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Biomedical subjects

K Yudoh

Publications and source records attributed to K Yudoh.

At least 19 recordsLinked to original sources
PubMed2006

Expression of proteinase-activated receptors (PAR)-2 in articular chondrocytes is modulated by IL-1beta, TNF-alpha and TGF-beta.

OBJECTIVE: To investigate the modulation of expression of proteinase-activated receptor-2 (PAR-2) in articular chondrocytes by inflammatory cytokines. DESIGN: Articular synovium and cartilage tissues were collected from eight patients with osteoarthritis (OA), and three patients without arthropathy ("normal"). Chondrocytes were stimulated with interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha or transforming growth factor (TGF)-beta1. The expression of PAR-2 was detected using reverse transcriptase-polymerase chain reaction (PCR), Western blotting and immunofluorescence. Quantitative PCR was performed to assess the expression levels of PAR-2 messenger RNA (mRNA). RESULTS: The expression of PAR-2 mRNA was demonstrated in both OA and normal chondrocytes as well as in synovial fibroblasts. However, the level of PAR-2 in OA chondrocytes was much higher than in normal chondrocytes. Long-term culture revealed that PAR-2 mRNA expression was maintained up to three passages in OA but not in normal chondrocytes. IL-1beta and TNF-alpha both upregulated PAR-2 expression in normal and OA chondrocytes. In contrast, TGF-beta1 significantly decreased expression of PAR-2 in OA chondrocytes but increased PAR-2 in normal chondrocytes. CONCLUSIONS: Overexpression of PAR-2 in OA chondrocytes is upregulated by proinflammatory cytokines IL-1beta and TNF-alpha, and down-regulated by regulatory cytokine TGF-beta1. PAR-2 may be involved in the pathogenesis of OA.

Aged↗
PubMed2005

The role of subchondral bone resorption pits in osteoarthritis: MMP production by cells derived from bone marrow.

OBJECTIVE: The vascular invasion of bone marrow tissue into the subchondral plate is often observed in articular cartilage and we named it the subchondral bone absorption pit; however, its implication in the pathogenesis of osteoarthritis (OA) has been poorly understood. The purpose of this study was to evaluate its characteristics and roles in osteoarthritic conditions. METHODS: Articular cartilage specimens from 11 patients with medial type knee OA and 7 non-arthritic cadavers were analyzed with HE staining. OA sections were stained with safranin-O, TRAP (tartrate resistant acid phosphatase) and immunostained with anti-MMP-1, MMP-3, MMP-13, vitronectin receptor (VNR)-alpha chain, vimentin and bone morphogenic protein (BMP) 2/4 antibodies. RESULTS: Subchondral bone resorption pits were classified according to the extent of invasion: pits with bone marrow tissue were located within uncalcified cartilage below the tidemark in grade I and invaded beyond the tidemark in grade II, while no invasion was seen in grade 0. Grade II pits were dominant in OA compared to non-arthritic joints, especially medial condyles. Proteoglycan detected with safranin-O staining was lost around the tip of grade II pits and the density of pits was related to the modified Mankin Score. Cells in pits expressed vimentin, MMP-1, MMP-3 and MMP-13. Some polynuclear cells co-expressed VNR-alpha chain and MMP-13, whereas pits showed reparative features expressing BMP. CONCLUSION: These results suggest that subchondral bone resorption pits contribute to cartilage degradation by expressing matrix metalloproteinases in OA.

Aged↗
PubMed2005

Implication of interleukin 18 in production of matrix metalloproteinases in articular chondrocytes in arthritis: direct effect on chondrocytes may not be pivotal.

OBJECTIVE: To clarify the effect of interleukin (IL) 18 on cartilage degeneration by studying the profile of IL18 receptor (IL18R) on chondrocytes and the direct effect of IL18 on production of matrix metalloproteinases (MMPs), aggrecanases, and tissue inhibitors of metalloproteinases (TIMPs) in articular chondrocytes. METHODS: Monolayer cultured human articular chondrocytes were isolated from non-arthritic subjects and patients with rheumatoid arthritis or osteoarthritis. Gene expression of IL18, IL18Ralpha, IL18Rbeta, MMPs, and aggrecanases was detected by RT-PCR. Protein levels of IL18Ralpha were analysed by flow cytometry. Protein levels of IL18, MMPs, and TIMPs were measured by ELISA. Aggrecanase-2 mRNA expression was quantitatively analysed by real time RT-PCR. Protein levels of signalling molecules were assayed by western blotting. RESULTS: IL18 mRNA was constitutively expressed in chondrocytes, and was enhanced by IL1beta stimulation. Flow cytometric analysis showed that IL1beta, tumour necrosis factor alpha, and IL18 up regulated IL18Ralpha expression levels. The level of IL18Rbeta mRNA was much lower than that of IL18Ralpha, and was slightly up regulated by IL1beta. In chondrocytes responding to IL18, IL18 (1-100 ng/ml) slightly increased the production of MMP-1, MMP-3, and MMP-13, which was blocked by NF-kappaB inhibitor and p38 mitogen activated protein kinase inhibitor. IL18 up regulated mRNA expression of aggrecanase-2, but not aggrecanase-1. IL18 also slightly stimulated TIMP-1 production?through extracellular signal regulated kinase activation. CONCLUSION: IL18 induces production of MMPs from chondrocytes in inflammatory arthritis. Although the direct effect of IL18 on chondrocytes may not be pivotal for the induction of cartilage degeneration, IL18 seems to play some part in the degradation of articular cartilage in arthritis.

ADAM Proteins↗
PubMed2004

Telomerized presenescent osteoblasts prevent bone mass loss in vivo.

Previously, we showed that human osteoblasts expressing the human telomerase reverse transcriptase (hTERT) gene exhibited specific survival advantages--the result of breaching the replicative senescence barrier and maintaining the phenotypic and functional properties of primary osteoblasts in vitro over the total replicative capacity of primary osteoblasts. We postulated that rejuvenated osteoblasts may have a potential to correct bone loss or osteopenia in age-related osteoporotic diseases. In the present study, we studied whether telomerized presenescent osteoblasts prevent bone mass loss in vivo. After obtaining the informed consent from a patient with osteoarthritis who underwent the arthroplastic knee surgery, osteoblastic cells were isolated from donor bone sample. We transfected the gene encoding hTERT into human osteoblastic cells. Human bone fragments from a donor were incubated with human hTERT-transfected presenescent (in vitro aged) osteoblasts or mock-transfected presenescent osteoblasts in culture medium containing Matrigel. We subcutaneously implanted human bone fragments with telomerized presenescent osteoblasts or primary presenescent osteoblasts as three-dimensional Matrigel xenografts in severe combined immunodeficiency (SCID) mice (each group: six mice) and analyzed the grafts at 6 weeks after implantation. We also determined whether telomerized osteoblasts affect the bone-forming capacity in vivo, using a well-established mouse transplantation model in which ceramic hydroxyapatite/tricalcium phosphate particles are used as carrier vehicle. Telomerized presenescent osteoblasts were rejuvenated, and maintained the functional properties of young osteoblasts in vitro. Bone mineral content (BMC) and bone mineral density (BMD) were measured by ash weight and dual-energy X-ray absorptiometry, respectively. Whereas BMC and BMD of human bone fragments, which were inoculated with aged osteoblasts in SCID mice, decreased with time, telomerized presenescent osteoblasts maintained the BMC and BMD of human bone fragments, indicating that telomerized and rejuvenated osteoblasts may be functional to prevent bone mass loss in vivo. In xenogenic transplants, telomerized osteoblasts generated more bone tissue with lamellar bone structure and cellular components, than did control osteoblasts. These findings suggest that telomerized/rejuvenated presenescent osteoblasts may be used in the development of tissue engineering or cell-based therapy for bone regeneration and repair.

Animals↗
PubMed2004

Interleukin (IL) 18 stimulates osteoclast formation through synovial T cells in rheumatoid arthritis: comparison with IL1 beta and tumour necrosis factor alpha.

OBJECTIVE: To determine whether IL18 has any indirect effects on osteoclastogenesis mediated by T cells in RA synovium, and compare its effects with those of IL1 beta and TNF alpha. METHODS: Resting T cells were isolated from peripheral blood of healthy donors, and stimulated with 2 microg/ml phytohaemagglutinin (PHA) and 0.5 ng/ml IL2 for 24 hours. Synovial T cells were isolated from RA synovial tissue. The levels of soluble receptor activator of the NF-kappa B ligand (RANKL), osteoprotegerin (OPG), IFN gamma, M-CSF, and GM-CSF were determined by ELISA. Membrane bound RANKL expression was analysed by flow cytometry. Commercially available human osteoclast precursors were cocultured with T cells to induce osteoclast formation, which was determined with tartrate resistant acid phosphatase staining and pit formation assay. RESULTS: In PHA prestimulated T cells or RA synovial T cells, IL18, IL1 beta, or TNFalpha increased soluble RANKL production and membrane bound RANKL expression in a dose dependent manner. IL18, IL1 beta, and TNF alpha did not induce M-CSF, GM-CSF, IFN gamma, or OPG production in PHA prestimulated T cells or RA synovial T cells. IL18 increased the number of osteoclasts and bone resorption area on dentine slices in the coculture of human osteoclast precursors with PHA prestimulated T cells or RA synovial T cells; its ability was equivalent to that of IL1 beta, but less potent than that of TNF alpha. In the coculture system, OPG completely blocked osteoclast induction by IL18 or IL1 beta, and greatly inhibited induction by TNF alpha. CONCLUSION: IL18, IL1 beta, or TNF alpha can indirectly stimulate osteoclast formation through up regulation of RANKL production from T cells in RA synovitis; IL18 is as effective as IL1 beta, but less potent than TNF alpha.

Analysis of Variance↗
PubMed2002

The role of TNF-alpha in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis (RA): a study using a human RA/SCID mouse chimera.

OBJECTIVE: In order to elucidate which cytokine preferentially stimulates the synovium in patients with rheumatoid arthritis (RA), we investigated the roles of tumour necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) using SCID mice engrafted with human RA tissue (SCID-HuRAg). METHODS: The SCID-HuRAg mice were prepared according to our previously described method. First, SCID-HuRAg mice were treated with chimeric anti-TNF-alpha monoclonal antibody (mAb, 100 microg/mouse) and histological changes were examined 4 weeks after the initial treatment. Secondly, a total of 100 microg of recombinant TNF-alpha or IL-6 (0.6 microg/h) was administered daily to mice using an osmium pump. The histological changes and serum cytokine levels were examined 4 weeks after the initial administration. Human immunoglobulin G (IgG) was administered to mice as a control. RESULTS: Synovial inflammatory cells were significantly decreased after the anti-TNF-alpha mAb treatment; conversely, the degree of synovial inflammation was significantly exacerbated by TNF-alpha administration. The levels of both IL-6 and TNF-alpha in sera were significantly increased by recombinant TNF-alpha administration, while TNF-alpha levels were unchanged by IL-6 administration. This suggests that TNF-alpha controls IL-6 production. Despite the profound changes in inflammation, we found no effects on bone and no articular cartilage damage was produced by TNF-alpha. CONCLUSION: This study provides strong evidence that TNF-alpha is a key molecule in the control of the inflammatory changes that occur in the RA synovium. In addition, TNF-alpha regulates IL-6 production. However, other inflammatory pathways independent of TNF-alpha may contribute to the bone and cartilage damage seen in RA.

Animals↗
PubMed2001

Concentration of vascular endothelial growth factor in the tumour tissue as a prognostic factor of soft tissue sarcomas.

Previous studies have shown that the prognosis of patients who have tumours with high microvessel density (MVD) is worse than that of patients who have a lower density in a variety of cancers. In this study, we investigated the clinical relevance of neovascularity assessed by MVD and the concentration of vascular endothelial growth factor (VEGF) in the tumour tissue of patients with soft tissue sarcoma in comparison with major clinicohistologic parameters by univariate and multivariate analysis. In 115 patients with soft tissue sarcoma, MVD was measured by counting vessels stained with factor VIII antibody. The concentration of VEGF in the tumour tissue was determined by enzyme-linked immunosorbent assay. These parameters were then compared with disease outcome. The concentration of VEGF in the tumour tissue, but not MVD, was found to be correlated with disease outcome in patients with soft tissue, sarcoma. VEGF concentration in the tumour tissue showed a relationship with the clinical stage and histologic grade of the tumour. There was no significant difference in the levels of tissue VEGF concentration and MVD among soft tissue sarcomas classified according to histologic type. The level of tissue VEGF concentration in patients who had subsequent local recurrence and metastasis were significantly higher than the respective values in patients who did not have such disease outcome. No significant correlation existed between MVD and the concentration of VEGF in the tumour tissue. Univariate analysis showed that a high tissue VEGF concentration was associated with poor overall survival of the patient and a greater probability that local recurrence and metastasis had occurred. Multivariate analysis revealed that the tissue concentration of VEGF is an independent prognostic factor for the disease outcome of patients with soft tissue sarcoma. VEGF concentration in the tumour tissue, but not MVD, is an additional prognostic parameter for disease outcome in patients with soft tissue sarcoma, regardless of histologic type.

Adult↗
PubMed2001

Reconstituting telomerase activity using the telomerase catalytic subunit prevents the telomere shorting and replicative senescence in human osteoblasts.

The rate of bone formation is largely determined by the number of osteoblasts, which in turn is determined by the rate of replication of progenitors and the life span of mature cells, reflecting the timing of death by apoptosis. However, the exact age-dependent changes of the cellular activity, replicative potential, and life span of osteoblasts have not been investigated to date. Here, we present evidence that the cellular activity, telomere lengths, and replicative life span of osteoblastic cells obtained from juxta-articular bone marrow gradually decrease with the advance of donor age. Recently, telomerase reverse transcriptase (hTERT) has been identified as a human telomerase catalytic subunit. We transfected the gene encoding hTERT into telomerase-negative human osteoblastic cells from donors and osteoblastic cell strain NHOst 54881 cells and showed that expression of hTERT induces telomerase activity in these osteoblastic cells. In contrast to telomerase-negative control cells, which exhibited telomere shortening and senescence after 10-15 population doublings, telomerase-expressing osteoblastic cells had elongated telomere lengths and showed continued alkaline phosphatase activity and procollagen I C-terminal propeptide (PICP) secretion for more than 30 population doublings. These results indicate that osteoblasts with forced expression of hTERT may be used in cell-based therapies such as ex vivo gene therapy, tissue engineering, and transplantation of osteoblasts to correct bone loss or osteopenia in age-related osteoporotic diseases.

Aged↗
PubMed2001

Stromelysin-1 (MMP-3) in synovial fluid of patients with rheumatoid arthritis has potential to cleave membrane bound Fas ligand.

OBJECTIVE: To investigate the relationship between matrix metalloproteinases (MMP) and the soluble form of Fas ligand (sFasL) in the synovial fluid (SF) of patients with rheumatoid arthritis (RA), and to determine which MMP have a major role in cleaving FasL. METHODS: The concentrations of sFas and sFasL in SF from 48 patients with RA and 43 patients with osteoarthritis (OA) were measured using specific ELISA. The levels of different MMP (MMP-1, 2, 3, 7, 9) in SF were also measured by ELISA. The active forms of gelatinases were detected by gelatin zymogram. Human FasL-expressing transfected cells (hFasL/L5178Y) were used to investigate whether FasL is cleaved from membrane bound FasL. RESULTS: Significantly higher levels of MMP-1, 3, and 9 were found in SF from RA patients compared to OA patients, but MMP-7 was not detectable in either group. The concentrations of sFas and sFasL in SF were also higher in RA than in OA patients. However, there was no relationship between the concentration of sFas and sFasL. Among MMP, MMP-3 concentrations in SF were closely correlated with the level of sFasL and with disease activity of RA. Enzymatic cleavage assay indicated that MMP-3 has potential to cleave the FasL expressed on hFasL/L5178Y cells and to produce sFasL. CONCLUSION: There was significant correlation between the concentration of sFasL and MMP-3 in SF of patients with RA. In addition, our data indicate that the shedding of FasL may be regulated by MMP-3 in the joint of patients with RA.

Apoptosis↗
PubMed2001

Methotrexate inhibits rheumatoid synovitis by inducing apoptosis.

OBJECTIVE: To clarify the pharmacological action of methotrexate (MTX) on the synovium of patients with rheumatoid arthritis (RA) using severe combined immunodeficient (SCID) mice in which human RA synovial tissue had been grafted (SCID-HuRAg). METHODS: One month after engraftment of human RA tissue into SCID mice, MTX (0.3 mg/kg) was administered orally, then the appearance of apoptosis in the grafted tissue was examined by TdT mediated dUTP nick end labeling (TUNEL) staining and electron microscopy at various time points after MTX administration. In cultured synovial cells, synovial apoptotic changes after MTX treatment were studied by agarose gel electrophoresis and flow cytometric analysis. To compare the histological changes induced by MTX with those induced by other disease modifying antirheumatic drugs (DMARD) and a nonsteroidal antiinflammatory drug, histological examination of the grafted synovial tissues from SCID-HuRAg mice was conducted after 4 weeks of oral administration of MTX (0.3 mg/kg/week), salazosulfapyridine (30 mg/kg/day), auranofin (0.2 mg/kg/day), bucillamine (10 mg/kg/day), or indomethacin (2 mg/kg/day). RESULTS: A significant decrease in the number of inflammatory cells was observed in the grafted synovial tissue of MTX treated SCID-HuRAg. A similar antiinflammatory effect was not observed with the other DMARD. Induction of apoptosis was noted with MTX treatment but not with the others. The pro-apoptotic effect of MTX was also observed in synovial cell cultures. CONCLUSION: MTX induces apoptosis in RA synovium that, in turn, may contribute to its antiinflammatory effect on RA synovitis.

Animals↗
PubMed2001

[Relationship between periarticular osteoporosis and osteoblast senescence in patients with rheumatoid arthritis].

The rate of bone formation is largely determined by the number of osteoblasts, which in turn is determined by the rate of replication of progenitors and the life-span of mature cells, reflecting the timing of death by apoptosis. However, the exact age-dependent changes of the cellular activity, replicative potential and life-span of osteoblasts have not so far been investigated to date. Here we present evidence that the cellular activity, telomere lengths and replicative life-span of osteoblastic cells obtained from juxta-articular bone marrow gradually decrease with the advance of donor age in patients with rheumatoid arthritis or osteoarthritis. Recently, human telomerase reverse transcriptase (hTERT) has been identified as a human teromerase catalytic subunit. We postulate that an expansion of the life-span of osteoblasts and their maintenance as differentiated bone matrix-producing cells may allow for autologus or allogenic cell and gene therapy in bone and joint diseases including osteoporosis. We therefore transfected human osteoblasts with a vector expressing hTERT cDNA, and investigated whether the replicative life-span can be expanded by the introduction of telomerase in human osteoblasts.

English Abstract↗
PubMed2000

Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis.

OBJECTIVE: To elucidate the involvement of the regulatory CD4+ T cells that produce high levels of interleukin-10 (IL-10) and low levels of IL-4 and IL-2 in the pathogenesis of rheumatoid arthritis (RA), we investigated whether the frequency of this type of CD4+ T cell subset in peripheral blood lymphocytes (PBL) or synovial lymphocyte infiltrates of patients with RA correlated with disease severity and histologic features in rheumatoid synovium. METHODS: PBL and synovial lymphocyte infiltrates were isolated from peripheral blood samples and synovial tissues obtained from 25 patients with RA. Control specimens were obtained from 18 patients with osteoarthritis (OA) and 10 patients with traumatic injuries of the knee joint. CD4+ T cell subsets were categorized as Th1 (production of interferon-gamma [IFNgamma], but not IL-4), Th2 (production of IL-4, but not IFNgamma), or CD4+ T cell subsets producing IL-10, IL-2, or IL-4. The percentages of these T helper subsets among PBL and among synovial infiltrating lymphocytes were determined by an intracellular staining assay with flow cytometric analysis. RESULTS: The level of expression of CD4+ T cells producing IL-10 but not IL-2 and IL-4 in the peripheral blood and synovial tissue was significantly lower in RA patients than in OA patients and trauma patients. In RA patients, the frequency of this type of CD4+ T cell subset among synovial infiltrating CD4+ T cells was inversely correlated with the frequency of Th1 cells and the Th1/Th2 balance in synovial lymphocytes, serum C-reactive protein value, disease activity score, and the degree of synovial lining hyperplasia and lymphocyte infiltration in rheumatoid synovium. There was a reciprocal relationship between the frequency of Thl cells and CD4+ T cells producing IL-10 but not IL-2 and IL-4 in the peripheral blood of RA patients. CONCLUSION: In RA, reduced expression of the CD4+ T cell subset producing IL-10 but not IL-2 and IL-4 may be responsible for the dominance of Th1 over Th2 cells at sites of inflamed synovium and in the peripheral blood. Decreases in this type of CD4+ T cell subset may induce the down-regulation of T cell tolerance and exacerbate the inflammatory process in RA.

Adult↗
PubMed2000

Decreased cellular activity and replicative capacity of osteoblastic cells isolated from the periarticular bone of rheumatoid arthritis patients compared with osteoarthritis patients.

OBJECTIVE: Periarticular osteopenia is frequently observed in rheumatoid arthritis (RA). Bone loss has been considered to be at least partly due to inadequate bone formation, which in turn, is largely dependent on the number of osteoblasts and the osteoblastic activity. Normal human somatic cells undergo a finite number of cell divisions and ultimately enter a nondividing state called replicative senescence. It has been proposed that the telomere, the terminal sequence of chromosomes, is the mitotic clock that triggers senescence. In the present study, we sought to clarify the relationship between periarticular osteopenia and osteoblast replicative senescence in RA. METHODS: We examined age-related changes in cellular activity (alkaline phosphatase activity, osteocalcin and C-terminal type I procollagen secretion, and cAMP response to parathyroid hormone), replicative capacity, and senescent cell expression in osteoblasts from periarticular bone samples obtained from 15 patients with RA and 15 age-matched patients with osteoarthritis (OA). Cellular replicative capacity was analyzed by the mean telomere length and in vitro remaining replicative lifespan of the cells. RESULTS: In both OA and RA groups, the cell proliferation rate, the levels of osteoblastic markers, mean telomere length, and replicative lifespan in osteoblastic cells gradually decreased with the increasing age of the donor. The percentage of senescent osteoblastic cells in the periarticular bone increased with age in both groups, and the rate of expression of senescent cells was higher in RA patients than in age-matched OA patients. The osteoblastic activities and replicative capacity of osteoblastic cells from RA patients were lower than those from OA patients at any donor age. The age-related decreases in the osteoblastic activity and replicative capacity of osteoblastic cells from periarticular bone were greater in RA patients than in OA patients. CONCLUSION: Our results suggest that osteoblast replicative senescence in periarticular bones occurs more rapidly with aging in RA than in OA patients and contributes to periarticular osteopenia in RA.

Aged↗
PubMed2000

Cementless cup supporter for protrusio acetabuli in patients with rheumatoid arthritis.

The MC cup supporter is an acetabular reinforcement ring for the Harris-Galante (HG) cementless porous-coated socket. This supporting ring has been used with autogenous bone graft since 1991 in the management of protrusio acetabuli in patients with rheumatoid arthritis (RA). We have reviewed 15 hips in 13 patients at an average of 53.6 months (range 24-84 months) after operation. The clinical results of total hip arthroplasty (THA) in protrusio acetabuli using this ring were satisfactory. All grafts appeared to have united radiologically with no radiolucent lines between graft and acetabulum.

Acetabulum↗
PubMed2000

Significance of serum type IV collagenolytic activities and gelatinase levels for detection of metastasis in murine RCT sarcoma.

We investigated the usefulness of serum type IV collagenolytic activities and gelatinase levels as diagnostic markers of metastasis in the animal model of spontaneous lung metastasis by FITC-labeled type IV collagen degradation assay and zymographic analyses. High-metastatic RCT(+) and low-metastatic RCT(-) clones were used in the present study. The mean serum type IV collagenolytic activity in the RCT(+) group started to increase from two weeks after hind limb amputation, and was 0.45 and 1.29 unit/ml at three and four weeks. These values were significantly higher than those in the control group (p < 0.01 at three weeks; p < 0.001 at four weeks). A correlation between the number of lung nodules and serum type IV collagenolytic activities in the RCT(+) group was found (r = 0.89, p < 0.001). Zymographic analyses indicated that 105-kD gelatinolytic activities of the RCT(+) group were higher than those of the RCT(-) group at three and four weeks. Thus, type IV collagenolytic activities and serum gelatinase levels might be valuable markers for the detection of metastasis.

Animals↗
PubMed1999

Different mechanisms of synovial hyperplasia in rheumatoid arthritis and pigmented villonodular synovitis: the role of telomerase activity in synovial proliferation.

OBJECTIVE: To elucidate the involvement of telomerase activity in the pathogenesis of rheumatoid arthritis (RA) and pigmented villonodular synovitis (PVS). METHODS: Peripheral blood lymphocytes (PBL), synovial infiltrating lymphocytes, and synoviocytes were isolated from peripheral blood samples and synovial tissue obtained from 18 patients with RA, 9 with PVS, 12 with osteoarthritis (OA), and 10 with knee joint trauma. Cellular telomerase activity was measured by the telomeric repeat amplification protocol assay. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was assessed for correlations with histologic features in rheumatoid synovium. RESULTS: A high level of telomerase activity was detected in the PBL and synovial infiltrating lymphocytes from RA patients and in the synoviocytes from PVS patients, whereas the enzyme activity was expressed at a low-to-borderline level in the PBL and synovial lymphocytes from OA, PVS, and trauma patients and was absent in the synoviocytes from RA as well as OA and trauma patients. In RA patients, the telomerase activity level in synovial infiltrating lymphocytes was significantly correlated with the intensity of synovial lining hyperplasia, microvessel proliferation, lymphocyte infiltration, and percentage of synovial cells positive for proliferating cell nuclear antigen in rheumatoid synovium. CONCLUSION: Telomerase activation in lymphocytes may provide insights into the progression of synovitis and synovial proliferation in RA. Moreover, the enzyme may be implicated in the proliferation of synoviocytes in PVS.

Adult↗