +/- 1.8 nmol/L). Subculturing of primary OA chondrocytes resulted in the up-regulation of the number of GR binding sites per cell to values comparable to those obtained in normal chondrocytes. Analysis of protein-immuno dot-blots of cytosolic extracts from normal (n = 4) and OA chondrocytes (n = 4) revealed that the former cytosols contained a 1.9 +/- 0.2 (P < 0.05) higher relative density of GR protein than the latter. By comparing the optical densities of GR-polymerase chain reaction products generated from normal (n = 6) and OA (n = 9) chondrocyte total RNA (normalized using an internal standard, glyceraldehyde phosphate dehydrogenase), we established a relative ratio, normal/OA, of 1.4. Experiments comparing the biological responsiveness of normal and OA chondrocytes to glucocorticoid suppression of interleukin-1-stimulated metalloprotease synthesis showed that dexamethasone inhibited collagenase synthesis in a dose-dependent manner with an IC50 of 6.3 +/- 1.2 x 10(-10) mol/L (n = 5) in normal cells while an IC50 of 5.0 +/- 0.4 x 10(-9) mol/L (P < 0.05) was recorded using OA (n = 5) chondrocytes. The results suggest that OA chondrocytes express fewer GR than normal cells as a result of a decrease in specific gene expression. The decreased responsiveness of OA cells to circulating glucocorticoids may be among the factors responsible for an increased level of metalloprotease synthesis by chondrocytes in OA cartilage.

Base Sequence↗

PubMed1993

Elevated metalloproteinase and tissue inhibitor of metalloproteinase mRNA in human osteoarthritic synovia.

The levels of metalloproteases and inhibitor expression in synovial membranes were measured by analyzing mRNA of collagenase, stromelysin, and tissue inhibitor of metalloproteinase (TIMP-1) in this tissue from 20 healthy persons and 20 patients with osteoarthritis (OA). Our results indicated that while most of the normal synovia expressed TIMP-1 mRNA at low levels, very few expressed metalloproteinase mRNA. In contrast 40% of patients with OA expressed a moderate level of collagenase compared to 55 and 80% cases with considerably elevated stromelysin and TIMP-1 mRNA, respectively. The mRNA expression of collagenase (p < 0.032), stromelysin (p < 0.0001) and TIMP-1 (p < 0.008) was significantly higher in OA than in normals. The greater abundance of stromelysin mRNA relative to collagenase indicates differential regulation of the 2 genes. We also demonstrated an association of IL-1 with metalloproteinase gene expression.

Adolescent↗

PubMed1992

Expression of c-fos, c-jun, jun-B, metallothionein and metalloproteinase genes in human chondrocyte.

Normal and osteoarthritic (OA) human articular cartilage chondrocytes, released enzymatically in the presence of 0.5% fetal calf serum, display constitutive expression of early response activating protein (AP-1) genes; c-fos, c-jun and jun-B. Among the late AP-1 responsive genes, total metallothionein (MT) and stromelysin mRNAs were expressed at high levels in both normal and OA chondrocytes, while collagenase and hMT-IIA mRNA levels were elevated only in OA individuals. Despite the common AP-1 sequences present in their promoter regions, the three late genes were differentially expressed.

Aged↗

PubMed1992

Effects of tiaprofenic acid on plasminogen activators and inhibitors in human OA and RA synovium.

The effect of therapeutic and pharmacological concentrations of tiaprofenic acid, a non-steroidal anti-inflammatory drug (NSAID), on the synthesis of the plasminogen activators, urokinase plasminogen activator (uPA) and tissue plasminogen activator (tPA), and the plasminogen activator inhibitors 1 and 2 (PAI-1 and PAI-2), by human synovial membranes isolated from osteoarthritis (OA) and rheumatoid arthritis (RA) sufferers was evaluated. Both forms of plasminogen activator (PA) and PA inhibitor (PAI) were synthesized by the arthritic synovium. PAI-1 and PAI-2 were both synthesized in greater amounts than the plasminogen activators. Tiaprofenic acid induced a dose-dependent decrease in uPA synthesis in both OA and RA, particularly in OA synovium, but had no true effect on tPA. Tiaprofenic acid also exerted a suppressive effect on the synthesis of PAI-1 in both OA and RA synovial membranes, and on the release of PAI-2 in RA synovium. The results of this study indicate that a decrease in uPA synthesis may be one of the mechanisms by which tiaprofenic acid could exert its effects on the arthritic process. The suppressive action of tiaprofenic acid on PAI is not likely to have a significant impact on the balance of plasminogen activators and plasminogen activator inhibitors, as plasminogen activator inhibitors are synthesized in greater amounts than plasminogen activators.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1991

[Repeated total knee arthroplasty].

The causes of failure of total knee arthroplasty are now better known and usually avoidable, being due to the surgical technique. Choosing a prosthesis with minimal constraint is of paramount importance. Exact technique for perfect placement of the implant, realignment of the limb and correction of asymmetrical bone lesions are stringent prerequisites. As for deep sepsis, which is still the most severe of post-arthroplasty complications, it can now be treated with success in nine out of ten knees, whilst preserving a functional knee prosthesis. The knee prosthesis placement technique is very demanding in most cases, but the excellent results obtained seem to be more durable than those of total hip replacement.

Humans↗

PubMed1991

Synovial membrane histology and immunopathology in rheumatoid arthritis and osteoarthritis. In vivo effects of antirheumatic drugs.

We examined the histologic and immunopathologic features of the synovial membrane of 18 patients with rheumatoid arthritis (RA) and 12 patients with osteoarthritis (OA) who had undergone total knee arthroplasty. Patients were classified into 5 groups according to therapeutic regimen and disease: RA treated with nonsteroidal antiinflammatory drugs (NSAIDs), RA treated with NSAIDs and prednisone, RA treated with NSAIDs and methotrexate (MTX), OA treated with analgesics, and OA treated with NSAIDs. There were no significant between-group differences in the percentages or the distribution pattern of the infiltrating T cell subsets (CD4, CD8), HLA-DR, or interleukin-2 receptor-bearing cells. However, inflammatory indices, which included the thickness of the lining cell layer and the density of the mononuclear cell infiltrate, were significantly higher in the RA patients treated with prednisone and those treated with MTX (P less than 0.05). Similarly, fibrosis was markedly reduced in these 2 groups. The RA patients treated with NSAIDs alone and the 2 groups of patients with OA demonstrated similar profiles. These data suggest that prednisone and MTX may inhibit the development of fibrosis without altering the subsets of the inflammatory cell population. This observation raises the possibility that the action of these 2 drugs may be partly mediated by the suppression of inflammatory mediators that are responsible for fibroblast activation.

Analgesics↗

PubMed1991

Plasmin, plasminogen activators and inhibitor in human osteoarthritic cartilage.

Osteoarthritis (OA) is characterized by a progressive erosion of cartilage, which is mediated by the protease degradation of the extracellular matrix components. Plasmin, plasminogen activators (PA) and the inhibitor of plasminogen activator (PAI) are thought to play an important role in the regulation of the OA pathophysiology process. Our study determined the activity of plasmin and PA in OA and normal cartilage. Moreover, the presence and the content of each form of PA, uPA and tPA, as well as the inhibitor PAI-1, were determined using immunohistological techniques and ELISA. Our studies were carried out on fresh cartilage, cultured tissue explants and chondrocytes. OA cartilage demonstrates about 5 times more plasmin activity than the controls (p less than 0.001). Moreover, a statistically significant correlation was found between the plasmin activity and the free collagenolytic form in OA specimens showing severe lesions (r = 0.50; p less than 0.05). Our study revealed that PA content and activity increase in OA cartilage following culture explant experiments. Immunohistochemical studies showed the presence of both uPA and tPA forms in OA cartilage lesions only. Protein determinations revealed uPA as the predominant form. PAI-1 was significantly decreased (p less than 0.04) in OA, and was located mainly extracellularly. Chondrocyte cultures showed the ability to synthesize both forms of PA and PAI-1. Our study demonstrated an increased level of plasmin activity in OA cartilage. This is likely related to increased PA activity, in which the urokinase type appeared to be predominant in OA.(ABSTRACT TRUNCATED AT 250 WORDS)

Cartilage, Articular↗

PubMed1991

Modulation of glucocorticoid receptor expression in human articular chondrocytes by cAMP and prostaglandins.

Endogenous glucocorticoids are believed to be extremely important in the maintenance of cellular homeostasis through their binding to specific cell receptors. In normal articular cartilage, physiological concentrations of cortisol are potentially capable of suppressing metalloprotease synthesis by chondrocytes. This hormone action is likely to represent one of the major pathways through which the catabolism of cartilage under normal physiological conditions is kept in a homeostatic state. In osteoarthritis (OA), a severe reduction in the glucocorticoid receptor (GR) level in chondrocytes is evident and could produce cellular steroid resistance in terms of the synthesis of destructive enzymes. Our aim was to look at agents which could upregulate GR expression in human chondrocytes. In this context, we have analyzed the effect of prostaglandins of the E series and cyclic AMP on normal and OA human articular chondrocytes. Dibutyryl cAMP at a concentration of 25 micrograms/ml, as well as prostaglandin E2 (PGE2) at 1 microgram/ml, increased the GR level. Although the GR level is dramatically reduced in OA chondrocytes, the sensitivity of the latter cells to both cAMP and PGE2 is similar. Synthetic PGE1 at therapeutic concentrations also induced identical upregulation of GR expression in chondrocytes. The addition of synthetic prostaglandins to the antiinflammatory glucocorticoid dosage regimen may prove to be of major therapeutic importance in the treatment of arthritic diseases by potentiating the effects of glucocorticoid on the reduction of the catabolism of articular cartilage.

Alprostadil↗

PubMed1991

Long-term results after nonconstrained total knee arthroplasty.

In 1975, in Montreal, a nonconstrained total anatomic resurfacing prosthesis was designed. After a follow-up period of ten to 13 years, 79% of knees had an excellent or good result (Hospital for Special Surgery score) and 21% had a fair or poor result. Seven knees had been revised. The flexion range, stability, and capacity to climb stairs normally were significantly better in the knees where both posterior and anterior cruciate ligaments were preserved. Only one knee was revised in the anterior cruciate ligament intact knees. The incidence of aseptic component loosening was 1.2%.

Adult↗

PubMed1990

Cathepsin B and cysteine protease inhibitors in human osteoarthritis.

The aim of this study was to determine the involvement of cathepsin B and its inhibitors in the proteolytic degradation of human osteoarthritic (OA) tissue. The characteristics of the cathepsin B found in both normal and OA cartilage and synovium were similar to those of the lysosomal cathepsin B. Two inhibitors of cysteine proteases were found with a molecular weight of 67,000 and 16,000 Da. The cartilage cathepsin B level of OA specimens (54.8 +/- 7.3 units/micrograms of DNA) was greater than the controls (39.8 +/- 3.2 units/micrograms of DNA). Mild-moderate graded samples (78.1 +/- 12.0 units/micrograms of DNA) had significantly higher levels of enzyme activity than the severely graded ones (31.4 +/- 3.9 units/micrograms of DNA, p less than 0.001) and controls (p less than 0.01). Compared to controls (2.3 +/- 0.4 units/mg of tissue w.w.), cysteine protease inhibitory activity in OA cartilage was decreased in specimens with severe lesions (1.5 +/- 0.2 units/mg of tissue). This was particularly noted in patients who had not received steroid injections (1.2 +/- 0.3 units/mg of tissue, p less than 0.05). In OA synovia, the cathepsin B level was greater (40.7 +/- 7.4 units/mg of tissue w.w., p less than 0.02) than in the controls (13.6 +/- 3.7 units/mg of tissue). The cysteine protease inhibitory activity was similar in OA synovium (1.7 +/- 0.2 units/mg of tissue w.w.) and in controls (1.5 +/- 0.3 units/mg of tissue). This data demonstrated an imbalance between the levels of cathepsin B and cysteine protease inhibitors in OA tissue. A decrease of specific inhibitors could be an important contributing factor, particularly in more severe lesions.

Adult↗

PubMed1989

In vitro effects of tiaprofenic acid, sodium salicylate and hydrocortisone on the proteoglycan metabolism of human osteoarthritic cartilage.

We examined the in vitro effects of therapeutic doses of tiaprofenic acid (26 micrograms/ml; 2.6 micrograms/ml), sodium salicylate (160 micrograms/ml), and hydrocortisone (7.25 micrograms/ml; 0.725 micrograms/ml) on the proteoglycan metabolism (catabolism and synthesis) and chondrocyte ultrastructure of organ explant cultures of human osteoarthritic (OA) articular cartilage. The effect of these drugs on chondrocyte neutral metalloprotease synthesis was also examined. Tiaprofenic acid and the higher concentration of hydrocortisone had a similar suppressive effect on proteoglycan catabolism (38%). The effect of the lower concentration of hydrocortisone was less marked (29%), while sodium salicylate had the least effect (21%). The proteoglycan released in each treated group was significantly lower (p less than 0.05) than that of the untreated one. The suppression of proteoglycan catabolism by tiaprofenic acid was reversible in all but one specimen. This reversal was only seen in 4 of the 8 patient specimens treated with sodium salicylate and in 2 of the 8 patient specimens treated with the higher dose of hydrocortisone. The decrease in proteoglycan catabolism induced by these drugs correlated with their potential to reduce synthesis of neutral metalloprotease. The proteoglycan synthesis in cartilage organ explant cultures was reduced by sodium salicylate and hydrocortisone, but not by tiaprofenic acid. These findings were corroborated through an electron microscopic study, showing extensive vesicular dilatation of chondrocytic endoplasmic reticulum seen only in explants treated with hydrocortisone or sodium salicylate. Our data suggests that some nonsteroidal antiinflammatory drugs (NSAID) are able to decrease OA cartilage catabolism. However, caution should be taken since certain NSAID, like salicylate, may also possibly jeopardize the cartilage repair process by inhibiting the proteoglycan synthesis.

Aged↗

PubMed1988

In vivo effects of antirheumatic drugs on neutral collagenolytic proteases in human rheumatoid arthritis cartilage and synovium.

The destruction of joints in rheumatoid arthritis (RA) is thought to be related in part to an increased synthesis of proteolytic enzymes. We have determined neutral collagenolytic protease activity levels in human RA synovia and articular cartilage and examined the in vivo effects of various therapeutic regimens on enzyme levels. Neutral metallocollagenolytic enzyme (NMCE) was measured in 29 RA cartilages and synovial membranes. In addition, synovial serine protease levels were determined. Specimens were divided into 4 groups according to prescribed medications: (1) nonsteroidal antiinflammatory drugs alone; (2) steroids alone; (3) steroids and gold; and (4) steroids and methotrexate (MTX). Ten normal specimens were used as controls. Total and active NMCE measured in both RA cartilage and synovial membrane specimens showed a significantly higher level of activity than in controls (p less than 0.0001, p less than 0.005; p less than 0.004, p less than 0.02). MTX was found to markedly decrease NMCE activity; cartilage NMCE level in patients with RA receiving MTX was reduced, compared to the other subgroups. This was particularly noted for the active form. Synovial NMCE levels from the MTX subgroup for both enzyme forms were much lower than in any other RA subgroup, significantly lower than in the RA group as a whole (p less than 0.05), and similar to controls. RA synovial membrane serine protease activity showed an increase compared to controls. Again, MTX markedly decreased the activity of this class of enzyme. Our data strongly support the role of neutral proteases in the destruction of RA joints. MTX was the only drug to consistently decrease these enzyme levels in joint tissues.

Adult↗

PubMed1987

Proteoglycan-degrading acid metalloprotease activity in human osteoarthritic cartilage, and the effect of intraarticular steroid injections.

Cartilage samples from both the immediate and remote lesion areas were obtained from the tibial plateaus of 21 patients with osteoarthritis, and were subjected to histologic and enzymatic study. There was a frequent loss of pericellular metachromatic staining in the OA cartilage. Seven patients had received intraarticular injections of steroids, and in 21% of those cartilage samples, a pericellular halo was seen. This halo was seen in 71% of patients who had not received steroid injections. The total acid metalloprotease activity was increased more than twofold in specimens from OA lesions and in those samples graded moderate, as compared with age-matched control cartilages. These differences were greater when the specimens from patients who had received steroid therapy were excluded from the data. The cartilage specimens from steroid-treated patients were not significantly different from those of controls with respect to the enzyme activity in the lesions or in cartilage with moderate disease. The active form of the protease was suppressed by steroids. In samples from patients who did not receive steroid injections and who had a moderate grade of OA, a significantly elevated level of the active protease was present, as compared with control samples. Those samples graded moderate which came from patients who received steroid treatments showed no difference in the active protease level versus that of controls. Our results are consistent with the hypothesis that acid metalloprotease activity is involved in the degradation of the cartilage matrix in OA. Since the protease retains a significant fraction (40%) of its activity at neutral pH, its physiologic role might occur either at acid pH or at neutral pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Inflammatory Agents↗

PubMed1987

Newly synthesized and endogenous proteoglycans in human osteoarthritic knee cartilage.

Newly synthesized and endogenous proteoglycans of human osteoarthritic knee cartilages were studied in short term explant culture. There were more newly synthesized proteoglycans than endogenous uronic acid containing proteoglycans found in the A1 fraction generated by associative CsCl density gradient centrifugation. Thirty-five percent of the proteoglycans in the A1 fraction were shown to elute in the void volume on Sepharose CL-2B, under associative conditions. Reduction and alkylation of the A1 fraction indicated that the endogenous proteoglycan monomer was hydrodynamically smaller than the newly synthesized macromolecule. This was confirmed by a Sepharose CL-2B chromatography of the A1D1 fraction. In comparison to endogenous proteoglycans, the newly synthesized proteoglycan monomers were less capable of forming stable aggregates with exogenous hyaluronic acid. We also found a statistically significant decrease (p less than 0.05) in the amount of already existing proteoglycan subclass when compared to the amount of newly synthesized proteoglycans in the most dense A1D1 fraction. By contrast, a statistically significant increase (p less than 0.05) in the amount of endogenous vs newly synthesized proteoglycans was seen in the A1D2 fraction but not in fractions of a lower buoyant density.

Aged↗

PubMed1986

Neutral proteases in human osteoarthritic synovium.

The activities of neutral collagenolytic enzymes (CE) and neutral proteoglycan-degrading enzymes (PE) in the synovial membranes of osteoarthritis (OA) patients were determined. The total neutral metallo-CE activity showed a significantly higher level of activity when the membranes of OA patients were compared with those of controls. The severely and moderately inflamed synovia had significantly more enzyme activity than did either mildly inflamed or control synovia. Steroids reduced the total metallo-CE activity. In specimens with severe inflammation, the active form of the neutral metallo-CE was significantly elevated over that found in controls. The serine-CE activity was also significantly elevated in OA synovia with severe inflammation and synovial hypertrophy. The total and active neutral metallo-PE was significantly elevated in synovial membranes of OA patients with severe inflammation. Moreover, the serine-PE showed much more activity in OA patients than in controls. The enzyme activity remained at a significantly high level in the OA synovium, regardless of the presence or absence of macroscopic synovial hypertrophy or the histologic grading of the synovium (mild, moderate, severe). Our data indicate that, in OA, an increased level of neutral proteases in the synovia could be involved in the local tissue destruction of the periarticular structures. Because of the very high level of serine proteases, their diffusion may render plausible a degradative action on the cartilage surface.

Aged↗