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1.
OBJECTIVE: To measure and compare activities of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and matrix metalloproteinase-3 (MMP-3); as well as sulfated glycosaminoglycan (S-GAG) content in synovial fluid from dogs with cranial cruciate ligament rupture (CCLR) and dogs with clinically normal stifles. To determine whether correlations exist between demographic and disease-related variables and these synovial markers. STUDY DESIGN: Prospective clinical study. ANIMALS: Dogs with CCLR (n=23) and Beagles with normal stifle joints (n=21). METHODS: Synovial fluid activities of proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) were determined by bioassay. MMP-3 activity was measured using fluorogenic substrate. S-GAG contents were determined by dimethylmethylene blue dye-binding assay. Mann-Whitney U-test was used to compare results from CCLR joints with normal controls. Spearman's rank correlation test was used to evaluate associations between demographic and disease-related markers and synovial markers. RESULTS: Mean values for synovial markers were significantly higher in CCLR joints compared with controls. IL-1beta and MMP-3 were positively correlated with lameness duration. CONCLUSIONS: Activities of proinflammatory cytokines, MMP-3 activity and S-GAG contents were significantly elevated in synovial fluid from canine stifle joints with naturally acquired CCLR. These results indicate that there is joint inflammation and increased release of GAGs into synovial fluid, suggesting that these inflammatory changes are associated with depletion of proteoglycan from articular cartilage. CLINICAL RELEVANCE: Medical and surgical treatments designed to decrease joint inflammation and breakdown of proteoglycans may be of value in the management of CCLR in the dog.  相似文献   

2.
Dysregulation of immune responses within joints plays an important role in development of inflammatory arthritis. We determined expression of a panel of immune response and matrix turnover genes in synovial fluid collected from a group of dogs with stifle oligoarthritis and associated degenerative cranial cruciate ligament (CCL) rupture (n=27). We also studied synovial fluid gene expression in dogs affected with other forms of degenerative arthritis (n=9) and in the stifle joint of healthy dogs with intact CCL (n=14). After collection, synovial cells were pelleted and RNA was isolated. Relative expression of cathepsin K, cathepsin S, tartrate-resistant acid phosphatase (TRAP), matrix metalloproteinase-9 (MMP-9), invariant chain (li), toll-like receptor-2 (TLR-2), and TLR-9 was determined using real-time quantitative RT-PCR. Data were normalized to peripheral blood mononuclear cells (PBMC) as an internal control. Relative expression of cathepsin K, MMP-9, TRAP, and li was increased in the stifle synovial fluid of dogs with oligoarthritis, when compared with the stifles of healthy dogs (P<0.05). In contrast, relative expression of all of the genes-of-interest in synovial fluid from joints affected with other forms of arthritis was not significantly different from the stifles of healthy dogs. TRAP expression was also significantly increased in the stifle joints of dogs with oligoarthritis, when compared to joint expression of TRAP in dogs with other forms of degenerative arthritis (P<0.05). In the dogs with stifle oligoarthritis, expression of both matrix turnover and immune response genes was increased in stifle synovial fluid, when compared with the internal PBMC control, whereas in healthy dogs and dogs with other forms of arthritis, only expression of matrix turnover genes was increased in synovial fluid, when compared with the internal PBMC control (P<0.05). Taken together, these findings suggest that antigen-specific immune responses within the stifle joint may be involved in the pathogenesis of persistent synovitis and associated joint degradation in dogs with oligoarthritis and degenerative CCL rupture.  相似文献   

3.
It has been proposed that small quantities of microbial material within synovial joints may act as a trigger for development of synovitis. We have previously identified an association between intra-articular bacteria and development of inflammatory stifle arthritis and cranial cruciate ligament rupture (CCLR) in dogs, and now wished to quantify bacterial load and markers of synovitis in dogs with and without stifle arthritis and CCLR. Joint tissues were collected from dogs with CCLR (n=51) and healthy dogs with normal stifles (n=9). Arthritis was assessed radiographically in CCLR dogs. Bacterial load was assessed using qPCR and broad-ranging 16S rRNA primers. qRT-PCR was used to estimate expression of the T lymphocyte antigen receptor (TCR Vβ), CD3?, tartrate-resistant acid phosphatase (TRAP), IL-4, IL-17, and TNF-α genes. Severity of synovitis was assessed histologically. Bacterial load was increased in arthritic stifles, when compared with healthy stifles. Histologic synovitis in arthritic stifles was mononuclear and was significantly correlated with bacterial load (1 of 2 primer sets) (S(R)=0.49, p<0.001). In arthritic stifles, expression of TRAP in synovium was increased relative to healthy stifles. Expression of pro-inflammatory genes was not correlated with bacterial load, histologic inflammation, or radiographic arthritis. Translocation of bacterial material to the canine stifle is related to the presence of joint inflammation. The lack of a strong positive correlation suggests that bacterial load is unlikely to be a primary pro-inflammatory factor. However, dysregulation of immune responses within synovial tissues may be dependent upon an environmental microbial trigger.  相似文献   

4.
OBJECTIVE: To examine longitudinal changes in serum and synovial fluid concentrations of keratan sulfate (KS) and hyaluronan (HA) after cranial cruciate ligament (CCL) transection in dogs. ANIMALS: 12 clinically normal adult mixed-breed dogs. PROCEDURE: Following CCL transection in the right stifle joint, KS and HA concentrations were determined in serum and neat (undiluted) synovial fluid prior to and 1, 2, 3, and 12 months after surgery. Postsurgical dilution of synovial fluid was corrected by use of urea as a passive marker. RESULTS: Synovial fluid KS and HA concentrations decreased at 1, 2, and 3 months after surgery in operated stifle joints, compared with baseline values. Synovial fluid KS concentration decreased in unoperated stifle joints at 1 month. A decrease in synovial fluid KS concentration was found in operated stifle joints, compared with unoperated stifle joints, at 2 and 3 months, and a decrease in synovial fluid HA concentrations was also found in operated stifle joints, compared with unoperated stifle joints, at 1, 2, and 3 months. Serum KS concentrations increased from baseline values at 3 months after surgery. Hyaluronan concentrations in operated stifle joints were lower than baseline values at 1, 2, and 3 months. Urea-adjusted synovial fluid concentrations revealed that dilution did not account for the decline in biomarker concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: The initial decrease and subsequent increase in synovial fluid concentrations of HA and KS may be caused by an acute inflammatory response to surgical intervention that negatively affects cartilage metabolism or an increase in production of immature proteoglycans.  相似文献   

5.
OBJECTIVE: To measure and compare synovial fluid antibody titers to type-I and -II collagen in stifle joints with instability caused by complete or partial cranial cruciate ligament (CCL) rupture and joints with osteoarthrosis secondary to other pathologic changes in dogs. ANIMALS: 82 dogs with diseased stifle joints. PROCEDURE: Synovial fluid samples were collected from 7 dogs with clinically normal stifles (control group) and 82 dogs with diseased joints (50 stifle joints with complete rupture of the CCL, 20 with partial damage of the CCL, and 12 joints with radiographic signs of osteoarthritis secondary to other arthropathies). Synovial fluid samples were tested for autoantibodies to type-I and -II collagen by an ELISA. RESULTS: In dogs with complete and partial CCL rupture, synovial fluid antibody titers to type-I and -II collagen were significantly increased, compared with control dogs. Forty-eight percent (24/50) of samples from dogs with complete CCL rupture and 35% (7/20) of samples from dogs with partial CCL rupture had antibody titers to type-I collagen that were greater than the mean plus 2 standard deviations of the control group titers. Synovial fluid antibody titers to type-II collagen were high in 40% of the dogs with partial or (8/20) complete (20/50) CCL rupture. Dogs with osteoarthrosis secondary to other pathologic changes had significantly increased synovial fluid antibodies to type-I and -II collagen, compared with control dogs. CONCLUSION: Increases in autoantibodies to collagen in synovial fluid are not specific for the type of joint disorder. It is unlikely that the anticollagen antibodies play an active role in the initiation of weakening of the CCL.  相似文献   

6.
Objective: To evaluate lymphocyte populations in stifle synovium and synovial fluid of dogs with degenerative cranial cruciate ligament rupture (CCLR). Study Design: Prospective clinical study. Animals: Dogs (n=25) with stifle arthritis and CCLR, 7 dogs with arthritis associated with cartilage degeneration (osteoarthritis [OA]), and 12 healthy Beagle dogs with intact CCL. Methods: Arthritis was graded radiographically in CCLR dogs. After collection of joint tissues, mononuclear cells were isolated and subsequently analyzed using flow cytometry for expression of CD3, CD4, CD8, and CD21. Results: The proportions of CD4+ T helper lymphocytes, CD8+ cytotoxic T lymphocytes, and CD3+CD4?CD8? T lymphocytes were increased in synovium from dogs with CCLR compared with synovium from healthy Beagle dogs (P<.05). The proportion of CD3+CD4?CD8? T lymphocytes in synovial fluid was increased in dogs with CCLR compared with dogs with OA (P<.05). In dogs with CCLR, the proportion of CD3+CD4?CD8? T lymphocytes in synovial fluid was inversely correlated with radiographic arthritis (SR=?0.68, P<.005). Conclusion: Lymphocytic inflammation of stifle synovium and synovial fluid is an important feature of the CCLR arthropathy. Lymphocyte populations include T lymphocytes expressing CD4 and CD8, and CD3+CD4?CD8? T lymphocytes. Presence of CD3+CD4?CD8? T lymphocytes was associated with development of stifle synovitis. Further work is needed to fully identify the phenotype of these cells.  相似文献   

7.
Objective: To investigate the incidence of caudal cruciate ligament (CaCL) damage in dogs with cranial cruciate ligament rupture (CCLR). Study Design: Prospective clinical study. Animals: Dogs (n=24) admitted for surgical stabilization of the stifle after CCLR and 8 healthy dogs with intact cranial cruciate ligament (CCL) and CaCL studied as controls. Methods: Preoperative radiographs and stifle joint images (arthrotomy, 6; arthroscopy, 18) were collected from dogs with CCLR. Severity of arthritis, synovitis, CCL damage, and CaCL damage were assessed using numerical rating scales. The CaCL was probed to determine whether minor fraying or a full thickness defect in the ligament was present. Data collected from the study population were compared with the control population of dogs. Results: The CaCL was damaged in 21/24 (88%) of dogs with CCLR; 6/24 (25%) had a full thickness defect in the CaCL. Severity of stifle synovitis and severity of damage to the CaCL were positively correlated (P<.05). Conclusions: The CaCL is damaged in a high percentage of dogs with CCLR. A significant and positive correlation exists between the degree of synovitis present and the extent of CaCL damage. Clinical Relevance: In dogs with CCLR, cruciate ligament pathology typically involves both the CCL and CaCL. As the severity of synovitis and the extent of CaCL damage are related, this observation supports the hypothesis that stifle synovitis may contribute to CCL and CaCL degeneration and subsequent damage.  相似文献   

8.
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10.
Degenerative joint disease and inflammation of the synovial membrane were produced in the left stifle of 16 dogs by severing the cranial cruciate ligament. Arthrotomy only was performed on the right stifle. Synovial membrane from these joints was histologically examined at 1, 2, 8, and 13 weeks after surgical operation. Similar tissue was obtained from 4 healthy dogs for comparison. Inflammatory changes in the synovium of the left stifle progressed with time and were prominent at 8 weeks postoperatively; subsynovial fibrosis was greatest at 13 weeks. Inflammation of the synovial membrane and subsynovial tissue was characterized by synovial cell hypertrophy and hyperplasia, plasma cell and lymphocyte infiltration, and increased vascularization of the subsynovial region.  相似文献   

11.
OBJECTIVES: To investigate changes in concentrations of insulin-like growth factors I (IGF-I) and II (IGF-II) and the expression of IGF-binding proteins (IGFBP) in synovial fluids from dogs with naturally occurring osteoarthritis (OA) of the canine stifle joint secondary to cranial cruciate ligament (CCL) rupture. STUDY DESIGN: Prospective study with synovial fluid sampling from diseased and contralateral unaffected joints at 0, 1.5, and 5 months. SAMPLE POPULATION: Eleven dogs with unilateral CCL deficiency, with unaffected contralateral joints. METHODS: IGF-I and IGF-II concentrations in synovial fluids were estimated by radioimmunoassay at 0, 1.5, and 5 months; Western ligand blotting was performed for intact IGFBPs at 0, 1.5, 5, and 9 months. Both stifle joints were radiographed at 0, 7, and 13 months. RESULTS: The IGF system is altered after CCL rupture and during development of early OA. Mean IGF-I and IGF-II concentrations in index stifle joints at study entry were 201.6 microg/mL and 345.7 microg/mL, respectively, compared with 57.7 microg/mL and 79.4 microg/mL, respectively, for contralateral joints. Index joint IGF concentrations increased after surgical treatment and then declined, although they remained higher than contralateral joints. Index joints had increases in IGFBP-3 and -4, and a decrease in IGFBP-2 expression compared with contralateral joints. CONCLUSIONS: Although IGF concentrations are increased in canine OA, alterations in IGFBP profiles may limit the tissue availability of IGF. CLINICAL RELEVANCE: Manipulation of the IGF system may provide an opportunity for novel treatments of OA in dogs.  相似文献   

12.
Degenerative cranial cruciate ligament (CCL) rupture is characterized histologically by degenerating extracellular matrix (ECM) and chondroid metaplasia. Here, we describe the progression of chondroid metaplasia and the changes in the expression of ECM components in canine CCL rupture (CCLR). CCLs from 26 stifle joints with CCLR (CCLR group) and normal CCLs from 12 young beagles (control group) were examined histologically and immunohistochemically for expression of type I (COLI), type II (COLII), type III collagen (COLIII) and Sry-type HMG box 9 (SOX9). Cell density and morphology of CCLs were quantified using hematoxylin–eosin staining. The percentage of round cells was higher in the CCLR group than in controls. COLI-positive areas were seen extensively in the connecting fibers, but weakly represented in the cytoplasm of normal CCLs. In the CCLR group, there were fewer COLI-positive areas, but many COLI-positive cells. The percentages of COLII-, COLIII- and SOX9-positive cells were higher in the CCLR group than in controls. The number of spindle cells with perinuclear halo was high in the CCLR group, and most of these cells were SOX9-positive. Deposition of COLI, the main ECM component of ligaments, decreased with increased COLIII expression in degenerated CCL tissue, which shows that the deposition of the ECM is changed in CCLR. On the contrary, expression of SOX9 increased, which may contribute to the synthesis of cartilage matrix. The expression of COLII and SOX9 in ligamentocytes showed that these cells tend to differentiate into chondrocytes.  相似文献   

13.
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14.
Collagen fragmentation in cranial cruciate ligament (CCL) explants and stifle synovial fluid was investigated in dogs with ruptured and intact CCL. Cathepsin K and tartrate-resistant acid phosphatase (TRAP) activities were determined in CCL explant supernatants. Formation of collagen fragments was determined in explant supernatants and stifle synovial fluid. Cathepsin K(+) and TRAP(+) cells were stained specifically in histological sections of CCL. Formation of telopeptide collagen fragments was increased in ruptured CCL explants and stifle synovial fluid from dogs with ruptured CCL. In ruptured CCL explants, release of collagen fragments was associated with extracellular release of TRAP and the presence of cathepsin K(+) cells within CCL tissue. Cathepsin K(+) and TRAP(+) cells were only seen in ruptured CCL. It was concluded that infiltration of the CCL with TRAP(+) cells in dogs with CCL rupture is associated with increased collagenolysis. It is hypothesized that recruitment and activation of TRAP(+) mononuclear cells within the synovium and CCL precipitates CCL rupture through upregulation of collagenolytic enzymes and collagen degradation.  相似文献   

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16.
OBJECTIVE: To evaluate effects of intra-articular and extracapsular reconstruction of the cranial cruciate ligament (CCL) on metabolism of articular cartilage as reflected by concentrations of chondroitin sulfate epitopes 3B3 and 7D4 in synovial fluid. ANIMALS: 13 adult dogs. PROCEDURE: Each dog underwent unilateral CCL transection (CCLT). One month after CCLT, sham CCL reconstruction (3 dogs), intra-articular CCL reconstruction (5), or extracapsular CCL reconstruction (5) was performed. Synovial fluid was collected by direct arthrocentesis from CCLT and contralateral stifle joints immediately before (time 0) and 1, 3, and 5 months after CCLT. Fluid was examined for concentrations of 3B3 and 7D4 epitopes and total sulfated glycosaminoglycan (GAG) content. RESULTS: Concentrations of 3B3, 7D4, and GAG, 3B3:GAG, or 7D4:GAG in CCLT joints did not differ significantly among treatment groups nor in the ratios of these variables in CCLT joints to contralateral joints at 3 months. In a longitudinal analysis, concentrations of 3B3 and 7D4, 3B3:GAG, and 7D4:GAG in CCLT joints in all groups changed significantly with time, but we did not detect time X group interactions. CONCLUSIONS AND CLINICAL RELEVANCE: Transection of CCL resulted in significant perturbation in articular cartilage metabolism as reflected by alterations in concentrations of 3B3 and 7D4 in synovial fluid. These changes over time were not significantly influenced by method of CCL reconstruction. We did not find evidence that surgical stabilization of CCL-deficient joints by intra-articular or extracapsular techniques had any effect on preventing alterations in composition of synovial fluid that have been associated with secondary osteoarthritis.  相似文献   

17.
The present study investigated whether the 14-3-3 η and γ proteins, which are potent matrix metalloprotease (MMP) stimulators, are detectable in the synovial fluid of dogs with cranial cruciate ligament rupture (CCLR). Synovial fluid samples from 7 dogs with unilateral CCLR and control samples from 4 dogs without a history of any joint inflammation or any other abnormalities underwent Western blot analysis for the 14-3-3 η, γ, and σ proteins as well as MMP-1 and MMP-3. Craniocaudal and lateral radiographic projections of the stifle joint were evaluated for the presence and severity of 13 specific radiographic markers of osteoarthritis and graded numerically. The Spearman method was used to detect any correlation between the 14-3-3-η level in the synovial fluid and the radiograph-based grade. The η isoform was present only in the samples from the dogs with CCLR. The levels of 14-3-3-γ, MMP-1, and MMP-3 were significantly higher in the samples from the dogs with CCLR than in the control samples (P < 0.05). However, there was no significant difference between the CCLR and control samples in the level of the σ isoform. The Spearman method showed a significant correlation between the 14-3-3-η level in the synovial fluid and the presence of either patellar osteophytes or lateral or medial (or both) condylar periarticular osteophytes (P < 0.05). The MMP stimulatory effect of the 14-3-3 η and γ isoforms may be the reason for the high levels of MMP-1 and MMP-3 observed. Thus, 14-3-3 proteins, especially the η isoform, may be important markers of osteoarthritis caused by CCLR.  相似文献   

18.
The majority of studies on cranial cruciate ligament (CrCL) disease to date have been carried out on dogs that already sustained a CrCL rupture, which is the end-stage of the disease. Investigations have recently been carried out to study humoral and cellular immunopathological mechanisms in predisposed dogs before clinical rupture of the contralateral CrCL. The cruciate ligaments are mainly composed of collagen type I, and immune responses to collagen have been suggested as a cause of CrCL degradation in dogs. None of these investigations showed evidence that anticollagen type I antibodies alone initiate CrCL damage. However, in predisposed dogs a distinct anticollagen type I antibody gradient was found towards the contralateral stifle joint that eventually sustained a CrCL rupture, suggesting that there was an inflammatory process present in these joints before detectable joint instability occurred. The importance of cellular reactivity to collagen type I in cruciate disease also remains unclear. Peripheral blood mononuclear cell proliferation to collagen type I was very diverse in dogs with cruciate disease whereas some sham operated dogs and healthy dogs tested positive as well. It is not yet determined whether cellular reactivity to collagen type I exists locally in the stifle joints nor whether this could initiate CrCL degradation. Inflammatory processes within the stifle joint can alter the composition of the cruciate ligaments. In animal models of immune-mediated synovitis, the mechanical strength of the CrCL is significantly reduced. Immunohistochemical studies on synovial tissues from dogs with rheumatoid arthritis and dogs with cruciate disease revealed that the pathologic features are similar in both joint pathologies and that the differences are mainly quantitative. Joint inflammation induced by biochemical factors such as cytokines has been implied in CrCL degeneration. In several studies, the levels of pro-inflammatory and T helper cytokines were measured in dogs that sustained a CrCL rupture, but the exact role of the various cytokines in the pathogenesis of CrCL disease remains inconclusive. More recently, the levels of the cytokines have been investigated over time in predisposed dogs before and after CrCL rupture. IL-8 expression tended to be higher in stifle joints that will rupture their CrCL during the next 6 months than in those that will not, indicating an inflammatory process in these joints before clinical rupture. This review provides a comprehensive overview of all possible implications of humoral and cell-mediated immune responses published in dogs with cruciate disease together with publications from human joint diseases. Furthermore, this review highlights recent findings on cytokines and proteinases in the accompanying joint inflammation.  相似文献   

19.
OBJECTIVE: To compare synovial fluid biomarkers of cartilage metabolism in joints with naturally acquired or experimentally induced cranial cruciate ligament (CCL) rupture and determine correlations with stage and severity of disease in dogs. ANIMALS: 95 dogs with ruptured CCL, 8 dogs with experimentally ruptured CCL, and 24 healthy dogs. PROCEDURES: Synovial fluid was assayed for chondroitin sulfate neo-epitopes 3B3(-) and 7D4 and glycosaminoglycan (GAG) concentration. Results were correlated with demographic data, duration of lameness, radiographic osteoarthritis score, and intra-articular lesions. RESULTS: The 7D4 concentrations and 7D4:GAG in synovial fluid from joints with naturally acquired CCL rupture and experimental CCL transection were similar and significantly greater than values for healthy control joints. The 3B3(-) concentrations in the CCL-deficient groups were not significantly different, although only values in the naturally acquired CCL rupture group were significantly greater than those in the healthy control group. Within the naturally acquired CCL rupture group there was a significant correlation between 3B3(-) and 7D4 concentrations. However, there were no significant correlations between biomarker concentrations and continuous demographic or disease-related variables or differences in biomarker concentrations with different categories of disease. CONCLUSIONS AND CLINICAL RELEVANCE: Synovial fluid biomarker concentrations were significantly increased in joints with secondary osteoarthritis associated with naturally acquired or experimental CCL rupture; however, lack of apparently simple relationships with demographic variables or stage or severity of disease limits their clinical usefulness.  相似文献   

20.
The caudal cruciate ligament (CaCL) of one stifle joint in seven dogs was transected and a 2 to 4 mm section was removed. Six months after surgery, none of the dogs were lame. Thigh muscle circumference, stifle range of motion, and internal tibial rotation in the operated limb were not significantly different from the preoperative measurements or the contralateral, unoperated limb. A caudal drawer motion was consistently present in the stifle joints with a transected CaCL. A radiographic evaluation of the operated stifle joints did not reveal osteoarthritic changes; four of seven stifle joints had an irregular fat pad 6 months after surgery. Results of a joint fluid analysis revealed a slight increase in synovial cells within treated stifle joints; inflammatory cells were not observed. The only gross morphologic change in stifle joints with a severed ligament was enlarged knobby remnants of the CaCL. Articular cartilage defects or osteophytes were not observed. Results of a histologic examination of the CaCL remnants revealed synovial cellular capping and intraligamentous fibroplasia. Based on a limited number of dogs, it was concluded that isolated transection of the CaCL produced minimal clinical and pathologic changes in the stifle joint during a 6 month period.  相似文献   

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