[Injuries of the posterior and lateral chest wall-importance of an additional clavicular fracture]. / Verletzungen der posterioren und lateralen Brustwand ­ Bedeutung einer zusätzlichen Klavikulafraktur.

BACKGROUND: Flail chest wall injuries (FCI) are common in younger patients due to high-speed trauma and in older patients due to low-energy trauma or falls from a low height. They show a high incidence of concomitant injuries and are therefore associated with high morbidity and mortality. If there is also an ipsilateral clavicular fracture (CF), the outcome is significantly poorer. The skeleton of the shoulder and chest loses stability and can lead to a loss of function of the shoulder and a pronounced deformation of the chest wall. OBJECTIVE: This article shows the origin and clinical importance of FCI. What importance does a concomitant ipsilateral CF have and how can these costoclavicular injuries (CCI) be managed conservatively and operatively? MATERIAL AND METHODS: After primary emergency care of the patients with appropriate diagnostics, in the presence of CCI operative stabilization was carried out by means of locked plate osteosynthesis of the clavicle and the affected ribs via minimally invasive approaches with the patient under general anesthesia. Patients were followed up postoperatively. Various minimally invasive posterolateral approaches to the chest wall were previously performed in a corpse study and then put into practice. RESULTS AND CONCLUSION: This study presents therapeutic options for the reconstruction of the chest wall based on the established literature and clinical examples. An ipsilateral CF combined with fractures of the 2nd-4th ribs can be treated through an innovative clavipectoral approach. For the other fractures, standard approaches to the anterolateral and posterolateral chest wall are performed, which are associated with a good outcome in clinical practice. An operative stabilization should be performed at the latest when FCI or CCI together with a dislocating fracture and a marked deformation of the thoracic wall are present. Remaining misalignments are associated with a simultaneous loss of function of the chest wall and shoulder.

[Lesions of the anterior chest wall-significance of additional fractures of the spine]. / Verletzungen der anterioren Brustwand ­ Bedeutung zusätzlicher Frakturen der Wirbelsäule.

BACKGROUND: Fractures of the anterior chest wall are rare among the total number of fractures. They include sternal fractures (SF) and the adjacent cartilaginous structures of the ribs. The accident mechanism can allow conclusions to be drawn about which further accompanying injuries may be present, e.g. rib and spinal fractures. OBJECTIVE: The present work is intended to give an overview of injuries of the anterior chest wall. It includes clinical aspects as well as imaging and popular literature. MATERIAL AND METHODS: Included are injury constellations of the anterolateral chest wall, in particular of the sternum in combination with injuries of the spinal column in the sense of a sternovertebral injury (SVI). Possible treatment strategies were reviewed and the corresponding advantages and disadvantages are presented. RESULTS: In symptomatic fractures of the anterior chest wall, their operative stabilization should be considered in order to restore the stability of the trunk. In addition, rib fractures in direct trauma and spinal injuries in indirect trauma are often included in the treatment. CONCLUSION: In the case of injuries of the thoracic trunk, this must always be regarded as a unit and must therefore be clarified in the context of the clinical examination and diagnostic apparatus. The possible accident mechanism can allow conclusions to be drawn about possible injury patterns, e.g. in the sense of SVIs.

[Frequency and age distribution of combined sternovertebral injuries : Analysis of routine data from German hospitals 2005-2012]. / Häufigkeit und Altersverteilung sternovertebraler Kombinationsverletzungen : Analyse aus Routinedaten deutscher Krankenhäuser 2005­2012.

BACKGROUND: Combinations of sternal and spinal fractures often occur due to high velocity accidents and are associated with a high incidence of concomitant injuries. The anterior thoracic wall is described as the fourth column of torso stability, which is why sternovertebral injuries (SVI) present a high risk of sagittal deformation of the trunk, in particular injuries of the thoracic spine. To date, no studies have been published on the frequency distribution of the involved vertebral bodies in large patient groups. OBJECTIVES: This study was intended to elaborate a frequency distribution of vertebral fractures accompanying sternal fractures (SF) and examine the risk of a vertebral fracture accompanying a SF. MATERIAL AND METHODS: A total of 48,193 cases with the main or secondary diagnosis of a SF and 897,963 cases with vertebral fractures based on routine data of German hospitals from the years 2005-2012 were evaluated. A concomitant injury to the spinal column was examined for each vertebral body and then evaluated statistically. RESULTS AND CONCLUSIONS: Of all patients with a SF 30.96% also suffered from a vertebral fracture. Of these 3.11% were SF as the main diagnosis and 60.89% the secondary diagnosis. While vertebral fractures generally occurred most frequently in the region of the thoracolumbar transition and the second cervical vertebral body, the SVI showed a further frequency peak in the range from the lower cervical spine to the middle thoracic spine. The present study was able to show a frequency distribution of accompanying vertebral body injuries in a large and representative collective in the case of SF for the first time.

De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

Stabilization of flail chest injuries: minimized approach techniques to treat the core of instability.

PURPOSE: Stabilizing techniques of flail chest injuries usually need wide approaches to the chest wall. Three main regions need to be considered when stabilizing the rib cage: median-anterior with dissection of pectoral muscle; lateral-axillary with dissection of musculi (mm) serratus, externus abdominis; posterior inter spinoscapular with division of mm rhomboidei, trapezius and latissimus dorsi. Severe morbidity due to these invasive approaches needs to be considered. This study discusses possibilities for minimized approaches to the shown regions. METHOD: Fifteen patients were stabilized by locked plate osteosynthesis (MatrixRib®) between May 2012 and April 2014 and prospectively followed up. Flail chest injuries were managed through limited incisions to the anterior, the lateral, and the posterior parts of the chest wall or their combinations. Each approach was 4-10 cm using Alexis® retractor. RESULTS: One minimized approach offered sufficient access at least to four ribs posterior and laterally, four pairs of ribs anterior in all cases. There was no need to divide latissimus dorsi muscle. Trapezius und rhomboid muscles were only limited divided, whereas a subcutaneous dissection of serratus and abdominis muscles was necessary. A follow-up showed sufficient consolidation. COMPLICATIONS: pneumothorax (2) and seroma (2). CONCLUSION: Minimized approaches allow sufficient stabilization of severe dislocated rib fractures without extensive dissection or division of the important muscles. Keeping the arm and, thus, the scapula mobile is very important for providing the largest reachable surface of the rib cage through each approach.

First clinical study of a novel complete metal-free ceramic total knee replacement system.

BACKGROUND: The aim of the study was to evaluate the safety and efficacy of a novel metal-free ceramic total knee replacement system. METHODS: Thirty-eight primary total knee arthroplasties (TKAs) were performed on 34 patients using the metal-free BPK-S ceramic total knee replacement system with both the femoral and tibial components of an alumina/zirconia ceramic composite. The clinical outcome was evaluated pre- and postoperatively at 3 (n = 32 TKA) and 12 months (n = 32 TKA) using the Knee Society Score (KSS), the Oxford Knee Score and the EQ-5D. Safety analysis was performed by radiological examination and assessment of adverse events. RESULTS: Postoperatively, the KSS, Oxford Knee Score and EQ-5D improved significantly at 3 and 12 months (p < 0.001). Non-progressive partial radiolucent lines were observed in six cases, but there was no osteolysis and no implant loosening. Induction or exacerbation of allergies did not occur during the follow-up. CONCLUSIONS: The metal-free BPK-S ceramic total knee replacement system proved to be a safe and clinically efficient alternative to metal implants in this short-term follow-up study.

Limited evidence of chondrocyte outgrowth from adult human articular cartilage.

OBJECTIVE: Cellular outgrowth from articular cartilage tissue has been described in a number of recent experimental studies. The aim of this study was to investigate the occurrence of cellular outgrowth from articular cartilage explants isolated from adult human donors. METHOD: Macroscopically intact articular cartilage specimens were isolated from adult human donors and cultured either in their native status, or in a cleansed status achieved by forced washing to minimize attaching cells. Additionally, the effect of chemotactic stimuli including cell lysate, High-Mobility-Group-Protein B1 (HMGB-1), Trefoil-factor 3 (TFF3), bone morphogenetic protein-2 (BMP-2), transforming growth factor-ß1 (TGF-ß1), or three-dimensional fibrin or collagen matrices were investigated. Co-cultures with synovial membrane served as a positive control for a source of migratory cells. The occurrence of cellular outgrowth was analyzed by histological examination after a culture period of 4 weeks. RESULTS: Spontaneous cellular outgrowth from cleansed cartilage specimens was not observed at a relevant level and could not significantly be induced by chemotactic stimuli or three-dimensional matrices either. A forming cartilage-adjoining cell layer was only apparent in the case of native cartilage explants with cellular remnants from surgical isolation or in co-culture experiments with synovial membrane. CONCLUSION: The relevance of cellular outgrowth from cartilage tissue is largely absent in the case of adult human articular cartilage samples. A cartilage-adjoining cell layer forming around the explants may instead originate from still attaching cells that remained from surgical isolation.

Functional ankle instability as a risk factor for osteoarthritis: using T2-mapping to analyze early cartilage degeneration in the ankle joint of young athletes.

OBJECTIVE: The aim of this study was to investigate, using T2-mapping, the impact of functional instability in the ankle joint on the development of early cartilage damage. METHODS: Ethical approval for this study was provided. Thirty-six volunteers from the university sports program were divided into three groups according to their ankle status: functional ankle instability (FAI, initial ankle sprain with residual instability); ankle sprain Copers (initial sprain, without residual instability); and controls (without a history of ankle injuries). Quantitative T2-mapping magnetic resonance imaging (MRI) was performed at the beginning ('early-unloading') and at the end ('late-unloading') of the MR-examination, with a mean time span of 27 min. Zonal region-of-interest T2-mapping was performed on the talar and tibial cartilage in the deep and superficial layers. The inter-group comparisons of T2-values were analyzed using paired and unpaired t-tests. Statistical analysis of variance was performed. RESULTS: T2-values showed significant to highly significant differences in 11 of 12 regions throughout the groups. In early-unloading, the FAI-group showed a significant increase in quantitative T2-values in the medial, talar regions (P = 0.008, P = 0.027), whereas the Coper-group showed this enhancement in the central-lateral regions (P = 0.05). Especially the comparison of early-loading to late-unloading values revealed significantly decreasing T2-values over time laterally and significantly increasing T2-values medially in the FAI-group, which were not present in the Coper- or control-group. CONCLUSION: Functional instability causes unbalanced loading in the ankle joint, resulting in cartilage alterations as assessed by quantitative T2-mapping. This approach can visualize and localize early cartilage abnormalities, possibly enabling specific treatment options to prevent osteoarthritis in young athletes.

Molecular differentiation between osteophytic and articular cartilage--clues for a transient and permanent chondrocyte phenotype.

OBJECTIVE: To identify the molecular differences between the transient and permanent chondrocyte phenotype in osteophytic and articular cartilage. METHODS: Total RNA was isolated from the cartilaginous layer of osteophytes and from intact articular cartilage from knee joints of 15 adult human donors and subjected to cDNA microarray analysis. The differential expression of relevant genes between these two cartilaginous tissues was additionally validated by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and by immunohistochemistry. RESULTS: Among 47,000 screened transcripts, 600 transcripts were differentially expressed between osteophytic and articular chondrocytes. Osteophytic chondrocytes were characterized by increased expression of genes involved in the endochondral ossification process [bone gamma-carboxyglutamate protein/osteocalcin (BGLAP), bone morphogenetic protein-8B (BMP8B), collagen type I, alpha 2 (COL1A2), sclerostin (SOST), growth arrest and DNA damage-induced gene 45ß (GADD45ß), runt-related transcription factor 2 (RUNX2)], and genes encoding tissue remodeling enzymes [matrix metallopeptidase (MMP)9, 13, hyaluronan synthase 1 (HAS1)]. Articular chondrocytes expressed increased transcript levels of antagonists and inhibitors of the BMP- and Wnt-signaling pathways [Gremlin-1 (GREM1), frizzled-related protein (FRZB), WNT1 inducible signaling pathway protein-3 (WISP3)], as well as factors that inhibit terminal chondrocyte differentiation and endochondral bone formation [parathyroid hormone-like hormone (PTHLH), sex-determining region Y-box 9 (SOX9), stanniocalcin-2 (STC2), S100 calcium binding protein A1 (S100A1), S100 calcium binding protein B (S100B)]. Immunohistochemistry of tissue sections for GREM1 and BGLAP, the two most prominent differentially expressed genes, confirmed selective detection of GREM1 in articular chondrocytes and that of BGLAP in osteophytic chondrocytes and bone. CONCLUSIONS: Osteophytic and articular chondrocytes significantly differ in their gene expression pattern. In articular cartilage, a prominent expression of antagonists inhibiting the BMP- and Wnt-pathway may serve to lock and stabilize the permanent chondrocyte phenotype and thus prevent their terminal differentiation. In contrast, osteophytic chondrocytes express genes with roles in the endochondral ossification process, which may account for their transient phenotype.

Injury risk evaluation in sport climbing.

The aim of this study was to quantify and rate acute sport climbing injuries. Acute sport climbing injuries occurring from 2002 to 2006 were retrospectively assessed with a standardized web based questionnaire. A total number of 1962 climbers reported 699 injuries, which is equivalent to 0.2 injuries per 1 000 h of sport participation. Most (74.4%) of the injuries were of minor severity rated NACA I or NACA II. Injury distribution between the upper (42.6%) and lower extremities (41.3%) was similar, with ligament injuries, contusions and fractures being the most common injury types. Years of climbing experience (p<0.01), difficulty level (p<0.01), climbing time per week during summer (p<0.01) and winter (p<0.01) months were correlated with the injury rate. Age (p<0.05 (p=0.034)), years of climbing experience (p<0.01) and average climbing level (p<0.01) were correlated to the injury severity rated through NACA scores. The risk of acute injuries per 1 000 h of sport participation in sport climbing was lower than in previous studies on general rock climbing and higher than in studies on indoor climbing. In order to perform inter-study comparisons of future studies on climbing injuries, the use of a systematic and standardized scoring system (UIAA score) is essential.

Transplanted chondrocytes inhibit endochondral ossification within cartilage repair tissue.

The aim of this study was to investigate the effect of transplanted chondrocytes on endochondral bone formation in cartilage repair tissue. In the knee joint of miniature pigs, cartilage lesions were treated by microfracturing and were then either left empty, covered with a collagen membrane, or treated by matrix-associated autologous chondrocyte transplantation. In control lesions, the subchondral bone plate was left intact (partial-thickness lesion). The repair tissues were analyzed after 12 weeks by histological methods focusing on bone formation and vascularization. The effect of chondrocytes on angiogenesis was assessed by in vitro assays. The presence of antiangiogenic proteins in cartilage repair tissue, including thrombospondin-1 (TSP-1) and chondromodulin-I (ChM-I), was detected immunohistochemically and their expression in chondrocytes and bone marrow stromal cells was measured by quantitative RT-PCR. Significant outgrowths of subchondral bone and excessive endochondral ossification within the repair tissue were regularly observed in lesions with an exposed or microfractured subchondral bone plate. In contrast, such excessive bone formation was significantly inhibited by the additional transplantation of chondrocytes. Cartilaginous repair tissue that resisted ossification was strongly positive for the antiangiogenic proteins, TSP-1 and ChM-I, which were, however, not detectable in vascularized osseous outgrowths. Chondrocytes were identified to be the major source of TSP-1- and ChM-I expression and were shown to counteract the angiogenic activity of endothelial cells. These data suggest that the resistance of cartilaginous repair tissue against endochondral ossification following the transplantation of chondrocytes is associated with the presence of antiangiogenic proteins whose individual relevance has yet to be further explored.

[Sports ability after patella dislocation]. / Sportfähigkeit nach Patellaluxation.

A dislocation of the patella is a serious injury which can far affect the career of every athlete or even finish it. In a retrospective study we examined 24 athletes (mean age 19.3 years, post surgical observation period 39 (13 to 79) months) which suffered from a patellar dislocation and received arthroscopic surgical treatment. The diagnostics contained clinical investigation and X-rays of the knee joint in 2 plains as well as patella tangential, in pathological axial deformations of the leg completed with whole-leg-images and optional a torsion computed tomography. All 24 patients received an arthroscopical assisted suturing of the medial retinaculum, in 12 patients additional a lateral release was carried out. The postoperative course followed a standard pattern. In 24 operated patients the reoccurrence rate was 12.5 % (3 patients), which is within the range of the latest published figures (average 12.0 %). The Lysholm score was in 15 (62.4 %) of all patients higher than 80 demonstrating the good to very good results, the average Lysholm score was 83.4. Out of 24 patients with patellar dislocation 11 patients (45.8 %) were able to continue their sport career after surgical therapy at the pre-trauma level, 4 patients (16.6 %) had to continue at lower level, 9 patients (37.5 %) had to finish their sport career. The Tegner activity score decreased from 7.2 to 6.0 at about 1.2 points what means a clear decrease of the activity level. On average a full sportive level was reached 9.7 months after surgery. Especially sport athletes needs to be informed about the seriousness of the injury and the long process of rehabilitation.

Magnetic resonance image segmentation using semi-automated software for quantification of knee articular cartilage---initial evaluation of a technique for paired scans.

PURPOSE: Software-based image analysis is important for studies of cartilage changes in knee osteoarthritis (OA). This study describes an evaluation of a semi-automated cartilage segmentation software tool capable of quantifying paired images for potential use in longitudinal studies of knee OA. We describe the methodology behind the analysis and demonstrate its use by determination of test-retest analysis precision of duplicate knee magnetic resonance imaging (MRI) data sets. METHODS: Test-retest knee MR images of 12 subjects with a range of knee health were evaluated from the Osteoarthritis Initiative (OAI) pilot MR study. Each subject was removed from the magnet between the two scans. The 3D DESS (sagittal, 0.456 mm x 0.365 mm, 0.7 mm slice thickness, TR 16.5 ms, TE 4.7 ms) images were obtained on a 3-T Siemens Trio MR system with a USA Instruments quadrature transmit-receive extremity coil. Segmentation of one 3D-image series was first performed and then the corresponding retest series was segmented by viewing both image series concurrently in two adjacent windows. After manual registration of the series, the first segmentation cartilage outline served as an initial estimate for the second segmentation. We evaluated morphometric measures of the bone and cartilage surface area (tAB and AC), cartilage volume (VC), and mean thickness (ThC.me) for medial/lateral tibia (MT/LT), total femur (F) and patella (P). Test-retest reproducibility was assessed using the root-mean square coefficient of variation (RMS CV%). RESULTS: For the paired analyses, RMS CV % ranged from 0.9% to 1.2% for VC, from 0.3% to 0.7% for AC, from 0.6% to 2.7% for tAB and 0.8% to 1.5% for ThC.me. CONCLUSION: Paired image analysis improved the measurement precision of cartilage segmentation. Our results are in agreement with other publications supporting the use of paired analysis for longitudinal studies of knee OA.

Chondrogenic differentiation of growth factor-stimulated precursor cells in cartilage repair tissue is associated with increased HIF-1alpha activity.

OBJECTIVE: To investigate the chondrogenic potential of growth factor-stimulated periosteal cells with respect to the activity of Hypoxia-inducible Factor 1alpha (HIF-1alpha). METHODS: Scaffold-bound autologous periosteal cells, which had been activated by Insulin-like Growth Factor 1 (IGF-1) or Bone Morphogenetic Protein 2 (BMP-2) gene transfer using both adeno-associated virus (AAV) and adenoviral (Ad) vectors, were applied to chondral lesions in the knee joints of miniature pigs. Six weeks after transplantation, the repair tissues were investigated for collagen type I and type II content as well as for HIF-1alpha expression. The functional role of phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling on BMP-2/IGF-1-induced HIF-1alpha expression was assessed in vitro by employing specific inhibitors. RESULTS: Unstimulated periosteal cells formed a fibrous extracellular matrix in the superficial zone and a fibrocartilaginous matrix in deep zones of the repair tissue. This zonal difference was reflected by the absence of HIF-1alpha staining in superficial areas, but moderate HIF-1alpha expression in deep zones. In contrast, Ad/AAVBMP-2-stimulated periosteal cells, and to a lesser degree Ad/AAVIGF-1-infected cells, adopted a chondrocyte-like phenotype with strong intracellular HIF-1alpha staining throughout all zones of the repair tissue and formed a hyaline-like matrix. In vitro, BMP-2 and IGF-1 supplementation increased HIF-1alpha protein levels in periosteal cells, which was based on posttranscriptional mechanisms rather than de novo mRNA synthesis, involving predominantly the MEK/ERK pathway. CONCLUSION: This pilot experimental study on a relatively small number of animals indicated that chondrogenesis by precursor cells is facilitated in deeper hypoxic zones of cartilage repair tissue and is stimulated by growth factors which enhance HIF-1alpha activity.

[The vacuum-assisted closure (V.A.C.) and instillation dressing: limb salvage after 3 degrees open fracture with massive bone and soft tissue defect and superinfection]. / Der Vacuum-assisted closure and instillation-" (VAC-Instill-)Verband: Extremitätenerhalt bei drittgradig offener superinfizierter Femurfraktur mit massivem Knochen- und Weichteildefekt.

We report the case of a 17-year-old boy who was hit by a high velocity train. The polytraumatized patient suffered a 3 degrees open femur defect fracture with a substantial loss of the lateral femoral muscles and significant disruption of the soft tissue of the lower leg. The enormous wound areas on the thigh and the lower leg were infected by Pseudomonas aeruginosa, Enterobacter cloacae, and Stenotrophomonas maltophilia. The enormous tissue defects and the superinfection did not leave any hope for saving the limb from amputation. After rapid aggressive debridement and pulsatile lavage, we covered the wounds as a last resort with a new technique of vacuum-assisted closure (V.A.C) and instillation (V.A.C. Instill(R)) dressings. In sequences of 1 min we instilled Lavasept, kept it for 20 min on the wound surface, and exhausted the liquid. We repeated this for 6 consecutive days and then changed the dressing. In the follow-up examinations the number of germs was significantly reduced. During follow-up care we used the V.A.C. treatment without instillation and finally we transplanted skin onto the clean wound surface and were able to save the leg of this young patient. We discharged him with a good function of his lower leg. This technique of V.A.C. Instill seems to offer great possibilities in critically infected wound situations.

Hypoxia-inducible factor 1alpha is involved in the prostaglandin metabolism of osteoarthritic cartilage through up-regulation of microsomal prostaglandin E synthase 1 in articular chondrocytes.

OBJECTIVE: To investigate crosslinks between catabolic and anabolic pathways in articular cartilage by examining the synthesis and distribution pattern of microsomal prostaglandin E synthase 1 (mPGES-1) in healthy and osteoarthritic (OA) cartilage and analyzing its functional relationship to hypoxia-inducible factor 1alpha (HIF-1alpha) in primary articular chondrocytes. METHODS: Normal cartilage and OA cartilage were subjected to immunohistochemical staining for mPGES-1 and HIF-1alpha. Isolated chondrocytes were cultivated under 21% or 1% O(2). Microarray analysis and quantitative reverse transcriptase-polymerase chain reaction were used to detect genes differentially expressed in chondrocytes cultured under normoxic compared with hypoxic conditions. Immunoblotting was conducted to evaluate intracellular protein levels of mPGES and nuclear accumulation of HIF-1alpha under different oxygen tension levels and with different stimulatory or inhibitory chemical agents. RESULTS: We found enhanced levels of expression of the mPGES-1 gene and an increased number of OA chondrocytes showing staining for mPGES-1 in OA cartilage. Microarray analysis demonstrated that mPGES-1 was among the genes that were up-regulated to the greatest degree in primary chondrocytes exposed to 1% O(2). In vitro, hypoxia led to an enhanced synthesis of mPGES-1, coinciding with a nuclear accumulation of the transcription factor HIF-1alpha. In chondrocyte culture, stimulation with dimethyloxaloylglycine promoted the expression of mPGES-1, phosphoglycerate kinase 1, and cyclooxygenase 2 (COX-2) by stabilizing HIF-1alpha protein levels. A reduction of mPGES-1 synthesis was detected after treatment with 2-methoxyestradiol, correlating with lower HIF-1alpha activity. In contrast, synthesis of mPGES-1 was not influenced by treatment with the specific COX-2 inhibitor NS398. CONCLUSION: These findings suggest that the transcription factor HIF-1alpha is involved in the up-regulation of mPGES-1 and may therefore play an important role in the metabolism of OA cartilage.