Géza Pap

Development of Osteoarthritis in the Knee Joints of Wistar Rats After Strenuous Running Exercise in a Running Wheel by Intracranial Self-Stimulation

The influence of excessive running load on the development of knee osteoarthritis (OA) was investigated in male Wistar rats. Running exercises were performed in a running wheel using intracranial self-stimulation to motivate Wistar rats to run daily distances of 500 m at 5 days/week. Hereby, ten rats ran a distance of 15 km within three weeks while a further ten rats run a total of 30 km within six weeks. Thirteen Wistar rats without running exercises served as controls. Complete knee joint sections of all rats were evaluated histologically using MANKINs grading system with categorization of the findings into non, mild moderate, and severe osteoarthritis. In addition, immunoreactivity of the chondrocytes to MMP-3 as an important cartilage degrading enzyme in OA was assessed by immunostaining with monoclonal MMP-3 IgG antibodies. Histological assessment of the knee joint sections revealed a significant increase in osteoarthritic changes with higher running load. While in rats with 15 km running all but two knee joints showed mild OA, moderate OA was the predominant finding in rats with 30 km running. In contrast, no OA was found in the controls. Immunostaining for MMP-3 revealed a significant increase in immunoreactivity of the chondrocytes to MMP-3 with higher running load, indicating a running load-depending production of this cartilage-degrading enzyme in the course of increasing OA. Compared to 47.4% immunoreactive chondrocytes to MMP-3 in the controls, this ratio rose to 70.4% in rats with 15 km running and even up to 89.9% in rats with 30 km running. In conclusion, in Wistar rats, excessive running load leads to marked, running distance-depending osteoarthritic changes which are caused, at least in part, by an increase in MMP-3 production rising with greater running distance. Within this exercise model of OA, intracranial self-stimulation is an effective method to motivate Wistar rats to extremely excessive running in a running wheel. This model offers a wide range of further approaches to studying different processes of the development of OA.

Strength and motion after hemiarthroplasty in displaced four-fragment fracture of the proximal humerus: 27 patients followed for 1-6 years.

We evaluated 27 patients with shoulder hemiarthroplasty after displaced four-fragment fracture of the proximal humerus after mean 4 (1-6) years. Isometric strength measurements (Kintrex) and threedimensional motion analysis (Elite-System) were performed on the operated and unoperated shoulders. Clinical assessment was based on Constants score and Neers scoring system. The isometric strength of the operated and unoperated sides were 22 (SD 8.6) Nm and 24 (SD 5.9) Nm in abduction and 48 (SD 14) Nm and 65 (SD 21) Nm, respectively in adduction (the latter was statistically significant). Motion analyses at follow-up showed a mean reduction in glenohumeral movement. Increases in acceleration and deceleration of the acromion at the operated side were noted, indicating a change in glenohumeral rhythm during maximal abduction. The Constant score was 45 (SD 15) points with a significant reduction in the range of motion. 15 patients had some degree of heterotopic ossification. On the basis of our findings, the impaired function seems to be caused by reduced glenohumeral mobility rather than muscle strength. We also found a better outcome after early than late hemiarthroplasty.

Strength and voluntary activation of the quadriceps femoris muscle at different severities of osteoarthritic knee joint damage

Objective: Improvements of quadriceps motor deficits represent a major therapeutical target in knee osteoarthritis (OA). In the present study, we investigated changes in quadriceps function at different stages of osteoarthritic cartilage damage.

Gene Transfer of Tissue Inhibitor of Metalloproteinases-3 Reverses the Inhibitory Effects of TNF-α on Fas-Induced Apoptosis in Rheumatoid Arthritis Synovial Fibroblasts

Apart from counteracting matrix metalloproteinases, tissue inhibitor of metalloproteinases-3 (TIMP-3) has proapoptotic properties. These features have been attributed to the inhibition of metalloproteinases involved in the shedding of cell surface receptors such as the TNFR. However, little is known about effects of TIMP-3 in cells that are not susceptible to apoptosis by TNF-α. In this study, we report that gene transfer of TIMP-3 into human rheumatoid arthritis synovial fibroblasts and MRC-5 human fetal lung fibroblasts facilitates apoptosis and completely reverses the apoptosis-inhibiting effects of TNF-α. Although TNF-α inhibits Fas/CD95-induced apoptosis in untransfected and mock-transfected cells, fibroblasts ectopically expressing TIMP-3 are sensitized most strongly to Fas/CD95-mediated cell death by TNF-α. Neither synthetic MMP inhibitors nor glycosylated bioactive TIMP-3 are able to achieve these effects. Gene transfer of TIMP-3 inhibits the TNF-α-induced activation of NF-κB in rheumatoid arthritis synovial fibroblasts and reduces the up-regulation of soluble Fas/CD95 by TNF-α, but has no effects on the cell surface expression of Fas. Collectively, our data demonstrate that intracellularly produced TIMP-3 not only induces apoptosis, but also modulates the apoptosis-inhibiting effects of TNF-α in human rheumatoid arthritis synovial fibroblast-like cells. Thus, our findings may stimulate further studies on the therapeutic potential of gene transfer strategies with TIMP-3.

Evaluation of quadriceps strength and voluntary activation after unicompartmental arthroplasty for medial osteoarthritis of the knee

Introduction: In early and moderate stages of osteoarthritis (OA) of the knee, arthrogenous muscle inhibition (AMI) is an important factor for the initiation and the progression of the disease. Although AMI has been shown to be reduced after physiotherapeutical exercises resulting in significant improvements in disability, implantation of unicondylar knee arthroplasties is much provided in these stages of OA. Therefore, in the present study we investigate changes in quadriceps muscle after implantation of such prostheses as compared to physiotherapeutical treatment, alone.

Osteoclast-independent bone resorption by fibroblast-like cells.

To date, mesenchymal cells have only been associated with bone resorption indirectly, and it has been hypothesized that the degradation of bone is associated exclusively with specific functions of osteoclasts. Here we show, in aseptic prosthesis loosening, that aggressive fibroblasts at the bone surface actively contribute to bone resorption and that this is independent of osteoclasts. In two separate models (a severe combined immunodeficient mouse coimplantation model and a dentin pit formation assay), these cells produce signs of bone resorption that are similar to those in early osteoclastic resorption. In an animal model of aseptic prosthesis loosening (i.e. intracranially self-stimulated rats), it is shown that these fibroblasts acquire their ability to degrade bone early on in their differentiation. Upon stimulation, such fibroblasts readily release acidic components that lower the pH of their pericellular milieu. Through the use of specific inhibitors, pericellular acidification is shown to involve the action of vacuolar type ATPases. Although fibroblasts, as mesenchymal derived cells, are thought to be incapable of resorbing bone, the present study provides the first evidence to challenge this widely held belief. It is demonstrated that fibroblast-like cells, under pathological conditions, may not only enhance but also actively contribute to bone resorption. These cells should therefore be considered novel therapeutic targets in the treatment of bone destructive disorders.

Development and characteristics of a synovial-like interface membrane around cemented tibial hemiarthroplasties in a novel rat model of aseptic prosthesis loosening

OBJECTIVE Aseptic prosthesis loosening (APL) is related to the formation and aggressive growth of a synovial-like interface membrane (SLIM) between prosthesis and bone. However, investigation of the early phases of SLIM development in humans presents major difficulties. This study was undertaken to develop and characterize the usefulness of a novel animal model of APL that is based on an established model of defined exercise in a running wheel by Wistar rats that have been subjected to intracranial self-stimulation (ICSS). METHODS Cemented tibial hemiarthroplasties were implanted into the left knees of 7 male Wistar rats. After 2 weeks, exercise in a running wheel was started in all rats, with a running-load of 2 hours/day for 5 days/week. Six months postoperatively, the knee joints were removed, decalcified, and embedded in paraffin. Histologic evaluation on hematoxylin and eosin-stained sections was performed to investigate the development of a SLIM and the presence of cement debris particles. To characterize the SLIM on a molecular level and investigate growth-regulating factors, the expression of transforming growth factor beta (TGFbeta) and the anti-apoptotic molecule Bcl-2 was analyzed by immunohistochemistry. RESULTS Although the prostheses appeared mechanically stable after 6 months, the development of SLIM with areas of bone resorption was seen in all samples. Resembling human SLIM, these membranes consisted of loose fibrous tissue, with cement debris particles located particularly at sites originally attached to the prostheses. Immunohistochemistry studies revealed the expression of TGFbeta and Bcl-2 in all specimens. Interestingly, staining for TGFbeta and Bcl-2 was restricted to areas where the SLIM were attached to bone. In contrast, there was only negligible expression of both proteins at sites adjacent to the prostheses. CONCLUSION Our findings demonstrate that the ICSS Wistar rat model constitutes a feasible tool for studying early stages of APL, and specifically the effect of defined running exercise on SLIM formation. The results further suggest that both cellular proliferation, as stimulated by TGFbeta, and altered apoptosis contribute to early stages of SLIM formation. The expression patterns of TGFbeta and Bcl-2 indicate that the growth of the SLIM is initiated and promoted from the bone rather than from the prosthesis.

A concept for comprehensively measuring health, function and quality of life following orthopaedic interventions of the upper extremity

The view that subjective complaints rather than “objective” measurements decide on whether to consult the doctor or allow for an intervention to be carried out, should contribute to the decision-making process. This is especially true in diseases with multiple joint impairments. Although a variety of patient self-assessment scores exists, no gold standard is available to measure function and quality of life (QoL) after interventions at the upper extremity. The goal of our concept is to establish a comprehensive score set where patients should rate their generic health resp. quality of life (QoL), function of the upper extremity and specific joint function including activities of daily living, function and pain. A comparison with normative data should be possible in order to estimate how the subjective results of the patient when compared to “healthy” people in the general population. Score sets for measuring intervention effect at the shoulder, elbow and the hand were established after previous methodological testing within an interdisciplinary research project. The provisional sets were defined following a systematic literature search. Each set received a score of measuring the quality of life (SF-36), the whole function of the arm (DASH) and the specific joint function (SPADI/ASES for shoulder, PREE/mASES for the elbow and PRWE/custom for the hand). Individual scores were translated, if necessary according to AAOS-guidelines, and tested for reliability and construct validity. All three score sets were then systematically tested in cross-sectional studies. In addition, characteristic values such as minimal detectable difference and effect size could already be determined in the shoulder set in a long-term study. Definite score sets were defined, which allow quantification of the intervention effect at the upper extremity on function and quality of life after.

Cementless CUT femoral neck prosthesis: increased rate of aseptic loosening after 5 years.

Background Bone-saving hip arthroplasty techniques, which facilitate revision, are gaining importance as the number of hip replacements in younger patients increases. Patients and methods 123 CUT femoral neck prostheses (ESKA Implants, Lübeck, Germany) were implanted in 113 patients (average age 53 years) between 1999 and 2002. After a mean follow-up of 5 (3–7) years, we determined the state of 120 prostheses; 3 patients could not be located. 97 patients with 107 prostheses, none of which had been revised, were evaluated clinically and radiographically. Results The median Harris hip score improved from 51 points to 92 points in the unrevised hips. 13 CUT prostheses (11%) had been revised, 7 because of aseptic loosening, 3 because of persisting thigh pain, 1 because of immediate vertical migration, and 2 because of septic loosening. The 5-year survival rate of the CUT prosthesis was 89%. Interpretation The medium-term survival with this type of femoral component is unsatisfactory, with a high rate of aseptic loosening. The surviving prostheses had a good clinical outcome.BACKGROUND Bone-saving hip arthroplasty techniques, which facilitate revision, are gaining importance as the number of hip replacements in younger patients increases. PATIENTS AND METHODS 123 CUT femoral neck prostheses (ESKA Implants, Lübeck, Germany) were implanted in 113 patients (average age 53 years) between 1999 and 2002. After a mean follow-up of 5 (3-7) years, we determined the state of 120 prostheses; 3 patients could not be located. 97 patients with 107 prostheses, none of which had been revised, were evaluated clinically and radiographically. RESULTS The median Harris hip score improved from 51 points to 92 points in the unrevised hips. 13 CUT prostheses (11%) had been revised, 7 because of aseptic loosening, 3 because of persisting thigh pain, 1 because of immediate vertical migration, and 2 because of septic loosening. The 5-year survival rate of the CUT prosthesis was 89%. INTERPRETATION The medium-term survival with this type of femoral component is unsatisfactory, with a high rate of aseptic loosening. The surviving prostheses had a good clinical outcome.

Kinesthetic sense of the shoulder in patients with impingement syndrome

A proprioceptive deficit is an important determinant of disability in various shoulder disorders, such as instability and osteoarthrosis. In 15 patients with impingement syndrome stage II (Neer 1983), who were treated by arthroscopic subacromial decompression, we measured movement sense by determining threshold levels for the perception of motion of the shoulder. The patients were placed in a specially designed chair allowing continuous passive motion of the shoulder joint, while avoiding cutaneous, auditory and visual stimuli. To assess movement detection thresholds, passive abduction movements of the shoulder were performed at a starting angle of 60°, an amplitude of 10° and an angular velocity of 1.3°/s. Before surgery, all patients had higher threshold levels for the perception of motion in their affected shoulders then in the other side. After decompression, proprioception had improved on the decompressed side, but was unchanged on the other side.