OA Changes Research Articles

A41 EPHB4 RECEPTOR ACTIVATION BY ITS SPECIFIC LIGAND EPHRIN B2 INDUCED A REDUCED REMODELING PROCESS IN HUMAN SUBCHONDRAL BONE OSTEOBLASTS

molecular chaperone activity (clusterin). Interestingly, other proteomic studies have identified clusterin and CILP-1 as being upregulated in early human OA. These biomarkers may be involved in early repair responses in cartilage and thus may be useful for the detection of early changes in OA. Acknowledgements: This work was supported by the BBSRC (BBS/S/M/2006/13141) and the WALTHAM Centre for Pet Nutrition.

Osteochondriitis Dissecans of the Talus – Autologous Chondrocytes Transplantation or Drilling? (SS-73)

The study has been focused on comparing of both methods in the treatment of OD of the talus - autologous chondrocytes transplantation (ACI) or drilling (microfracturing). Two groups of patients were treated randomisly by ACI (Group A – 7 pts) or by drilling (Group B – 10 pts). Clinical pre-, intra- and postoperative evaluation included Anderson, Berndt and Harty, Mazur and Weber scores for the evaluation. MRI examination in all cases was evaluated pre- and postoperatively in 2w, 2m, 6m and 1 to 3 yrs intervals. The surgical procedure sustained either from drilling or from two-steps procedure: harvesting of the full cartilage sample from the edge ot the talar dome followed by the autologous chondrograft transplantation after the 28 to 42 days cultivation. 7 to 10 pts were compared, among them 2 to 3 children in 2003-2006. The age range was 10 to 47 years, the mean age was 28.7 years, in children 16.2 years resp. The follow-up period in ranges from 12 to 36 months with the average of 22.4 months. Clinical results according to all scores improved significantly comparing both preop and postop at least 1 year f-u status in both groups. MRI evaluation showed a good integration of ACI in the Group A. MRI ingrowth of ACI in the Group A supports this method′s advantage against the drilling from the point of view of future OA changes.

Landscape‐scale variability of acidity and dissolved organic carbon during spring flood in a boreal stream network

Acidity is well known to influence stream biota, but the less well‐studied spatial and temporal distributions of acidity are likely to play a larger ecological role than average values. We present data on spatial variability of chemical parameters contributing to acidity during winter baseflow and spring flood periods in Krycklan, a fourth‐order boreal stream network in northern Sweden. Fifteen stream sites were monitored in subcatchments spanning 3 orders of magnitude in size and representing a wide range of percent wetland. At baseflow, pH ranged from 3.9 to 6.5 at the different sites. Baseflow dissolved organic carbon (DOC) concentration varied by an order of magnitude and was positively correlated with subcatchment percent wetland, resulting in high spatial variability in dissociated organic acids (OA−). During spring flood, DOC and OA− increased in forested sites and decreased in wetland sites, resulting in reduced spatial variability in their concentrations. In contrast, base cations and strong acid anions diluted throughout the stream network, resulting in decreased acid neutralizing capacity (ANC) at all sites. The spatial variability of base cations increased slightly with high flow. As a result of the changes in OA− and ANC, pH dropped at all but the most acidic site, giving a slightly narrowed pH range during spring flood (4.2–6.1). The transition from winter to spring flood stream chemistry could largely be explained by: (1) a shift from mineral to upper riparian organic soil flow paths in forested catchments and (2) dilution of peat water with snowmelt in wetland catchments.

TAK1 downregulation reduces IL-1β induced expression of MMP13, MMP1 and TNF-alpha

The paper provides evidence that transforming growth factor-beta activated kinase 1 (TAK1, MEKK7), a downstream mediator of IL-1β signal transduction, plays an important role in the regulation of catabolic events and inflammatory processes in the context of degenerative joint diseases. We investigated the expression of TAK1 in human articular chondrocytes and in the murine growth plate by cDNA array, quantitative RT-PCR and immunohistochemistry, respectively. The human chondrosarcoma cell line SW1353 was stimulated with the proinflammatory cytokine IL-1β. The subsequent expression of proteolytic enzymes and proinflammatory cytokines was quantified. TAK1 specific siRNA was used to study the influence of TAK1 downregulation on the expression of MMP-13, MMP1 and TNF-α. As a result we demonstrated the expression of TAK1 in normal and osteoarthritic human articular cartilage. Expression of TAK1 in the hypertrophic zone of the growth plate gave us a first evidence for a catabolic function of TAK1 concerning cartilage metabolism. By gene suppression with RNAi technology we could show that TAK1 downregulation leads to a 60–70% reduced release of TNF-α, a 40–50% reduced release of MMP13, and a 20–30% reduction of MMP1 release. As TNF-α is a main player in inflammatory processes, and MMP13 is one of the major proteases involved in cartilage degradation, our results suggests that TAK1 has an important regulatory role in the context of degenerative joint diseases and thus is an attractive drug target in attempts to reduce inflammation and suppress structural changes in OA induced by IL-1β.

Early and stable upregulation of collagen type II, collagen type I and YKL40 expression levels in cartilage during early experimental osteoarthritis occurs independent of joint location and histological grading

While morphologic and biochemical aspects of degenerative joint disease (osteoarthritis [OA]) have been elucidated by numerous studies, the molecular mechanisms underlying the progressive loss of articular cartilage during OA development remain largely unknown. The main focus of the present study was to gain more insight into molecular changes during the very early stages of mechanically induced cartilage degeneration and to relate molecular alterations to histological changes at distinct localizations of the joint. Studies on human articular cartilage are hampered by the difficulty of obtaining normal tissue and early-stage OA tissue, and they allow no progressive follow-up. An experimental OA model in dogs with a slow natural history of OA (Pond–Nuki model) was therefore chosen. Anterior cruciate ligament transection (ACLT) was performed on 24 skeletally mature dogs to induce joint instability resulting in OA. Samples were taken from different joint areas after 6, 12, 24 and 48 weeks, and gene expression levels of common cartilage molecules were quantified in relation to the histological grading (modified Mankin score) of adjacent tissue. Histological changes reflected early progressive degenerative OA. Soon after ACLT, chondrocytes responded to the altered mechanical conditions by significant and stable elevation of collagen type II, collagen type I and YKL40 expression, which persisted throughout the study. In contrast to the mild to moderate histological alterations, these molecular changes were not progressive and were independent of the joint localization (tibia, femur, lateral, medial) and the extent of matrix degeneration. MMP13 remained unaltered until 24 weeks, and aggrecan and tenascinC remained unaltered until 48 weeks after ACLT. These findings indicate that elevated collagen type II, collagen type I and YKL40 mRNA expression levels are early and sensitive measures of ACLT-induced joint instability independent of a certain grade of morphological cartilage degeneration. A second phase of molecular changes in OA may begin around 48 weeks after ACLT with altered expression of further genes, such as MMP13, aggrecan and tenascin. Molecular changes observed in the present study suggest that dog cartilage responds to degenerative conditions by regulating the same genes in a similar direction as that observed for chondrocytes in late human OA.

Nonoperatively managed stage 5 osteochondral talar lesions.

Thirty-five ankles in 34 subjects with non-surgically managed stage 5 (chronic) osteochondral lesions of the talus (OLT) were reassessed an average of 38 months post diagnosis--88 months post symptom onset. The overall clinical result was rated good or excellent in 54%, fair in 17% and poor in 29%. Six patients opted for surgery--arthroscopic drilling--after a trial of one year of nonsurgical treatment and were therefore rated as poor. Tomogram or CT scans at the time of diagnosis and follow-up were compared in 25 patients. We found no significant change in lesion size and there was a poor correlation between change in lesion size and clinical outcome. X-rays performed at follow-up on 20 patients showed mild degenerative changes in 13 of 20 ankles with OLT. No correlation was found between the presence of degenerative changes and the clinical outcome. We conclude that: 1. Non-surgical management of stage 5 OLT is a viable option with little or no risk of developing significant osteoarthritis. 2. Most lesions remain radiographically stable. 3. There is a poor correlation between changes in lesion size and clinical outcome. However, the few patients with lesions which decrease significantly in size tend to do well and those with lesions which increase significantly in size do poorly. 4. The development of mild radiographic changes of OA does not correlate with clinical outcome. 5. The general course of stage 5 OLT is benign with over half of the patients improving to good or excellent results with non-surgical management. 6. Lateral lesions tend to do better than medial ones. 7. Adult onset lesions tend to do better than juvenile onset lesions.

Quantitative imaging of the structural changes of osteoarthritis: an exciting challenge for the new millennium.

The progression of structural changes, including cartilage degradation in knee OA, over time is an extremely important parameter that must not be overlooked in the study of therapeutic interventions for this disease. Existing radiologic methods used to evaluate the disease progression are useful and allow for several clinical trials to take place. However, these methods are imperfect and time consuming. A faster and more accurate method to evaluate the efficacy of various medications on the progression of OA is required. Current tools lack sensitivity to change over short periods of observation (plain and standardized radiographs) or are invasive (arthroscopy). Due to its greater sensitivity to change, evaluation by MRI is promising and appears to surpass the other available technologies in measuring the structural changes of knee OA, including the gradual loss of cartilage. The development of the new software tool will allow for the MRI technology to provide quantitative measurement, and the evaluation of the efficacy of new therapeutic interventions in a more accurate and rapid fashion, dramatically changing the way knee OA clinical trials are conducted. Studies will be performed in a time-wise fashion, allowing for the testing of a larger number of molecules having the potential to retard or stop progression of the disease.

Synovial fluid markers of osteoarthritis in dogs.

Although none of these markers currently have any clinical applications, researchers have made strong advances in understanding molecular markers of OA and remain optimistic that the goal of identifying clinically useful markers of OA is attainable.(3-6,8,9) Much of this positive sentiment arises from the large array of molecules that have been identified.(8) Molecular markers of the greatest potential clinical use will be those that allow early detection of OA, permit disease progression to be monitored, or allow efficacy of various treatment regimens to be assessed. Earlier and more sensitive detection of OA changes may increase effective opportunities for treatment intervention during reversible phases of the OA disease process and allow more objective assessment of treatment efficacy and prognosis.(6)

Ｇｌａｓ法による足関節外側々副靭帯損傷の治療経験

We followed up on 7 cases of ruptures of the lateral ligament of the ankle joint treated by Glas' procedure.Clinically, the results of the Seligson's scale were excellent except for 2 cases with OA changes in the pre-operative period.Radio logically, the mean of the talar-tilt-angle improved from 14.6° to 3.4° in the post-operative period, and no ossification of the periosteum was seenin all cases.

Markers of cartilage and synovial metabolism in joint fluid and serum of patients with chondromalacia of the patella

Objective: To further our understanding of the pathogenesis of chondromalacia of the patella (CM), we have studied the release into knee joint fluid and serum, obtained from patients with CM, of molecules associated with the metabolism of joint cartilage matrix and synovium.Methods: Interleukin-1 α (IL-1α), interleukin-1 β (IL-1β), interleukin-6 (IL-6), stromelysin-1 (MMP-3), interstitial collagenase (MMP-1), tissues inhibitor for metalloproteinases-1 (TIMP-1), phospholipase activity A2(PLA2), hyaluronan (HA), aggrecan fragments (AGN) and antigenic keratan sulfate (KS) were quantified in knee joint lavage fluid from 96 patients with CM; KS and HA also was measured in serum. Chondromalacia was graded on a scale of I to IV according to Outerbridge (1961). The histopathology of the synovial membrane close to the patellofemoral joint was evaluated. Control samples were obtained from nine patients with knee pain presenting with arthroscopically normal knee joints.Results: The concentrations of MMP-3, MMP-1 and TIMP-1 proteins in joint lavage fluid were increased in advanced (grade IV) CM, compared with controls. Levels of MMP-1 in lavage fluid correlated with the severity of CM (r=0.38,P<0.01) and MMP-1 and MMP-3 concentrations correlated with each other (r=0.45,P<0.001). TIMP-1 was elevated in grade IV CM compared with grades II and III CM (P<0.02,P<0.01). Interleukins (IL-1α, IL-1β and IL-6) showed no significant change in CM. The lavage fluid level of PLA2increased with the severity of CM (r=0.40,P<0.001). Serum KS was higher in CM IV than in controls (P=0.05), while lavage fluid KS concentration was elevated in CM I (P=0.04). There were no differences in the lavage fluid levels of AGN and HA between the different study groups. Synovium showed slight or moderate histological signs of inflammation in 9% of CM patients.Conclusion: The changes in the release and activity of these marker molecules from serum and synovial fluid may reflect changes in the metabolism of articular cartilage and synovium in CM, that are consistent with those observed in early-stage tibiofemoral cartilage changes in OA.

(i) Molecular mechanisms underlying auto-destruction of cartilage in osteoarthritis

Cartilage changes in OA consist of a slowly progressive loss of PG, increased water content, and no alteration in collagen content but a probably bigger significant change in the arrangement and the size of collagen fibers. In the normal joint, there exists a fine balance between the ongoing processes of degradation and repair. In this article, the pathogenesis of OA is viewed as a disruption of this ‘steady-state’ balance, particularly focusing on MMP-3 and TIMP-1 balance. This imbalance could be created by a variety of cytokines and growth factors which may play an important role in mediating cartilage destruction in OA. However, some of these factors are capable of mediating both stimulatory and inhibitory effects and in vivo function of these cytokines has not been clearly elucidated. Furthermore, specific inhibitors of IL-1 and TNFa exist, which, if also released from chondrocytes, may antagonize the pro-inflammatory effects of these cytokines. Thus, various cytokines produced by the chondrocyte itself are interrelated and form a complex cytokine network. We believe that expanded research in this field may result in a significantly increased understanding of the pathophysiologic processes occurring in OA. These mechanisms are probably multifaceted, but is hoped that careful analysis to interlink and relate the various components of these speculations will lead to the development of more specific and effective therapeutic agents.

Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler (P-MDI)

OBJECTIVE: To determine whether the previously noted low prevalence of knee pain (KP) and lumbar pain (LP) in rural southern China compared with the high prevalence observed in North China was also true in a southern urban population. METHODS: A population based sample of 2040 adults &gt; or = 16 years of age was studied in Chenghai City, close to the rural area previously studied on the southeast coast of China. Primary healthcare workers administered the COPCORD Phase I and II questionnaires. Those with rheumatic symptoms were recalled for medical examination, with a response rate at examination (phase III) of 98.4%. Those suspected of having arthritis had radiographs and laboratory tests. Prevalences were age and sex adjusted to the total of populations previously reported. RESULTS: (1) The prevalence for all rheumatic symptoms at phase III was 18.1%. Of the 7.5% with KP, 55% had osteoarthritic changes on radiograph (KOA) compared with 29% of a sample with no KP (p &lt; 0.001). Of the 11.5% with LP, 69% had degenerative changes on lumbar spine radiograph (LOA). (2) Of residents in single-level houses the prevalence was 5.6% for KP and 7.9% for LP, whereas in 4 to 6-level apartment buildings these rates were significantly higher, 9.1% and 16.2%, respectively. All these pain rates were significantly lower than noted in rural North China. The prevalence of pain together with radiographic OA changes in the knee (KOA) was half the rate in single-floor residents (2.7%) compared to apartment residents (5.3%), as was lumbar spine degenerative disease (5.3% vs 11.5%). CONCLUSION: The prevalence of knee and lumbar spine pain in this southern urban sample was confirmed to be much lower than in the rural sample in the North, although higher than in the rural sample in the South. Comparing COPCORD studies of Han Chinese in Shanghai and Malaysia there was a decrease in prevalence of knee and back pain with latitude, suggesting an association with climate. Knee and back pain and radiological degenerative changes in the knee and lumbar spine were twice as prevalent in apartment residents than in those living in older single-level houses. Further study is needed to explain these observations.

Repair process of surgically produced supraspinatus tendon tear

REPAIR PROCESS OF SURGICALLY PRODUCED SUPRASPINATUS TENDON TEAR dun Kumagai, Hirotaka Sano, Hinoru Sakurai, Takashi Sawai% K i r i t i Sarkar ~ and Hans K.Uhthoff ~ Dept .of Orthop. Surg.and *Pathology, Tohoku Univ. and *~Univ. o f Ottawa This study was undertaken to f ind out the c e l l s c o n t r i b u t i n g to the repa i r of the supraspinatus tendon and col lagen types dur ing the process. A t ransverse i nc i s i on was made on the supraspinatus tendon on 37 adu l t female r a b b i t s . The animals were euthanized at 4 days, I , 2, 4 and 8 weeks. Besides the rou t ine s t a i n ings, immunostainings of col lagens ( type I and I I I ) and p r o l i f e r a t i n g ce l l nuclear ant igen (PCNA) were performed. At 4 days and 1 week a f t e r surgery, the stumps were covered only p a r t l y by p r o l i f e r a t i n g c e l l s coming most ly from both bursal s ides. At 2 weeks, the gap was not recognizable macroscop ica l ly . I t was br idged at 4 weeks and uni ted complete ly at 8 weeks. From the ea r l y stage, type I l l co l lagen was p o s i t i v e , wh i le type I appeared c l e a r l y a f t e r 2 weeks. PCNA were p o s i t i v e in the p r o l i f e r a t i n g c e l l s from bursal and a r t i c u l a r s ides, espec ia l l y around the vessels. This study shows tha t the c o n t r i b u t i n g ce l l s are coming mainly from the bursal side and tha t two types of co l lagen appear at the d i f f e r e n t per iod a f t e r the i n j u r i e s . COMPARISON WITH MODIFIED DEWAR'S PROCEDURE AND PERCUTANEOUS PINNING FOR COMPLETE DISLOCATION OF THE ACROMIOCLAVICULAR JOINT. K. Yamaguchi, H. Hanamura, H. Maeda, & N. Yasuhara. Kasugai Orthopedic Hospital, K. Ida. Nagoya University School of Allied Health Sciences Since 1982 we performed modified Dewar's procedure (D method) for complete dislocation of the acromioclavicular (A-C) joint in 18 cases, but since 1988 changed method into percutaneous pinning (P method) and treated 27 cases, In this study, we compared the results of two methods. We evaluated 13 patients (9 males and 4 females) in D method and 17 patients (16 males and 1 female) in P method. The average age was 34.1 years (D ~fiethod) , and 30.3 years (P method) . The average postoperative observation period was 8 years and 9 months (D method) , 2 years and 7 months (P method) . In the modified Dewar's procedure, we added temporary fixation of the A-C joint using Kirschner wire. In the percutaneous pinning, we fixed the A-C joint with two Kirschner wires, one of them was not passed through the A-C joint avoiding osteoarthritic change. According to Kawabe's score, D method was 92.3 points, f 3 method was 95.8 points in average. In Xray findings, subluxation were observed in 6 cases (46.2% D method) , and in 9 cases (52.9% P method) . OA change of the acromioclavicular joint were observed in 10 cases (76.9% D method) , and in 3 cases (17.6% P method) . The clinical results of P method were as good as thoses of D method. Therefore, we think percutaneous pinning is one of the useful methods for fresh dislocation of the acromioclavicular joint.

Studies of the articular cartilage proteoglycan aggrecan in health and osteoarthritis. Evidence for molecular heterogeneity and extensive molecular changes in disease.

Changes in the structure of the proteoglycan aggrecan (PG) of articular cartilage were determined immunochemically by RIA and gel chromatography and related to cartilage degeneration documented histologically by the Mankin grading system. Monoclonal antibodies to glycosaminoglycan epitopes were used. In all cartilages, three chondroitin sulfate (CS)-rich populations of large size were observed in addition to a smaller keratan sulfate (KS)-rich population. In grades 7-13 OA cartilages (phase II), molecules were significantly larger than the equivalent molecules of grades 2-6 (phase I). CS chain lengths remained unchanged. In most OA cartilages, a CS epitope 846 was elevated in content, this being most marked in phase II (mean: fivefold). Loss of uronic acid, KS, and hyaluronic acid were only pronounced in phase II OA because of variations in normal contents. Aggregation of PG was unchanged (50-60%) or reduced in OA cartilages, but molecules bearing epitope 846 exhibited almost complete aggregation in normal cartilages. This study provides evidence for the capacity of OA cartilage to synthesize new aggrecan molecules to replace those damaged and lost by disease-related changes. It also defines two phases of PG change in OA: an early predominantly degenerate phase I followed by a net reparative phase II accompanied by net loss of these molecules.

Epidemiologic associations of pain in osteoarthritis of the knee: Data from the national health and nutrition examination survey and the national health and nutrition examination-i epidemiologic follow-up survey

0 STEOARTHRITIS (OA) is the most common joint disorderlm3; however, it is clear from numerous population studies that many persons with radiographic changes of OA have no symptoms or resulting disability.4-7 In 1981, Kelsey suggested that although “physical reasons must exist which explain this anomaly, . . . evidence [exists] that illness behavior also plays a role.“’ At the same conference, Kuller also commented on the occurrence of asymptomatic radiographic OA and noted that the study of factors linking disease with symptoms and disability was an important aspect that merited further study.9 He suggested that although “a simple relationship [might exist] between the severity of the joint disease and symptomatology, it is more likely that the behavioral characteristics of the individual and the type of activity engaged in are important determinants of the symptomatology and disability associated with the pathology.“’ The availability of national arthritis data, specifically the National Health and Nutrition Examination Survey (NHANES-I)7 and the Na-

ＯＡしつに対する足底そう板の使用経験 重回帰分析による検討

The shoe insert for the treatment of the osteoarthritic knee was made on an experimental basis. Its result was good and reduction of pain was 74.3%. Moreover, the roentgenograms, the functional evaluation of the knee joint and grade of satisfaction in patient were employed as parameter, and the multiple regression analysis was performed using a computer, and then, the range of the indication was determined.—Our results showed that the medial joint space was a most important factor followed by the score of functional evaluation of the knee joint, and varus deformity was not an expectant factor.The indication of the shoe insert was concluded as follows.1. Width of medial joint space is over 2mm, 2. Score of functional evaluation of the knee is over 50 point, 3. OA change of knee joint is not severe.

Osteoarthritic Changes of the Knee in Hemiplegic Patients

The patients with hemiplegia were investigated if they have some trouble in their knees or not. Of twenty-eight hemiplegic in-patients, ten (35%) had painful knee, nineteen (67%) had osteoarthritic changes at involed side. Osteoporotic changes were seen in most patients. OA changes were seen with greater frequency in patients with duration of seven months or more than those of six months or less. And those changes were seen more frequently in wheelchair group than in ambulatory one. OA changes were not related with spasticity or sensory disturbance. (p>0.05). Discussion was made about these findings.

Late Results After Meniscectomy

To know some problem after meniscectomy, we undertake long-term study. There were 13 male and 6 female, age range at operation was from 10 to 49 years. The range of post-operative follow-up was from 10 to 15 years and average was 12.7 years.1) Thirteen patients had excellent or good results. Five patients undergone discoid meniscectomy in their youth had all good results.2) Roentogenographic changes noted in all cases, but no related with clinical results.3) Severe OA changes was seen in 10 patients. (53%)4) Degree of ligamentous instability was related with OA changes.5) Two patients of poor result was seen retained posterior horn.