Stemless shoulder prosthesis versus conventional anatomic shoulder prosthesis in patients with osteoarthritis: a comparison of the functional outcome after a minimum of two years follow-up.

BACKGROUND: The stemless shoulder prosthesis is a new concept in shoulder arthroplasty. To date, only a few studies have investigated the results of this prosthesis. The aim of this study was to investigate the clinical and radiological midterm results of this implant in comparison with a standard anatomic stemmed shoulder prosthesis. MATERIALS AND METHODS: The Constant score, the DASH score, the active range of motion (abduction, anteversion, external rotation), and the radiological results were examined in 82 patients with primary osteoarthritis of the shoulder treated with either the Total Evolutive Shoulder System(®) (Biomed, France) stemless shoulder prosthesis or the Affinis(®) (Mathys, Switzerland) stemmed shoulder prosthesis to detect possible differences in the functional outcome and to evaluate radiological properties of the implants. Patients were examined before and 32 ± 4 months after surgery. RESULTS: There was no significant difference in the Constant scores of the groups treated with the stemless shoulder prosthesis (65.0 ± 11.0 points) and the stemmed shoulder prosthesis (73.2 ± 11.3 points; P = 0.162). The estimated blood loss (P = 0.026) and the mean operative time (P = 0.002) were significantly lower in the group with the stemless shoulder prosthesis. CONCLUSIONS: The use of the stemless shoulder prosthesis yielded good results which, in a mid-term follow-up, were comparable with those provided by a standard anatomic shoulder prosthesis. Further investigations are needed regarding the long-term performance of this prosthesis.

Prospective study of double-eccentric hemi shoulder arthroplasty in different aetiologies: midterm results.

This prospective study aimed to analyse the effect of a newly developed double-eccentric adjustable stemmed prosthesis on reconstruction of the osseous anatomy, range of motion, strength and pain relief. A total of 91 consecutive hemiprostheses were evaluated preoperatively and three, six, 12, 24 and 48 months postoperatively (mean±SD 46.2 ± 10.9 months) by the American Shoulder and Elbow Surgeons (ASES) and Constant scores as well as radiological assessment. Clinical evaluations showed an increase in Constant score from 21.9 to 64.8 points and in ASES score from 24.9 to 77.9 points after two years. The results depend mainly on the underlying pathology. The best results were observed for primary osteoarthritis and avascular necrosis of the humeral head. All heads were eccentrically positioned. Specific stem-related complications were not observed. Because of the eccentric positioning of all heads it is reasonable to use adjustable shaft prostheses. The clinical results are comparable to data in the literature. Additional study provided a better or comparable clinical outcome and a low revision rate, when compared with other modern adjustable implants in the literature.

Short-term results after reversed shoulder arthroplasty (Delta III) in patients with rheumatoid arthritis and irreparable rotator cuff tear.

The purpose of this study was to describe the outcome after reversed Delta III shoulder prosthesis in patients with rheumatoid arthritis (RA) and irreparable rotator cuff tear. Fifteen patients (17 joints) were prospectively analysed using the Constant-Murley score (CS). Comprehensive outcome measure was carried out by means of four widely used questionnaires as well as clinical and radiographic examinations at an average of 24.3 months postoperatively. The CS improved significantly from 19 to 59.5 points. The mental (MSC) and physical (PCS) component summary score of the Short Form 36 (SF-36) reached 108% and 77%, respectively, while the DASH (Disabilities of the Arm, Shoulder, and Hand) was 58% of a comparative norm population. Remaining deficits were documented by SPADI (Shoulder Pain and Disability; 54.4 points) and ASES (clinical and patient-orientated American Shoulder and Elbow Surgeons; 84.3 and 61.3 points, respectively). No radiological signs of loosening were found, but scapular notching occurred in four cases. Reversed arthroplasty provides a substantial improvement of shoulder function in patients with RA. The high incidence of notching is of concern.

Altered neuromuscular control of a hand muscle in chronic rotator cuff tears.

INTRODUCTION: Previous EMG studies have shown that chronic rotator cuff tears (RCT) may be associated with an altered activation of adjacent shoulder muscles. The effect of RCT on central neuromuscular control mechanisms of hand muscles has as yet not been studied in detail. This study investigated the cortico-motor excitability of the first dorsal interosseus muscle (FDI) in patients with RCT. MATERIALS AND METHODS: The resting motor threshold (RMT) of the FDI on both sides were obtained from patients with unilateral chronic RCT and compared with healthy control subjects without any shoulder pathologies with transcranial magnetic stimulation. Analysis of variance for repeated measures was performed to detect possible differences in RMT of the FDI in patients and healthy controls. RESULTS: The RMT of FDI in patients on the affected side was lower when compared to the non-affected side (p = 0.015) and to both sides in control subjects (p = 0.041, F = 4.8). CONCLUSIONS: The reduced RMT of FDI in patients with unilateral RCT may be related to alterations in the sensory output from the shoulder and points toward a complete sensimotor restriction of the involved upper limb. These findings seem to be assigned to adaptive changes in the motor cortex as a consequence of chronic RCT.

Massive rotator cuff tears: functional outcome after debridement or arthroscopic partial repair.

BACKGROUND: The surgical treatment of massive rotator cuff tears (RCT) is still controversial and can be based on a variety of different surgical repair methods. This study investigated the effectiveness of arthroscopic debridement or arthroscopic partial repair in patients with massive RCT. MATERIALS AND METHODS: This prospective, randomized study involved forty-two patients with massive RCT (fatty infiltration stage 3 or 4) treated with either arthroscopic partial repair or arthroscopic debridement were selected to detect possible differences in functional outcome. Both groups were matched according to age and gender. Patients were examined before, and 16 +/- 3 and 24 +/- 2 months after surgery. The status of the rotator cuff repair was determined using ultrasonographic evaluation. RESULTS: Regardless of the treatment group, postoperative results demonstrated highly significant improvements compared with preoperative values in most parameters. The overall Constant score in the partial repair group was superior to the outcome in the debridement group (P < 0.01, F = 8.561), according to better results in abduction (P < 0.01, F = 13.249), activity (P < 0.01, F = 21.391) and motion (P < 0.01, F = 4.967). All treatment groups had similar pain relief (P = 0.172, F = 1.802) and satisfaction, reflected in equal values of disabilities of the arm, shoulder and hand (DASH) score (P = 0.948, F = 0.004). Ultrasonography revealed structural failure of the partial rotator cuff repair in 52% at final follow-up. CONCLUSIONS: During the follow-up period all patients in our series had good or satisfactory outcome after rotator cuff surgery. Regardless of high rates of structural failure of the partial rotator cuff repair, the results of arthroscopic partial rotator cuff repair demonstrated slightly better functional outcome than debridement.

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.

Central neuromuscular dysfunction of the deltoid muscle in patients with chronic rotator cuff tears.

BACKGROUND: Previous surface electromyogram (EMG) studies have shown that chronic rotator cuff tears (RCT) may be associated with a altered activation of adjacent shoulder muscles. The effect of RCT on central neuromuscular control mechanisms of the shoulder girdle muscles such as the deltoideus muscle (DM), a key muscle of shoulder function, has as not yet been studied in detail. MATERIALS AND METHODS: This study investigated the corticospinal excitability of the DM to assess the effects of RCT on the central neuromuscular function of proximal upper limb muscles. The motor-evoked potentials (MEP) in response to transcranial magnetic stimulation of DM on both sides were obtained from patients with unilateral RCT and compared with healthy control subjects. RESULTS: In patients, stimulus response curves of DM demonstrated a bilateral hyperexcitability at rest and a hypoexcitability during voluntary activation (F = 3.82, P = 0.007). CONCLUSIONS: The DM hyperexcitability may be related to alterations in the sensory output from the shoulder. The insufficient facilitation of the DM points toward a bilateral central activation deficit. These findings seem to be assigned to adaptive changes in the motor cortex as a consequence of chronic RCT, and the neuromuscular alteration of the DM should be considered when treating patients with RCT.

Lessons learned during the cross-cultural adaptation of the American Shoulder and Elbow Surgeons shoulder form into German.

Cross-cultural adaptation and testing of reliability and validity were performed by use of a sample of 118 patients after shoulder arthroplasty. They completed a questionnaire booklet containing the American Shoulder and Elbow Surgeons (ASES) questionnaire, Shoulder Pain and Disability Index (SPADI), Short Form 36, and Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, and 1 week later, they completed the ASES questionnaire again. The cross-cultural adaptation procedure revealed no major problems. The intraclass correlation coefficients (ICCs) for the subscales for pain and function and for the total score were very high (>0.84); the ICC for the subscale instability was unacceptably low. Function of the contralateral side was consistently better for all items (P < .01). Reliability for both function scales was similar (ICC >0). The ASES scores showed moderate correlation of 0.57 to 0.67 with the various scales of the SF-36 and higher correlation with the DASH (0.84) and SPADI (0.92). The German ASES showed good reliability and validity and can be used for shoulder-specific patient self-assessment in comparison to the contralateral (unaffected) side and provides additional information to objective parameters. The instability domain does not provide any additional clinical information.

Disease-specific expression patterns of proteases in synovial tissues.

UNLABELLED: To assess whether protease expression patterns can be discriminated according to matrix degradation mechanisms in aseptic prosthesis loosening (APL), rheumatoid arthritis (RA), and osteoarthritis (OA), we immunohistochemically examined the expressions of matrix metalloproteinase-1 and cathepsins B, D, and L in periprosthetic synovial-like interface tissues from 32 patients with failed prosthetic hips, from 29 RA-patients with hip synovial membranes, and from 35 patients with primary OA. Numerical values, calculated for the positivity of each protease, were used to rank the staining patterns, and a multivariate analysis was carried out to examine the discriminant probabilities. As a result of stepwise linear discriminant analyses, the three groups were successfully discriminated with probabilities of 100%, 62.1%, and 77.1%, respectively. Cathepsin L was significantly related to the discrimination of APL from RA and primary OA. Disease-specific protease activation pathways might exist, and cathepsin L can be a key enzyme for APL pathogenesis. LEVEL OF EVIDENCE: Prognostic study, level III (retrospective study).

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. METHODS: Measurements of quadriceps voluntary activation (VA) and maximum voluntary contraction (MVC) were performed by a twitch interpolation technique and the total muscular capacity (TMC) was calculated as the ratio of MVC and VA. We assessed 68 patients (56.7+/-9.5 years) with stage II and 154 patients (65.6+/-6.0 years) with stage IV chondropathy. As controls, we used 85 age related healthy subjects (58.1+/-8.7 years). RESULTS: While TMC was significantly lower in stage IV (90.6+/-43.7 Nm) than in stage II chondropathy (109.6+/-51.0) there were no differences in the MVCs between both groups. Quadriceps VA was even higher in stage IV (77.2+/-13.2%) than in stage II chondropathy (70.8+/-16.0%). In the controls, MVC, VA and TMC were significantly higher than in both OA groups. CONCLUSION: We assume that a decrease of TMC might occur within the course of OA and, in consequence, VA increases to maintain quadriceps MVC.

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. METHODS: In eighteen patients with bilateral moderate knee OA, who were treated with unicondylar knee arthroplasty we investigated voluntary activation (VA) and maximum voluntary contraction (MVC) of the quadriceps femoris muscle. There were 7 males and 11 females, the mean age at time of operation was 67 years (range 58-76 years). Measurements on both sides were performed preoperatively and 18 months postoperatively using the twitch-interpolation technique. RESULTS: Follow-up assessment revealed a significant VA and MVC increase in both the surgically treated knees and in the contralateral knees treated by physiotherapy alone. However, VA and MVC improvements were significantly higher in the operated on knees than in those treated by physiotherapy alone. DISCUSSION: Both physiotherapeutical exercise and unicondylar knee replacements lead to an improvement of quadriceps motor function in knee OA. The greater improvement in knees with both knee replacement and physiotherapy might be related to the intraoperative removal of arthritic tissue in these knees.

Evaluation of arthroscopic articular cartilage biopsy for osteoarthritis of the knee.

PURPOSE: Arthroscopic evaluation of the articular surface by visualization and palpation has proved to be unreliable; therefore, we investigated arthroscopically procured biopsy specimens and conventional sections by using the same histopathomorphologic techniques and compared the results for possible differences. METHODS: Cartilage biopsy specimens of 1.7 mm in diameter and conventional cartilage sections (pieces of 8 x 2 mm) were removed from the lateral femoral condyle of 53 osteoarthritis patients undergoing total knee arthroplasty. Biopsies and conventional sections were evaluated histologically by using Mankin's grading system and immunohistochemically by assessing the immunoreactivity of the chondrocytes to MMP-1 and MMP-3. RESULTS: The comparison between the biopsies and conventional sections revealed that there were no differences between these forms of obtaining specimens. Moreover, the expression of MMP-1 and MMP-3 in biopsy specimens showed a strong correlation with that in conventional sections. CONCLUSIONS: We conclude that in small biopsy specimens taken (e.g., during arthoscopy), the histological grading of osteoarthritis severity and the evaluation of MMP expression yield results similar to those obtained in conventional sections.

Evaluation of wrist and hand handicap and postoperative outcome in rheumatoid arthritis.

Functional instruments in rheumatology should use standardized procedures and should be quantifiable, valid, reliable, and responsive/sensitive to change. For most assessment tools, these aspects have been considered and tested. One of the most important questions in assessing hand involvement in patients with RA is what the single assessment should be used for. There could be a substantial difference should hand assessment be done in a routine way in a hand practice or should it be performed within scientific studies on disease progression or the effect of operative interventions. Among other points, answering this question has a significant impact on the time the patient has to spend with the tests and on the time the hand therapist or hand surgeon is involved with it. In addition to aspects such as accuracy, reliability, and validity, therefore, in some evaluation tools the time needed to perform the clinical examination and assessment of hand function has also been considered to be of importance. In addition, it has to be considered that description of the anatomic status, measurements of impairment, and assessment of disability cannot simply be replaced by each other, and even measurements of single aspects often are not sufficient. It has been stated, therefore, that the combination of different discrete hand-function assessment methods provides a more complete picture of hand ability. Moreover, although better responsiveness of disability outcome measures over impairment measures has been demonstrated previously (eg, in patients treated for Colle fracture), the relationship between disability and impairment measures is not clearly established. Although some studies reported significant correlations between impairment and disability tests, other studies showed only poor or moderate correlations between disability scores, impairment, and disease activity measures when rheumatoid hands were assessed. It has been concluded that the relationship between impairment and disability is not straightforward. The new ICF-model addresses these two levels of health-related quality of life by different concepts of assessment. Because impairment reflects the consequences of the disease at the organ level, whereas disability reflects the consequences of the disease for functional performance and activity, for comprehensive assessment of hand handicap, measurement of disability is more comprehensive and closer to the patient's needs for performing ADLs.

Small ubiquitin-like modifier 1 [corrected] mediates the resistance of prosthesis-loosening fibroblast-like synoviocytes against Fas-induced apoptosis.

OBJECTIVE: To study the expression of small ubiquitin-like modifier 1 (SUMO-1) in aseptic loosening of prosthesis implants and to investigate its role in regulating the susceptibility of prosthesis-loosening fibroblast-like synoviocytes (FLS) to Fas-induced apoptosis. METHODS: Specimens of aseptically loosened tissue were obtained at revision surgery, and the expression of SUMO-1 was analyzed by in situ hybridization. SUMO-1 levels in FLS were determined by quantitative polymerase chain reaction and Western blot analysis. Immunohistochemistry and confocal microscopy were used to study the subcellular localization of SUMO-1. The functional role of SUMO-1 in Fas-induced apoptosis of prosthesis-loosening FLS was investigated by small interfering RNA-mediated knockdown of SUMO-1 and by gene transfer of the nuclear SUMO-specific protease SENP1. RESULTS: SUMO-1 was expressed strongly in aseptically loosened tissue and was found prominently at sites adjacent to bone. Prosthesis-loosening FLS expressed levels of SUMO-1 similar to the levels expressed by rheumatoid arthritis (RA) FLS, with SUMO-1 being found mainly in promyelocytic leukemia protein nuclear bodies. Knockdown of SUMO-1 had no effect on spontaneous apoptosis but significantly increased the susceptibility of prosthesis-loosening FLS to Fas-induced apoptosis. Gene transfer of the nuclear SUMO-specific protease SENP1 reverted the apoptosis-inhibiting effects of SUMO-1. CONCLUSION: These data suggest that SUMO-1 is involved in the activation of both RA FLS and prosthesis-loosening FLS by preventing these cells from undergoing apoptosis. Modification of nuclear proteins by SUMO-1 contributes to the antiapoptotic effects of SUMO-1 in prosthesis-loosening FLS, providing evidence for the specific activation of sumoylation during their differentiation. Therefore, SUMO-1 may be an interesting target for novel strategies to prevent aseptic prosthesis loosening.

Hemi- versus bipolar shoulder arthroplasty for chronic rotator cuff arthropathy.

Both bipolar and hemiarthroplasty have been used to treat rotator cuff arthropathy (RCA) of the shoulder in patients with low functional demands. In this study, 41 patients treated with either a bipolar or hemiarthroplasty were selected retrospectively to detect possible differences in the functional outcome and to evaluate radiological properties of the implants. Patients were examined before and 30 +/- 6 months after surgery. There were no differences in the Constant scores between the groups treated with hemiarthroplasty and bipolar arthroplasty, 58.9 +/- 13.1 points and 55.8 +/- 13.5 points, respectively (P = 0.457). We found a significant increase in abduction postoperatively in both groups (P = 0.041 bipolar, P = 0.000 hemiarthroplasty) but without statistical significance between the hemiarthroplasty and bipolar arthroplasty groups (P = 0.124, F = 2.6). This result is related in the bipolar group due to movement between the shell and inner head (P = 0.042) and in the hemiarthroplasty group due to movement between the humeral head component and the glenoid (P = 0.000). In conclusion, we found that both hemiarthroplasty and bipolar arthroplasty are effective treatment options for carefully selected patients with RCA and low functional demands, with no differences between the groups.

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.

Comprehensive assessment of clinical outcome and quality of life after resection interposition arthroplasty of the thumb saddle joint.

OBJECTIVE: To explore the biometric and psychometric properties of clinical, generic, and condition-specific instruments and to assess quantitatively the outcome after resection interposition arthroplasty (RIAP) of the thumb saddle joint. METHODS: One hundred three patients requiring 112 arthroplasties were assessed in a 4.5-7.7-year cross-sectional catamnesis by means of 4 widely used questionnaires and clinical and radiographic examinations. RESULTS: In all dimensions of the Short Form 36 (SF-36), the outcome was equal or significantly better than expected by the norm. The Disability of the Arm, Shoulder and Hand questionnaire (DASH) revealed some small, mainly functional limitations (mean score 78.4, norm 86.4). The SF-36, the DASH, and the Patient Related Wrist Evaluation form (PRWE) correlated highly and loaded on the same factor. The Hand Function Index was independent of the clinical measurements (range of motion, strength, etc. on the specially designed Custom Form) and of the self rating. CONCLUSION: Long-term followup of 112 RIAP patients showed excellent health and quality of life. A questionnaire set consisting of the SF-36, the DASH (or alternatively the short PRWE), and the Custom Form is proposed for the comprehensive and specific assessment of thumb joint conditions.

Comprehensive assessment of clinical outcome and quality of life after total elbow arthroplasty.

OBJECTIVE: To assess quantitatively the outcome and to explore the physiometric and psychometric properties of clinical, generic, and condition-specific instruments after total elbow arthroplasty. METHODS: Seventy-nine patients were assessed in a 6-19-year cross-sectional catamnesis by means of 6 widely used questionnaires, clinical examinations, and radiographic examinations. RESULTS: With regard to pain, general physical health, and all the mental health dimensions of the Short Form 36 (SF-36), the patients showed scores comparable to normative values. Elbow joint stability and satisfaction were both good. Significant functional limitation was evidenced by the low mean scores of the SF-36 physical functioning measure (48.7, normative 69.9) and the Disabilities of the Arm, Shoulder and Hand questionnaire (DASH) function measure (51.1, normative 89.3). The SF-36 physical component summary and the DASH correlated highly (r = 0.76) and, in factor analysis, loaded on the factor "physical unspecific." The patient and clinical modified American Shoulder and Elbow Surgeons questionnaire (mASES) correlated with the Patient Related Elbow Evaluation form (r = 0.92 with the patient mASES) and loaded on "physical specific." The SF-36 mental component summary loaded on "mental quality of life." CONCLUSION: The patients' self-rated health, quality of life, and clinical outcome were good and were not affected by impairment in some specific functional abilities. A questionnaire set comprising the SF-36 and the patient and clinical mASES is proposed for the comprehensive and specific assessment of outcome after elbow arthroplasty.

Gene transfer of tissue inhibitor of metalloproteinases-3 reverses the inhibitory effects of TNF-alpha 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-alpha. 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-alpha. Although TNF-alpha 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-alpha. Neither synthetic MMP inhibitors nor glycosylated bioactive TIMP-3 are able to achieve these effects. Gene transfer of TIMP-3 inhibits the TNF-alpha-induced activation of NF-kappaB in rheumatoid arthritis synovial fibroblasts and reduces the up-regulation of soluble Fas/CD95 by TNF-alpha, 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-alpha 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.

Retroviral gene transfer of an antisense construct against membrane type 1 matrix metalloproteinase reduces the invasiveness of rheumatoid arthritis synovial fibroblasts.

OBJECTIVE: Membrane type 1 matrix metalloproteinase (MT1-MMP) is expressed prominently in rheumatoid arthritis synovial fibroblasts (RASFs), but the specific contribution of MT1-MMP to fibroblast-mediated destruction of articular cartilage is incompletely understood. This study used gene transfer of an antisense expression construct to assess the effects of MT1-MMP inhibition on the invasiveness of RASFs. METHODS: Retroviral gene transfer of a pLXIN vector-based antisense RNA expression construct (MT1-MMPalphaS) to MT1-MMP was used to stably transduce RASFs. Levels of MT1-MMP RNA and protein were determined by quantitative polymerase chain reaction, Western blotting, and immunocytochemistry in MT1-MMPalphaS-transduced RASFs as well as in control cells, with monitoring for 60 days. The effects of MT1-MMPalphaS on the invasiveness of RASFs were analyzed in the SCID mouse co-implantation model of RA. RESULTS: MT1-MMPalphaS-transduced RASFs produced high levels of antisense RNA that exceeded endogenous levels of MT1-MMP messenger RNA by 15-fold and resulted in a down-regulation of MT1-MMP at the protein level. Inhibition of MT1-MMP production was maintained for 60 days and significantly reduced the invasiveness of RASFs in the SCID mouse model. Whereas prominent invasion into cartilage by non-transduced and mock-transduced RASFs was observed (mean invasion scores 3.0 and 3.1, respectively), MT1-MMPalphaS-transduced cells showed only moderate invasiveness (mean invasion score 1.8; P < 0.05). CONCLUSION: The data demonstrate that an antisense RNA expression construct against MT1-MMP can be generated and expressed in RASFs for at least 60 days. Inhibition of MT1-MMP significantly reduces the cartilage degradation by RASFs.