[The S2k guideline: Indications for knee endoprosthesis : Evidence and consent-based indications for total knee arthroplasty]. / S2k-Leitlinie: Indikation Knieendoprothese : Evidenz- und konsensbasierte Indikationsstellung in der Knie-Endoprothetik (EKIT-Knie).

Total knee arthroplasty (TKA) is one of the most frequent surgical procedures in orthopaedic surgery. Until now there have not been any standardized indication criteria, which might contribute to the large geographical differences in the frequency of TKA. This guideline aims to consent minimal requirements (main criteria), additional important aspects (minor criteria), as well as relative and absolute contraindications for TKA. The following main criteria have been consented: knee pain, radiological confirmation of osteoarthritis or osteonecrosis, inadequate response to conservative treatment, adverse impact of knee disease on the patient's quality of life and the burden of suffering due to the knee disease. Relative contraindications have been consented as severe general disease with reduced life expectancy and a BMI ≥40; absolute contraindications are an active infection and if the patient is not able to undergo major surgery.

Artificial organs: a new option for treating osteoarthritis.

Osteoarthritis is usually regarded as a localized disease whose optimal treatment is a therapy applied directly to the affected joint. Unfortunately, current local therapies such as repeated intraarticular injections or constant infusions are associated with a higher risk of infection. One way to overcome this would be to transfer substances made locally by cells within the joint. However, attempts using direct vector transfers or intraarticular injections of ex vivo modified cells could not achieve a sustained protein secretion over several months. Another method of delivering biological factors (i.e.growth hormones) intraarticularly is to transplant an artificial organ, capable of supporting the regeneration of natural cartilage, directly into the affected joint The main difficulty of having to produce bioactive factors over a long period of time is overcome by implanting a chamber-like system filled with either genetically modified cells or a drug-releasing matrix. This drug delivery system would be located at a peripheral site of the joint and could release substances directly into the joint cavity which would be transported via the synovial fluid and/or diffused to the chondrocytes or synoviocytes.

Bone morphogenetic protein 7 (bmp-7) stimulates proteoglycan synthesis in human osteoarthritic chondrocytes in vitro.

BMP-7 is a member of the TGF-beta superfamily which is supposed to be one of the most potent anabolic factors of chondrocytes. In this study we analysed the effect of BMP-7 on three dimensional cultured chondrocytes with and without serum. Cartilage samples from fourteen patients with osteoarthritis of the knee were harvested and chondrocytes were cultivated in alginate-beads with and without serum supplementation (10% FCS). BMP-7 was added in three different concentrations (200, 600 and 1000 ng/ml). After 4 and 21 days PG concentration was determined by a Blyscan-Assay. For gene expression analysis of aggrecan (AGG) quantitative Lightcycler-PCR was used to estimate the mRNA levels. Under serumfree culture conditions there was no stimulation after 4 days but there was a twofold increase of PG concentration after 21 days. Using BMP-7 together with serum supplemented medium we found comparable results, however not as pronounced. AGG expression was increased only after 4 days but not after 21 days. Beside a stimulatory effect under serumfree conditions we also found a stimulatory effect of BMP-7 in the presence of serum. This study pronounces that BMP-7 might be a suitable anabolic activator of osteoarthritic chondrocytes.

Collagens--major component of the physiological cartilage matrix, major target of cartilage degeneration, major tool in cartilage repair.

Collagens serve important mechanical functions throughout the body and in particular in the connective tissues. Additionally, collagens exert important functions as cellular microenvironment and partly via binding and release of cellular growth mediators. In articular cartilage, fibrillar collagens are providing most of the biomechanical properties of the extracellular matrix essential for its functioning. The collagenous matrix is one main target of destructive processes in general degenerative joint disease and focal matrix lesions. The development of an adequate collagen framework represents the major aim of therapeutic cartilage repair. In this respect, collagenous matrices or collagen-imitating scaffolds are more and more emerging as highly suitable vehicles for cell and (growth) factor transport into cartilage lesion. Thus, collagens are not only major constituents of connective tissues in terms of integrity and function, they are also major targets of tissue destruction and regeneration and might become major tools to achieve tissue repair.

Clinical phenotype and molecular diagnosis of multiple epiphyseal dysplasia with relative hip sparing during childhood (EDM2).

We report on a family of 19 individuals over four generations in which 12 members are affected with a variant of multiple epiphyseal dysplasia. Beginning in childhood, the disease leads to pain and stiffness of knees, ankles, elbows and finger joints. Some adult patients repeatedly suffer from free articular bodies resulting in locking of the joint. Finally, affected individuals are prone to the development of early degenerative joint disease. Mutation screening of candidate regions revealed a novel point mutation at position -1 in the COL9A2 exon 3/intron 3 splicing region. This G --> C substitution most probably induces an alteration of the splicing process. Family screening was carried out by both automated sequencing and by digestion of amplicons with BsaWI. We confirmed the nucleotide substitution in eight clinically affected family members as well as in three presymptomatic young children. Electron microscopy showed that the diameter of collagen fibrils from arthroscopically removed free articular bodies of two patients was not obviously different from that of normal articular cartilage. Together with previous reports our results indicate that mutations leading to skipping of exon 3 within the COL3 domain of the alpha2-chain of collagen type IX may be relatively common in patients with a special subtype of multiple epiphyseal dysplasia (MED) in which the hips are not markedly affected at early age (EDM2). In these patients and their families, mutation screening of the candidate regions may help to confirm the diagnosis, lead to appropriate advice for lifestyle and well based genetic counseling.

Interactions between human osteoarthritic chondrocytes and synovial fibroblasts in co-culture.

OBJECTIVE: To imitate the in vivo joint situation and to allow cell interactions, a co-culture system of human osteoarthritic chondrocytes and synovial fibroblasts from a single joint was established and characterized with or without stimulation by IL-1 beta. METHODS: Culture settings included chondrocytes in alginate alone, synovial fibroblasts in monolayer alone and a co-culture of both. Proteoglycan (PG) synthesis was measured by 35S-incorporation, PG content by a dimethylmethylene blue assay, DNA content by a fluorometric assay, and prostaglandin-E2 and IL-1 beta release by ELISA. RESULTS: In co-culture PG synthesis by chondrocytes was significantly reduced in the presence of IL-1 beta (1 ng/ml) compared to controls. PG content of chondrocyte cultures was reduced for controls and IL-1 beta treated co-cultures. Synovial fibroblasts in co-culture did not show significant change of PG synthesis or content when compared to cells in mono-cell culture. PG release into the medium was relatively high in co-cultures. IL-1 beta significantly decreased the proliferation rate of chondrocytes in co-cultures and slightly increased prostaglandin-E2 release. CONCLUSIONS: Co-culturing of osteoarthritic chondrocytes and synovial fibroblasts from a single human joint allows interactions between both entities and may offer a useful tool to study the effects of mediators or new drugs under more in vivo like conditions compared to mono-cell cultures.

First carpometacarpal and interphalangeal osteoarthritis of the hand in patients with advanced hip or knee OA. Are there differences in the aetiology?

Differences in the aetiology of osteoarthritis (OA) of the first carpometacarpal joints (CMC-1) and the interphalangeal joints (IP) have been reported. It was the purpose of this investigation to evaluate whether isolated OA of the first carpometacarpal joints and the interphalangeal joints differs in its aetiology, considering potential risk factors such as age, gender, body mass index, occupational history, OA in the hip or knee joints, hypertension and diabetes in patients with advanced hip or knee OA. Included in this investigation were 639 patients scheduled for either hip or knee replacement because of advanced OA. As well as a standardised interview and clinical examination, bilateral radiographs of both hands were obtained. According to the presence or absence of radiographic OA, participants were categorised as having CMC-1 OA (= 1 joint) or IP OA (= 2 joints), either isolated or in combination. Odds ratios (OR) and their 95% confidence intervals (CI) for potential determinants of OA were estimated using multivariable logistic regression. Of the total number of patients, 184 had CMC-1 OA and 424 IP OA. Patients with CMC-1 OA were more likely to be female (77.2%), and to have knee OA (62.5%) and hypertension (63.0%), than patients without CMC-1 OA. No differences between CMC-1 OA and IP OA were observed for the role of age, body mass index and diabetes. Age was associated with both CMC and IP OA. Female gender was independently associated with CMC-1 OA (OR=1.79; 95% CI: 1.16-2.74) but not with IP OA. Our data suggest a possible impact of age and female gender on the aetiology of CMC-1 OA and of age on IP-OA, at least in patients with advanced hip or knee OA.

Expression of collagen type I, II, X and Ki-67 in osteochondroma compared to human growth plate cartilage.

In order to characterize the consequences for the process of endochondral ossification we performed an immunohistochemical study and compared the expression of collagen type I, II and X as markers of cartilage differentiation and Ki-67 as a marker of cell proliferation in solitary (7-26 years, n=9) and multiple (11-42 years, n=6) osteochondromas with their expression in human fetal and postnatal growth plates. In fetal and young postnatal controls, we found a thin superficial layer of articular cartilage that stained positive for collagen type I while collagen II was expressed in the rest of the cartilage and collagen type X was restricted to the hypertrophic zone. Osteochondromas from children showed lobular collagen type II-positive areas surrounded by collagen type I. In adults, the separation of collagen type I- and type II-positive areas was more blurred, or the cartilaginous cap was missing. Collagen type X was detected in a pericellular distribution pattern within hypertrophic zones but also deeper between bone trabecula. The proliferative activity of osteochondromas from children younger than 14 years of age was comparable to postnatal growth plates, whereas in cartilage from individuals older than 14 years of age, we could not detect significant proliferative activity.

[Conservative therapy of arthritis]. / Konservative Therapie der Arthrose.

Therapy of osteoarthritis requires a combination of pharmacological and non-pharmacological modalities. Management should be individualized according to the constitutional features of the patient, comorbidities, disease status, treatment availability and costs. Paracetamol is the analgesic of choice. Beside NSAIDs and intra-articular steroids, SYSADOA have symptomatic effects and may modify structure. Patient education, exercises, orthopaedic devices and physical therapy are indicated as supportive therapy. Alternative therapy modalities should be discussed with the patient using the available evidence and the cost/benefit ratio.

[Predictors of tibial head transposition in the therapy of varus knee osteoarthritis]. / Prädiktoren der Tibiakopfumstellung in der Therapie der Varusgonarthrose.

PURPOSE: The aim of this study was to find predictors for the clinical outcome in patients who underwent a high tibial osteotomy (HTO). METHOD: Between 1984 and 1996 a high tibial valgus osteotomy was performed in 155 patients with genu varum. 133 HTO patients were available for follow-up at an average postoperative time of 9.3 +/- 3.0 years. The degree of osteoarthritis was evaluated by radiological (Kellgren) and arthroscopic scoring systems (Outerbridge). Survival time of HTO was estimated using Kaplan-Meier survivorship analysis. RESULTS: The survival rate of HTO was 95 % after 5 years and 77 % after 10 years. In the medial compartment of knee joints with a preoperative Outerbridge stage III/IV or Kellgren stage III/IV the survival rate of HTO was significantly lower when compared to stages 0/I/II (p < 0.05). Age, sex, tibial malalignment and severity of osteoarthritis in the lateral compartment had no influence on survival rates. The pre-postoperative comparison of radiologically visible signs of osteoarthritis showed mainly either no (46.5 %) or only small (50.5 %) progression. We found that patients who underwent a HTO had good and very good clinical outcomes. CONCLUSION: We identified severity of preoperative radiological osteoarthritis and intraoperative chondromalacia as predictors of survival rate.

[Overview of clinical and experimental use of hyaluronic acid in gonarthrosis]. / Ubersicht über die klinische und experimentelle Anwendung der Hyaluronsäure bei Gonarthrose.

AIM: The aim of this survey is to review the clinical and experimental background for the use of hyaluronan (HA) in the therapy of gonarthrosis. MATERIALS AND METHODS: Clinical and experimental studies were analysed following a medline literature-research. To determine the clinical efficiency of HA only randomised and controlled studies were taken into account. As a result of this analysis the current knowledge for the clinical and experimental use of HA is portrayed. RESULTS: Numerous controlled, randomised studies showed beneficial effects for pain relief and joint function after i.art.injection with HA. Placebo, NSAIDs and steroids were used as control medications. The effect of HA was significantly better compared to placebo, and similar or superior in comparison to other verums (NSAIDs, steroids). After completion of HA-therapy a long lasting effect compared to steroids was shown. Review of the literature reveals side-effect rates for HA-therapy similar to those for placebos. In various experimental studies a clear working mechanism could not be identified, especially reasons for the long lasting effects are still unknown. However, some studies showed an anti-inflammatory effect in inflamed joints and in stimulated culture-conditions. A stimulating effect of the HA-production by synoviocytes after administration of HA was shown. Further studies will have to demonstrate the cellular effects in vitro and in animal models in detail. CONCLUSION: HA is therefore classified as a "symptom slow acting drug for osteoarthritis" because a "structure-modifying (chondroprotective) effect" has not been proven yet.

[Pain symptoms of osteoarthritis-aspects of etiology and therapy]. / Aktuelle Aspekte zur Atiologie und Therapie des Arthroseschmerzes.

Due to demographic changes and associated socioeconomic problems osteoarthritis is of increasing value. Simultaneously there are more and more older people who want to practice sports. Pain symptoms of osteoarthritis can be positively influenced by paracetamol and NSAR, in combination with orthopedic aids and physical therapy in early stages. Apart from these established pain-therapeutic procedures as well as first evident results of osteoarthritis modifying drugs, gene-therapy offers promising approaches that will have to be confirmed in further studies. In case of failure of conservative treatment there are several surgical options. Arthroscopic surgery mostly offers pain reduction only for a short period of time. A slower progression of osteoarthritis in the long run can only be achieved by osteotomy provided the right indication. Ultimately joint replacement exists as a reliable and successful treatment option in hip, knee and shoulder surgery.

Massive osteolysis of the pelvis, femur and sacral bone with a Gorham-Stout syndrome.

We report a case of a 49-year-old white woman with Gorham-Stout syndrome. This very rare massive osteolysis occurred in the left pelvis and included the femur and the sacral bone. Histology study revealed typical ectatic vessels covered with endothelium. The therapy of choice in this region is radiotherapy with a dose of 40 Gy. However, in our case this therapy only led to short-term pain relief and cessation of the osteolysis. Stabilization with corticospongious bone did not seem to be effective against the progressing osteolysis.

[The Knee Injury and Osteoarthritis Outcome Score--a multifunctional questionnaire to measure outcome in knee arthroplasty]. / Der Knee Injury and Osteoarthritis Outcome Score--ein Funktionsfragebogen zur Outcome-Messung in der Knieendoprothetik.

AIM: It was the purpose of this investigation to create a German version of the Knee Injury and Osteoarthritis Outcome Score (KOOS) and to test its appropriateness in patients with advanced gonarthritis. METHOD: Reliability (test-retest reliability, internal consistency), validity (convergent construct validity and divergent construct validity), sensitivity to change as well as practicability and acceptance of this questionnaire were tested in 90 patients. RESULTS: The test-retest reliability was acceptably high for all subscales, it ranged between r = 0.65 and 0.78 and the questionnaire showed a high internal consistency in almost all of the subscales. The comparison to the results of the questionnaire "Short Form-12" (SF-12) as well as to the patients self-assessment of health status showed high concordance in nearly all subscales, however it was only moderate for the symptom scale. Furthermore the KOOS was able to show significant differences between patients and healthy controls. When testing the sensitivity to change, the KOOS could demonstrate significant improvements within 3 months and the instrument has shown to be practicable with a high acceptance by the patients. CONCLUSION: With the German version of the Knee Injury and Osteoarthritis Outcome Score a multidimensional instrument is available now to measure health status as well as therapeutic effects in patients with knee problems. Modifying the subscale "symptoms" could further optimize this questionnaire in patients with advanced gonarthritis.

[Outcome predictors of intertrochanteric osteotomy in avascular necrosis of the hip]. / Prädiktoren des Behandlungsverlaufes nach Umstellungsosteotomie bei Hüftkopfnekrose.

PURPOSE OF THE STUDY: To find radiographic predictors for the clinical outcome in patients who underwent an intertrochanteric osteotomy (ITO) because of avascular necrosis of the femoral head (AVN). METHOD: Between 1985 and 1996 in 93 patients with an AVN (mean age 39,5 years +/- 8.8 y.) an ITO was performed. 83 patients (89 %) were available for follow up at an average post-op time of 84 months +/- 40.7 mon. We used the Ficat and ARCO classifications for staging of the disease. The combined necrotic angle of Kerboul was used to measure the size of the lesion. The clinical outcome was estimated using the Harrisp hip score (HHS) and the WOMAC. Survival time of the ITO was estimated using Kaplan-Meier survivorship analysis with the implantation of a hip prosthesis as endpoint. RESULTS: 27 patients (30.8 %) underwent an arthroplasty after an average time of 35.1 mon. +/- 30,4 mon. after the osteotomy. Survival rate of an ITO was 67 % after 5 y, and 46 % after 10 y. In case of a preoperative Kerboul angle > 200 degrees the survival rate of an ITO was significantly lower and the WOMAC index (3.1 +/- 2.4) significantly worse (p < 0.05) than in patients with a Kerboul angle < 200 degrees (1,8 +/- 1.8). In Ficat stage III/IV or ARCO stage IVVI the survival rate of an ITO was significantly lower when compared to stages I/II and IIII. There was no clinical difference in the HHS comparing different stages. CONCLUSION: The Kerboul angle was the best parameter to predict the clinical outcome and the survival rate of an ITO. The classifications of Ficat and ARCO were found to be a predictor for the survival rate of an ITO but not for the clinical outcome.

[Review and comparison of culture-techniques for articular chondrocytes]. / Vergleichender Uberblick über Verfahren zur Kultivierung artikulärer Chondrozyten.

AIM: In-vitro techniques for articular chondrocytes allow the analysis of their metabolism in the presence and absence of mediators or drugs against osteoarthritis or rheumatoid arthritis, as well as the synthesis of de-novo cartilage tissue for implantation into articular defects in vivo. This review aims to give an overview about the basics of different methods of cultivation of articular chondrocytes and about several specific demands (e.g., phenotypical stability with synthesis of aggrecan and type-II collagen, no cell-to-cell contact, low proliferation rates, low matrix molecule turn-over) to such methods. METHOD: Current techniques for the cultivation of articular chondrocytes and their development were identified via "medline". Their evaluation was based on our own experience and on data from the literature. RESULTS: Two- and three-dimensional culture systems are employed to maintain articular chondrocytes in vitro. Two-dimensional cultures (monolayer) support the proliferation of articular chondrocytes, but lead to a de-differentiation to fibroblast-like cells. Three-dimensional set-ups (e.g., organ, alginate, agarose cultures) not only maintain the articular cartilage phenotype, but they also support the re-differentiation of de-differentiated chondrocytes. CONCLUSION: The choice of a culture system for in-vitro studies with articular chondrocytes should be adapted to the question asked.

Interleukin-1beta induces different gene expression of stromelysin, aggrecan and tumor-necrosis-factor-stimulated gene 6 in human osteoarthritic chondrocytes in vitro.

OBJECTIVE: To analyze the gene expression of osteoarthritic chondrocytes cultured in alginate after stimulation with interleukin (IL)-1beta. METHODS: Chondrocytes were isolated from osteoarthritic cartilage obtained during total knee replacement by sequential enzymatic digestion. After suspension in alginate, cells were cultured with and without 100 pg/ml IL-1beta. Quantitative RT-PCR reaction was used to estimate the messenger RNA (mRNA) of three different metabolites [tumor-necrosis-factor-stimulated gene 6 (TSG-6), stromelysin-1 (MMP-3) and aggrecan (AGG)]. RESULTS: After having shown the precision of quantitative PCR, this method allowed us to detect IL-1beta-induced changes in mRNA of TSG-6, MMP-3 and AGG. MMP-3 was found to be the most abundant transcript, IL-1beta induced a 12-fold upregulation of MMP-3 levels compared to control, and 7-fold of TSG-6. The AGG transcript level, indicating anabolic events, was found to be downregulated by between 2- and 3-fold. CONCLUSIONS: In our culture system, the response of osteoarthritic chondrocytes to IL-1beta is preserved. Therefore, this system might be helpful for further investigation of the influences of drugs, cytokines and growth factors, for example, on the metabolism of chondrocytes at the level of gene transcription as the most basic level of regulation.

Hysterectomy and patterns of osteoarthritis. The Ulm Osteoarthritis Study.

OBJECTIVE: To determine the association between hysterectomy (HE) and patterns of osteoarthritis (OA) METHODS: We performed a large cross-sectional study including 504 female patients admitted for arthroplasty of knee or hip joint. Patients with OA were categorized as having bilateral or generalized OA (GOA) according to the presence of radiographic OA in the contralateral or different finger joints. Odds ratios (OR) and their 95% confidence intervals (CI) for the association between HE and OA patterns were estimated adjusting for potential confounders. RESULTS: Hysterectomy (HE) was reported by 24.9 percent of the patients. Bilateral OA was present in 86.2 percent and GOA was present in 33.3 percent of the patients. HE was not associated with bilateral OA (adjusted OR=0.9; 95% CI: 0.5-1.8) but with a lower prevalence of GOA (adjusted OR=0.6; CI: 0.3-0.99). CONCLUSION: In contrast to earlier studies our results suggest that HE might be a marker for a reduced risk for a generalized pattern of OA.

Lipofection of rabbit chondrocytes and long lasting expression of a lacZ reporter system in alginate beads.

OBJECTIVE: Our aim was to investigate the maintenance of the transfection status of non-viral transfected chondrocytes in an alginate culture system. DESIGN: Chondrocytes harvested from rabbit knees were isolated by sequential digestion and cultivated in monolayer culture. At 60-70% cell density, chondrocytes were transfected with different transfection systems (FuGENE6, CaCl2, Lipofectin). A lac Z expression vector (pcDNA 3.1/Myc-His+ lacZ) was used as a reporter system. In order to improve transfection rates, hyaluronidase (4 U/ml) was used prior and during the transfection procedure. Thereafter, transfected cells were either kept in monolayer culture or embedded in alginate beads and kept in culture for up to the next 30 weeks. RESULTS: Transfection efficiency was maximal using FuGENE6TM/DNA at a ratio of 3:2 and hyaluronidase (4 U/ml). Transfection efficiency reached up to 40.8% (+/- 3.2%) after 36 h. In alginate beads lac Z positive cells declined to 8.5% +/- 3.3% after 4 weeks and to 4.6% +/- 3.2% after 12 weeks of culturing. After 30 weeks 3% of chondrocytes still expressed lac Z. In contrast, during culturing in monolayer, no lac Z expression was detectable after 4 weeks. Differentiation status of the chondrocytes was confirmed by histology and immunohistochemistry methods. CONCLUSIONS: After successful gene transfer to rabbit chondrocytes the alginate system made it possible to culture lipofected chondrocytes phenotypically stable. Genetically engineered chondrocytes express the lac Z reporter gene over a period of at least 30 weeks. This transfection and culture system provides a promising tool to further investigate the over-expression of growth factors and enzyme inhibitors.