Three-dimensional efficacy of correction surgeries in adolescent idiopathic scoliosis / Gerinckorrekciós mutétek háromdimenziós hatékonysági vizsgálata serdülokori idiopathiás gerincferdülésben.

Összefoglaló. Bevezetés: Nincs egységesen elfogadott álláspont, hogy a serdülokori idiopathiás gerincferdülés sebészi korrekcióját melyik életkorban optimális elvégezni. Világszerte 11 éves kortól akár (kezeletlen esetben) 50-60 éves korig végeznek fúziós mutétet a betegségben, 63-83%-os átlagos koronális síkú korrekciós hatékonysággal. Célkituzés: Célul tuztük ki, hogy felmérjük a gerinckorrekciós mutétek hatékonyságát három dimenzióban, illetve a páciens életkorának függvényében. Módszerek: A vizsgálatba 23, serdülokori idiopathiás gerincferdüléssel diagnosztizált beteget (12 fo 17 évnél fiatalabb, 11 fo 17 évnél idosebb) vontunk be. Minden betegnél csavaros derotációt és spondylodesist végeztünk, és a beavatkozás elott és után EOS 2D/3D felvételeket, majd sterEOS 3D rekonstrukciókat készítettünk. A következo paramétereket számítottuk: Cobb-fok, háti kyphosis, ágyéki lordosis, apicalis csigolyarotáció, maximális csigolyarotáció. A különbözo életkorú csoportok közötti különbséget kétmintás t-próbával, illetve Wilcoxon-féle próbával vizsgáltuk. Eredmények: A gerinckorrekciós mutétek során a koronális síkú eltérést 78,2%-ban (átlagosan 55,1 Cobb-fokról 12,0 Cobb-fokra), az apicalis csigolyarotációt 56,7%-ban (átlagosan 21,0 fokról 9,1 fokra) tudtuk korrigálni. A 17 éves életkor után operált páciensek esetén átlagosan 79,2%-os Cobb-fok-csökkenést értünk el, míg a fiatalabb betegcsoportban 77,0%-ban korrigáltuk a koronális fogörbületet (p = 0,614). Az idosebb betegcsoportban szignifikánsan kevésbé sikerült az apicalis csigolyarotáció korrekciója (átlagosan 38,1%; 21,8 fokról 12,4 fokra), mint a fiatalabb pácienseknél (átlagosan 68,5%; 20,2 fokról 6,2 fokra; p = 0,016). Következtetés: Összességében a nemzetközi publikációknak megfelelo korrekciót értünk el. A koronális síkban közel azonos korrekciós hatékonyság figyelheto meg a különbözo életkorú betegcsoportok között, a csigolyarotáció azonban 17 éves életkor elott hatékonyabban korrigálható. Orv Hetil. 2021; 162(39): 1573-1578. INTRODUCTION: There is no clear recommendation for the optimal age to perform corrective surgery in adolescent idiopathic scoliosis. Fusion surgery is performed from the age of 11 to 50-60 years, with an average coronal plane correction efficiency of 63-83%. OBJECTIVE: We aimed to evaluate the effectiveness of correction surgeries in three dimensions in adolescent idiopathic scoliosis. In addition, our objective was to examine the influence of the patient's age on the correction. METHODS: The study included 23 patients with adolescent idiopathic scoliosis (12 patients younger than 17 years, 11 patients older than 17 years). All patients underwent screw-derotation and spondylodesis and underwent EOS 2D/3D imaging before and after the operation, followed by sterEOS 3D reconstructions. The following parameters were calculated: Cobb degree, thoracic kyphosis, lumbar lordosis, apical vertebral rotation, maximal vertebral rotation. Differences between different age groups were examined by paired-sample t-test and Wilcoxon rank sum test. RESULTS: The mean efficiency of correction surgeries was 78.2% in the coronal plane (from an average of 55.1 Cobb degrees to 12.0 Cobb degrees) and 56.7% in the axial plane (from an average of 21.0 degrees to 9.1 degrees). We achieved an average 79.2% reduction of Cobb angle in patients operated after the age of 17 years, which was 77.0% in the younger group (p = 0.614). Apical vertebral rotation correction was significantly less successful in the elderly group (mean 38.1%; from 21.8 degrees to 12.4 degrees) than in patients operated before the age of 17 years (mean 68.5%; from 20.2 degrees to 6.2 degrees; p = 0.016). CONCLUSION: We achieved scoliosis correction in line with the international publications. Nearly the same correction efficiency was observed between different age groups of patients in the coronal plane. However, vertebral rotation can be derotated more effectively before the age of 17 years. Orv Hetil. 2021; 162(39): 1573-1578.

Analysis of Proximal Femoral Parameters in Adolescent Idiopathic Scoliosis.

BACKGROUND: Assessment of the proximal femoral parameters in adolescent idiopathic scoliosis using three-dimensional radiological image reconstructions may allow better characterization than conventional techniques. METHODS: EOS 3D reconstructions of spines and femurs of 320 scoliotic patients (10-18 years old) and 350 control children lacking spinal abnormality were performed and 6 proximal femoral parameters measured. RESULTS: Individuals with adolescent idiopathic scoliosis showed a small but statistically significant decrease in neck shaft angle (average difference=2.58°) and a higher (0.22°) femoral mechanical axis-femoral shaft angle. When the two sides were compared based on curve direction, greater changes in the neck shaft angle and femoral mechanical axis-femoral shaft angle were found on the side of the convexity. CONCLUSIONS: Patients with adolescent idiopathic scoliosis were found to have a small but significantly lower neck shaft angle and higher femoral mechanical axis-femoral shaft angle, which related to the curve direction. This is postulated to be due to mechanical compensation for altered balance and centre of gravity associated with a scoliosis deformity, although the observed difference likely has negligible clinical effect.

Introducing the craniocervical Y-ligament.

PURPOSE: We examined the accessory atlantoaxial ligaments and found them to be a part of a complex ligamentous structure, which we named craniocervical Y-ligament with respect to its shape. METHODS: The ligaments of the upper cervical spine were dissected in ten Thiel embalmed human cadavers. Origin and attachment of the Y-ligament were described and a detailed photo and video-documentation was carried out with the head in the neutral position, flexion, extension and rotation to study the ligament during these movements. RESULTS: The Y-ligaments were found to be paired and symmetric in all specimens. The shape of the ligament is similar to an Y, its lateral arm connecting the atlas to the axis, its medial arm connecting the occipital bone to the axis, fusing with the two main ligaments, the alar and transverse ligaments. The lateral arm of the Y-ligament was found to be analogous to the accessory atlantoaxial ligament. During cervical flexion, both arms of the Y-ligament became taut while extension made the Y-ligaments relaxed. During rotation both Y-ligaments became taut, moving in the opposite directions in the sagittal plane while following the gliding movements of the lateral masses of the atlas. CONCLUSIONS: The craniocervical Y-ligament is a complex ligamentous structure and has a constant anatomy. Because of its shape and special arrangement, it probably plays a role in limiting both atlantooccipital and atlantoaxial movements. Acknowledgement of this ligamentous structure will help understand upper cervical stability. The present study should serve as a basis for future biomechanical and radiological studies.

[Comparing the function of the temporomandibular joint before and after surgical treatment in a young patient with idiopathic scoliosis. Case presentation]. / Fiatalkori idiopathiás scoliosis mutéti korrekciójának hatása az állkapocs mozgástartományára.

From an anatomic and functional point of view, the stomatognathic system and the upper cervical spine are closely connected. Together with the complex neuromuscular relationships, this generates an important field of cooperation between dentists and orthopedics. The aim of this case report was to demonstrate the improvements of temporomandibular joint (TMJ) function after orthopedic surgery in case of a patient with idiopathic scoliosis. A 15-year-old female patient who had adolescent idiopathic scoliosis was surgically treated in 2016. Functional analyses of the TMJ were performed before the day of the operation and 10 months after the surgery. For detection, an ultrasound-based testing machine was used. The analyses of the data showed that almost all ranges of motions (ROM) were improved. The deviation to the right side was reduced from 8 mm to 2 mm during mouth opening. The patient had limited left lateral movement before the operation, however, after 10 months following the operation, there were free motions towards both sides. The originally asymmetrical protrusion became almost completely symmetrical. Regarding the functions of the TMJ, the surgery was successful; this in itself had a beneficial effect on the range and the path of the mandibular movements without any other treatment. These improved functions are indirect evidences for the connection of the function of the spine and TMJ. Orv Hetil. 2018; 159(50): 2144-2149.

Sagittal plane assessment of spino-pelvic complex in a Central European population with adolescent idiopathic scoliosis: a case control study.

BACKGROUND: Scoliosis is a complex three-dimensional deformity. While the frontal profile is well understood, increasing attention has turned to balance in the sagittal plane. The present study evaluated changes in sagittal spino-pelvic parameters in a large Hungarian population with adolescent idiopathic scoliosis. METHODS: EOS 2D/3D images of 458 scoliotic and 69 control cases were analyzed. After performing 3D reconstructions, the sagittal parameters were assessed as a whole and by curve type using independent sample t test and linear regression analysis. RESULTS: Patients with scoliosis had significantly decreased thoracic kyphosis (p < 0.001) with values T1-T12, 34.1 ± 17.1o vs. 43.4 ± 12.7o in control; T4-T12, 27.1 ± 18.8o vs. 37.7 ± 15.1o in control; and T5-T12, 24.9 ± 15.8o vs. 32.9 ± 15.0o in control. Changes in thoracic kyphosis correlated with magnitude of the Cobb angle (p < 0.001). No significant change was found in lumbar lordosis and the pelvic parameters. After substratification according to the Lenke classification and individually evaluating subgroups, results were similar with a significant decrease in only the thoracic kyphosis. A strong correlation was seen between sacral slope, pelvic incidence, and lumbar lordosis, and between pelvic version and thoracic kyphosis in control and scoliotic groups, whereas pelvic incidence was also seen to be correlated with thoracic kyphosis in scoliosis patients. CONCLUSION: Adolescent idiopathic scoliosis patients showed a significant decrease in thoracic kyphosis, and the magnitude of the decrease was directly related to the Cobb angle. Changes in pelvic incidence were minimal but were also significantly correlated with thoracic changes. Changes were similar though not identical to those seen in other Caucasian studies and differed from those in other ethnicities. Scoliotic curves and their effect on pelvic balance must still be regarded as individual to each patient, necessitating individual assessment, although changes perhaps can be predicted by patient ethnicity.

The effect of coronal decompensation on the biomechanical parameters in lower limbs in adolescent idiopathic scoliosis.

STUDY HYPOTHESIS: We hypothesized that altered coronal balance in adolescent scoliosis leads to asymmetric stress on the lower limbs, with subsequent effects on bone maturation and later morphology. We aimed to assess the correlation between the biomechanical parameters of the lower limbs and coronal balance in idiopathic scoliosis. MATERIALS AND METHODS: In this study, EOS images of 280 patients and 56 controls were randomly selected from our clinics' database. The average age of AIS patients was 14.5years and average Cobb angle 33.48°. Three D reconstructions of the pelvis and lower limbs were performed and coronal balance assessed. Reliability of measurements was ensured by intra- and inter-observer agreement. During statistical analysis the Kolmogorov-Smirnov test, t-test and linear regression analysis were performed. A p value <0.05 was considered significant. RESULTS: Of the 15 examined lower limb parameters, a significant difference between sides was found in those with AIS for femur length, total length, collodiaphyseal angle, angle between the femoral mechanical and anatomical axis and tibial torsion. In addition, the tibial length and the mechanical tibiofemoral angle were significantly higher than those of the controls. The coronal balance was found to be the strongest predictive factor showing a significant correlation with all of the previous parameters, except tibial torsion. With patients grouped based on coronal balance (compensated, right and left decompensated) the paired t-test also supported these findings. CONCLUSION: The biomechanical parameters of the lower limbs are affected in cases of scoliosis with an altered coronal balance. It was thought that a shift in balance in the coronal plane accounted for the small but significant changes seen in our study, with the lower limb on the side of decompensation becoming shorter in comparison to its' counterpart, with a lower collodiaphyseal angle and increased varus at the knee joint. LEVEL OF EVIDENCE: III, case-control study.

[Assessment of sacroiliacal joint mobility in patients with low back pain]. / A keresztcsonti ízület mobilitásának vizsgálata derékpanaszos betegcsoportban.

INTRODUCTION: Sagittal alignment of the pelvis is typically characterized using three fundamental parameters. Among these, pelvic incidence is traditionally considered to be anatomically 'constant'. AIM: We aimed to analyze the pelvic parameters of low back pain patients with suspected sacroiliac joint laxity. METHOD: Pelvic parameters were assessed in standing and seated EOS 2D/3D radiographs of 48 cases of persistent low back pain, and compared to upper body position using cluster analysis and t-test. RESULTS: Median pelvic incidence did not differ statistically between standing and sitting (47.8°-47.7°). However, in individual analysis 7 cases (15%) exhibited a forward tilt in their upper body with an increased pelvic incidence, and 7 cases (15%) showed a backward upper body tilt. No change was found in 34 cases. CONCLUSION: Our results indicate the pelvis should not be regarded as a rigid unit, as in some cases significant appreciable sacroiliac joint laxity can occur. Orv Hetil. 2017; 158(52): 2079-2085.

Surgical management of moderate adolescent idiopathic scoliosis with ApiFix®: a short peri- apical fixation followed by post-operative curve reduction with exercises.

Surgery in adolescent idiopathic scoliosis (AIS) is a major operative intervention where 10-12 vertebrae are instrumented and fused. A smaller motion preserving surgery would be more desirable for these otherwise healthy adolescents. The ApiFix® system is a novel less invasive short segment pedicle screw based instrumentation inserted around the apex of the main curve. The system has a ratchet mechanism that enables gradual postoperative device elongation and curve correction. The ratchet is activated by performing specific spinal exercises. The unique features of the device allow curve correction without fusion. The system which has a CE approval was employed in adolescents with main thoracic curves. More than a dozen of ApiFix surgeries have been performed so far. The preoperative Cobb angle was 45° ± 8, and 25° ± 8 at final follow up. The following is a report on three adolescent females aged 13-16 years with curves between 43°-53° and Risser sign of 1-4 who underwent surgery with ApiFix®. Two pedicle screws were inserted around the curve apex and the ratchet based device with polyaxial ring connectors was attached to the screws. No fusion attempt was made. Operative time was around one hour. Two weeks after surgery the patients were instructed to perform Schroth like daily exercises with the aim of rod elongation and gradual curve correction. Patients were followed between 6 months to 2 years. Curves were reduced and maintained between 22- 33°. Patients were pain free and were able to perform their spinal exercises. Postoperative gradual elongation of the device was observed. No screw loosening or rod breakage were observed. No adding on or curve progression was seen. Three factors may contribute to the ApiFix® success: polyaxial connections that prevent mechanical failure, gradual curve correction by spinal motion and spinal growth modulation. The ApiFix® system allows managing moderate AIS with a simple and minor surgical intervention. Recovery is rapid with negligible motion loss. It allows gradual and safe curve correction with high patient satisfaction. It may also serve as an internal brace for AIS.

Accuracy and reliability of coronal and sagittal spinal curvature data based on patient-specific three-dimensional models created by the EOS 2D/3D imaging system.

BACKGROUND CONTEXT: Three-dimensional (3D) deformations of the spine are predominantly characterized by two-dimensional (2D) angulation measurements in coronal and sagittal planes, using anteroposterior and lateral X-ray images. For coronal curves, a method originally described by Cobb and for sagittal curves a modified Cobb method are most widely used in practice, and these methods have been shown to exhibit good-to-excellent reliability and reproducibility, carried out either manually or by computer-based tools. Recently, an ultralow radiation dose-integrated radioimaging solution was introduced with special software for realistic 3D visualization and parametric characterization of the spinal column. PURPOSE: Comparison of accuracy, correlation of measurement values, intraobserver and interrater reliability of methods by conventional manual 2D and sterEOS 3D measurements in a routine clinical setting. STUDY DESIGN/SETTING: Retrospective nonrandomized study of diagnostic X-ray images created as part of a routine clinical protocol of eligible patients examined at our clinic during a 30-month period between July 2007 and December 2009. PATIENT SAMPLE: In total, 201 individuals (170 females, 31 males; mean age, 19.88 years) including 10 healthy athletes with normal spine and patients with adolescent idiopathic scoliosis (175 cases), adult degenerative scoliosis (11 cases), and Scheuermann hyperkyphosis (5 cases). Overall range of coronal curves was between 2.4° and 117.5°. Analysis of accuracy and reliability of measurements were carried out on a group of all patients and in subgroups based on coronal plane deviation: 0° to 10° (Group 1, n=36), 10° to 25° (Group 2, n=25), 25° to 50° (Group 3, n=69), 50° to 75° (Group 4, n=49), and more than 75° (Group 5, n=22). METHODS: Coronal and sagittal curvature measurements were determined by three experienced examiners, using either traditional 2D methods or automatic measurements based on sterEOS 3D reconstructions. Manual measurements were performed three times, and sterEOS 3D reconstructions and automatic measurements were performed two times by each examiner. Means comparison t test, Pearson bivariate correlation analysis, reliability analysis by intraclass correlation coefficients for intraobserver reproducibility and interrater reliability were performed using SPSS v16.0 software (IBM Corp., Armonk, NY, USA). No funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this article. RESULTS: In comparison with manual 2D methods, only small and nonsignificant differences were detectable in sterEOS 3D-based curvature data. Intraobserver reliability was excellent for both methods, and interrater reproducibility was consistently higher for sterEOS 3D methods that was found to be unaffected by the magnitude of coronal curves or sagittal plane deviations. CONCLUSIONS: This is the first clinical report on EOS 2D/3D system (EOS Imaging, Paris, France) and its sterEOS 3D software, documenting an excellent capability for accurate, reliable, and reproducible spinal curvature measurements.

Clinical validation of coronal and sagittal spinal curve measurements based on three-dimensional vertebra vector parameters.

BACKGROUND CONTEXT: For many decades, visualization and evaluation of three-dimensional (3D) spinal deformities have only been possible by two-dimensional (2D) radiodiagnostic methods, and as a result, characterization and classification were based on 2D terminologies. Recent developments in medical digital imaging and 3D visualization techniques including surface 3D reconstructions opened a chance for a long-sought change in this field. Supported by a 3D Terminology on Spinal Deformities of the Scoliosis Research Society, an approach for 3D measurements and a new 3D classification of scoliosis yielded several compelling concepts on 3D visualization and new proposals for 3D classification in recent years. More recently, a new proposal for visualization and complete 3D evaluation of the spine by 3D vertebra vectors has been introduced by our workgroup, a concept, based on EOS 2D/3D, a groundbreaking new ultralow radiation dose integrated orthopedic imaging device with sterEOS 3D spine reconstruction software. PURPOSE: Comparison of accuracy, correlation of measurement values, intraobserver and interrater reliability of methods by conventional manual 2D and vertebra vector-based 3D measurements in a routine clinical setting. STUDY DESIGN: Retrospective, nonrandomized study of diagnostic X-ray images created as part of a routine clinical protocol of eligible patients examined at our clinic during a 30-month period between July 2007 and December 2009. PATIENT SAMPLE: In total, 201 individuals (170 females, 31 males; mean age, 19.88 years) including 10 healthy athletes with normal spine and patients with adolescent idiopathic scoliosis (175 cases), adult degenerative scoliosis (11 cases), and Scheuermann hyperkyphosis (5 cases). Overall range of coronal curves was between 2.4 and 117.5°. Analysis of accuracy and reliability of measurements was carried out on a group of all patients and in subgroups based on coronal plane deviation: 0 to 10° (Group 1; n=36), 10 to 25° (Group 2; n=25), 25 to 50° (Group 3; n=69), 50 to 75° (Group 4; n=49), and above 75° (Group 5; n=22). METHODS: All study subjects were examined by EOS 2D imaging, resulting in anteroposterior (AP) and lateral (LAT) full spine, orthogonal digital X-ray images, in standing position. Conventional coronal and sagittal curvature measurements including sagittal L5 vertebra wedges were determined by 3 experienced examiners, using traditional Cobb methods on EOS 2D AP and LAT images. Vertebra vector-based measurements were performed as published earlier, based on computer-assisted calculations of corresponding spinal curvature. Vertebra vectors were generated by dedicated software from sterEOS 3D spine models reconstructed from EOS 2D images by the same three examiners. Manual measurements were performed by each examiner, thrice for sterEOS 3D reconstructions and twice for vertebra vector-based measurements. Means comparison t test, Pearson bivariate correlation analysis, reliability analysis by intraclass correlation coefficients for intraobserver reproducibility and interrater reliability were performed using SPSS v16.0 software. RESULTS: In comparison with manual 2D methods, only small and nonsignificant differences were detectable in vertebra vector-based curvature data for coronal curves and thoracic kyphosis, whereas the found difference in L1-L5 lordosis values was shown to be strongly related to the magnitude of corresponding L5 wedge. Intraobserver reliability was excellent for both methods, and interrater reproducibility was consistently higher for vertebra vector-based methods that was also found to be unaffected by the magnitude of coronal curves or sagittal plane deviations. CONCLUSIONS: Vertebra vector-based angulation measurements could fully substitute conventional manual 2D measurements, with similar accuracy and higher intraobserver reliability and interrater reproducibility. Vertebra vectors represent a truly 3D solution for clear and comprehensible 3D visualization of spinal deformities while preserving crucial parametric information for vertebral size, 3D position, orientation, and rotation. The concept of vertebra vectors may serve as a starting point to a valid and clinically useful alternative for a new 3D classification of scoliosis.

Breakthrough in three-dimensional scoliosis diagnosis: significance of horizontal plane view and vertebra vectors.

Scoliosis is a multifactorial three-dimensional (3D) spinal deformity with integral and directly related vertebral deviations in the coronal, sagittal and horizontal planes. Current classification and diagnostic methods rely on two-dimensional (2D) frontal and lateral X-ray images; no routine methods are available for the visualization and quantitative evaluation of deviations in the horizontal plane. The EOS 2D/3D system presented here is a new, low-dose, orthopedic radiodiagnostic device based on Nobel prize-winning X-ray detection technology with special software for 3D surface reconstruction capabilities that finally led to a breakthrough in scoliosis diagnosis with high-quality, realistic 3D visualization and accurate quantitative parametric analysis. A new concept introducing vertebra vectors and vertebra vector parametric calculations is introduced that furnishes simplified visual and intelligible mathematical information facilitating interpretation of EOS 2D/3D data, especially with regard to the horizontal plane top view images. The concept is demonstrated by a reported scoliotic case that was readily characterized through information derived from vertebra vectors alone, supplemented with the current angulation measurement methods in the coronal and sagittal planes and axial vertebral rotation measurements in the horizontal plane, with a calibrated 3D coordinate system suitable for inter-individual comparisons. The new concept of vertebra vectors may serve as a basis for a truly 3D classification of scoliosis.

Cytokine-controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: fibroblast-mediated pathologic bone resorption.

OBJECTIVE: To determine whether proinflammatory cytokine treatment or the complete absence of select cytokines modulates the expression of RANKL and osteoprotegerin (OPG) in synovial fibroblasts. METHODS: Fibroblasts were isolated from normal and rheumatoid human synovium and from normal or arthritic joints of wild-type and cytokine gene-deficient (interleukin-4-knockout [IL-4 (-/-)] and interferon-gamma-knockout [IFNgamma (-/-)]) mice. Fibroblasts were stimulated with proinflammatory cytokines (tumor necrosis factor alpha [TNFalpha], IL-1beta, and IL-17) or antiosteoclastogenic cytokines (IL-4 and IFNgamma), alone or in combination, and the expression of RANKL and OPG was measured. RESULTS: Proinflammatory cytokine-stimulated fibroblasts from rheumatoid and arthritic mouse joints expressed higher levels of RANKL and OPG than those from normal joints. IL-4 suppressed RANKL expression and increased OPG expression, IFNgamma reduced the production of both RANKL and OPG, and IL-17 had only a modest effect on the expression of RANKL or OPG. Additive effects of combination treatment (TNFalpha/IL-17 or IL-1beta/IL-17) were observed only in the human system. Extensive destruction was observed in the arthritic joints of IL-4 (-/-) mice, with a corresponding upward shift of the RANKL:OPG ratios. However, an IL-17 deficiency did not attenuate arthritis or reduce bone resorption. CONCLUSION: Proinflammatory cytokines induce the expression of RANKL and OPG in both human and murine synovial fibroblasts. The RANKL:OPG ratios are shifted in favor of bone protection by IL-4 treatment, and, to a lesser extent, by IFNgamma treatment. Unexpectedly, an IL-17 deficiency alone does not induce reduced inflammatory bone destruction. Our results suggest that synovial fibroblasts may significantly contribute to bone resorption through modulation of RANKL and OPG production in a cytokine-rich milieu of inflamed joints.

Role of fibroblasts and fibroblast-derived growth factors in periprosthetic angiogenesis.

The periprosthetic granulomatous soft tissue [designated iterfacial membrane (IFM) in this study] exhibits heterogeneous histopathological features, in which highly vascularized areas with dense cellularity alternate with fibrotic and pseudocapsule-like tissue structures. Although macrophage/monocyte activation is a prominent event in the periprosthetic environment, fibroblasts also phagocytose particulate wear debris both in vivo and in vitro. Particulate wear debris and/or cytokines/growth factors alone or in combination (e.g., in conditioned media of explant cultures of IFMs) stimulated normal synovial and IFM fibroblasts to express inflammatory mediators and growth factors such as interleukin (IL)-1beta, IL-6, IL-8, three isoforms of vascular endothelial growth factor (VEGF), monocyte/macrophage chemoattractant protein-1 (MCP-1), macrophage-colony-stimulating factor (M-CSF), cycloxygenases (Cox-1 and Cox-2), acid- and basic-fibroblast growth factors (FGF-1 and FGF-2), leukemia inhibitory factor-1 (LIF-1), transforming growth factor beta-1 (TGF-beta1), receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegerin (OPG). Thus, the fibroblast is capable of expressing a wide array of angiogenic and osteoclastogenic factors which are involved in the detrimental processes of the periprosthetic osteolysis.

Interleukin-4 regulates proteoglycan-induced arthritis by specifically suppressing the innate immune response.

OBJECTIVE: Interleukin-4 (IL-4) is an antiinflammatory cytokine that inhibits the onset and severity of proteoglycan-induced arthritis (PGIA). To distinguish the role of IL-4 in the innate immune response versus the adaptive immune response, we generated mice with a specific deletion of the IL-4 receptor alpha-chain (IL-4Ralpha) in macrophages and neutrophils. METHODS: To obtain mice in which IL-4Ralpha is deleted in macrophages and neutrophils, we intercrossed mice carrying a loxP-flanked (floxed) IL-4Ralpha allele and Cre recombinase expressed under control of the regulatory region for the lysozyme M gene (LysM(cre) mice) with conditional IL-4Ralpha(flox/flox) mice and then mated them to complete IL-4Ralpha(-/-) mice to obtain hemizygous LysM(cre)IL-4Ralpha(flox/-) mice. LysM(cre)-negative IL-4Ralpha(flox/-) mice (IL-4Ralpha(flox/-) mice) were used as control mice. PGIA was induced by immunization with human PG in adjuvant. The onset, incidence, and severity of arthritis were monitored over time. Levels of proinflammatory cytokines were measured in the sera of PG-immunized mice, and cytokine and chemokine transcripts were measured in joints. RESULTS: The severity of PGIA was exacerbated in IL-4Ralpha(-/-) and LysM(cre)IL-4Ralpha(flox/-) mice in comparison with control (IL-4Ralpha(flox/-)) mice. The increase in arthritis susceptibility in IL-4Ralpha(-/-) and LysM(cre)IL-4Ralpha(flox/-) mice correlated with elevated serum levels of the proinflammatory cytokines IL-1beta and IL-6 and with elevated cytokine (IL-1beta and IL-6) and chemokine (macrophage inflammatory protein 1alpha [MIP-1alpha] and MIP-2) transcripts from joints. However, arthritis susceptibility did not correlate with IL-2 or interferon-gamma (IFNgamma) concentrations or with PG-specific antibody IgG2a isotype, since levels of IL-2, IFNgamma, or PG-specific antibody IgG2a isotype in control (IL-4Ralpha(flox/-)) and LysM(cre)IL-4Ralpha(flox/-) mice were reduced in comparison with those in IL-4Ralpha(-/-) mice. CONCLUSION: These findings indicate that IL-4 functions as a major antiinflammatory cytokine in PGIA by governing the activity of macrophages/neutrophils and less so by controlling T cell activity and autoantibody isotype expression.

Antigen-induced differential gene expression in lymphocytes and gene expression profile in synovium prior to the onset of arthritis.

To explore early signature genes playing critical roles in the initial steps in an autoimmune murine model of rheumatoid arthritis (RA) (proteoglycan (PG)-induced arthritis; PGIA), we performed gene expression profiling of "arthritogenic" spleen cells stimulated with cartilage PG, and compared them to differentially expressed genes, identified in joints prior to the onset of arthritis, and then in the acute and chronic phases of the disease. A total of 280 genes were up-regulated and 226 genes were suppressed in in vitro PG-stimulated lymphocytes at a minimum of 2-fold expression change. Functional gene classification identified several major clusters of biological activity. Expression of immunoglobulin genes (66 transcripts) was downregulated by approximately 3.7-fold, whereas most of the other genes with immune/inflammation-associated functions such as interleukins (IL-1, -2, -4, -6, -10, -12, -16, -17), chemokine receptors and their ligands (Cxcl1, Ccl2, 7, 8, 9, 10, 22, Ccr2, Ccr5), and major components of the complement cascade were upregulated. Using adoptive disease transfer with stimulated lymphocytes into SCID mice, followed by gene expression profiling of SCID paws, indicated that 37 genes were differentially expressed in yet non-inflamed (pre-arthritic) paws; these genes were related mostly to chemokine, IFN-gamma and TNF-alpha signaling. However, the majority of differentially expressed immune response-related genes were silent in pre-arthritic joints, and only 12 genes were found differentially expressed both in antigen (PG)-stimulated lymphocytes and in the synovium prior to the onset of arthritis. Most of these "arthritis-initiation" genes belonged to chemokine mediated cell motility. Transcripts of chemokine receptor 5 (Ccr5), chemokine ligand 7 (Ccl7) and IFN-gamma-inducible proteins (Ifi47) and GTP-ase 1 were expressed at the highest levels in both antigen-stimulated lymphocytes and pre-inflamed synovium, which suggests a key role of these genes in both lymphocyte maturation and arthritis initiation.

The role of fibroblasts and fibroblast-derived factors in periprosthetic osteolysis.

OBJECTIVE: This study was undertaken to investigate how fibroblasts respond to stimulation with particulate wear debris and/or conditioned media obtained from pathologic tissue, and whether these activated fibroblasts express compounds that are involved in bone resorption. METHODS: Conditioned media from explant cultures of synovial tissue, periprosthetic soft tissue (interface membranes), titanium particles, and proinflammatory cytokines were used to stimulate fibroblasts. RNase protection assay was used to measure altered gene expression, and enzyme-linked immunosorbent assay, Western blot hybridization, and flow cytometry were used to determine fibroblast protein expression. Tartrate-resistant acid phosphatase staining was used to identify multinucleated osteoclast-like cells. RESULTS: The most dominant compounds measured in the conditioned media from interface membranes were tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein 1 (MCP-1), interleukin-1beta (IL-1beta), IL-6, IL-8, and vascular endothelial growth factor. Fibroblasts phagocytosed particulate wear debris and responded to cytokine/chemokine stimulation. The most prominent up-regulated genes and proteins secreted by fibroblasts in response to stimulation were matrix metalloproteinase 1, MCP-1, IL-1beta, IL-6, IL-8, cyclooxygenase 1 (COX-1), COX-2, leukemia inhibitory factor 1, transforming growth factor beta1 (TGFbeta1), and TGFbeta receptor type I. In addition, interface membrane fibroblasts expressed RANKL and osteoprotegerin in response to stimulation with conditioned media, TNFalpha, or IL-1beta. Stimulated fibroblasts cocultured with bone marrow cells in the presence of macrophage colony-stimulating factor induced osteoclastogenesis. CONCLUSION: Interface membrane fibroblasts respond directly to particulate wear debris, possibly via phagocytosis, expressing proinflammatory cytokines and RANKL. Thus, these cells may be actively involved in osteoclastogenesis and pathologic (periprosthetic) bone resorption.

Development of proteoglycan-induced arthritis is critically dependent on Fcgamma receptor type III expression.

OBJECTIVE: To study the necessity for activating Fcgamma receptor types I and III (FcgammaRI and FcgammaRIII) in proteoglycan-induced arthritis (PGIA), a murine model of rheumatoid arthritis, and to determine whether usage of FcgammaRI or FcgammaRIII correlates with the Th1 phenotype or the autoantibody isotype in PGIA. METHODS: PGIA was induced by immunizing FcgammaRI(-/-), FcgammaRIII(-/-), and wild-type (WT) littermate mice with human PG. The development and severity of arthritis were monitored over time. PG-specific T cell interleukin-2 (IL-2) production and B cell antibody responses were assessed. FcgammaRIII blocking antibodies were used to inhibit arthritis in an adoptive transfer system. Inflammation in the hind paws was evaluated by assessing cytokine and chemokine messenger RNA (mRNA) transcripts by real-time polymerase chain reaction. RESULTS: FcgammaRI(-/-) mice developed arthritis with similar kinetics and severity as WT littermate controls, whereas FcgammaRIII(-/-) mice failed to develop the disease. Both FcgammaRI(-/-) and FcgammaRIII(-/-) mice produced similar amounts of PG-specific antibody and IL-2 as littermate controls. Transfer of arthritis was successfully blocked in mice treated with a blocking antibody against FcgammaRIII. FcgammaRIII(-/-) mice displayed a significant decrease in cytokine and chemokine mRNA transcripts obtained from the hind paws of immunized mice, whereas FcgammaRI(-/-) mice demonstrated a similar increase in cytokine and chemokine transcripts as controls. CONCLUSION: These results demonstrate that FcgammaRIII expression is critical to the development of PGIA, and usage of FcgammaRIII correlates with the IgG1 isotype of the PG-specific antibody response. FcgammaRIII expression appears to be important in the effector phase of arthritis, possibly by activating cytokine- and chemokine-secreting cells in the joint.