Biomedical subjects
Publications and source records attributed to T Aigner.
We describe the rare entity of an intraosseous meningioma arising in the mandible. The meningioma was found incidentally in an asymptomatic adult patient on dental radiography, mimicking other cystic-appearing jaw masses. The CT and MR imaging features of mandibular meningioma are reviewed with reference to prior published descriptions of this unusual entity.
Anabolic and catabolic cytokines and growth factors such as BMP-7 and IL-1beta play a central role in controlling the balance between degradation and repair of normal and (osteo)arthritic articular cartilage matrix. In this report, we investigated the response of articular chondrocytes to these factors IL-1beta and BMP-7 in terms of changes in gene expression levels. Large scale analysis was performed on primary human adult articular chondrocytes isolated from two human, independent donors cultured in alginate beads (non-stimulated and stimulated with IL-1beta and BMP-7 for 48 h) using Affymetrix gene chips (oligo-arrays). Biostatistical and bioinformatic evaluation of gene expression pattern was performed using the Resolver software (Rosetta). Part of the results were confirmed using real-time PCR. IL-1beta modulated significantly 909 out of 3459 genes detectable, whereas BMP-7 influenced only 36 out of 3440. BMP-7 induced mainly anabolic activation of chondrocytes including classical target genes such as collagen type II and aggrecan, while IL-1beta, both, significantly modulated the gene expression levels of numerous genes; namely, IL-1beta down-regulated the expression of anabolic genes and induced catabolic genes and mediators. Our data indicate that BMP-7 has only a limited effect on differentiated cells, whereas IL-1beta causes a dramatic change in gene expression pattern, i.e. induced or repressed much more genes. This presumably reflects the fact that BMP-7 signaling is effected via one pathway only (i.e. Smad-pathway) whereas IL-1beta is able to signal via a broad variety of intracellular signaling cascades involving the JNK, p38, NFkB and Erk pathways and even influencing BMP signaling.
OBJECTIVE: Growth factor therapy may be useful for stimulation of cartilage matrix synthesis and repair. Thus, the purpose of our study was to further understand the effect of combined insulin-like growth factor-1 (IGF-1) and osteogenic protein-1 (OP-1) treatment on the matrix synthesized by human adult normal and osteoarthritic (OA) chondrocytes. DESIGN: Chondrocytes were isolated post-mortem from articular cartilage from tali of normal human donors and femoral condyles of OA patients undergoing knee replacement surgery. Cells were cultured in alginate beads for 21 days in four experimental groups: (1) "mini-ITS" control; (2) 100 ng/ml IGF-1; (3) 100 ng/ml OP-1; (4) IGF-1+OP-1, each at 100 ng/ml. Beads were processed for histological (Safranin O and fast green), morphometrical and immunohistochemical (aggrecan, decorin, type I, II, VI, and X collagens, and fibronectin accumulation) analyses. RESULTS: Histology showed that IGF-1 alone did not induce substantial matrix production. OP-1 alone caused a considerable matrix formation, but the highest matrix accumulation by normal and OA chondrocytes was found when OP-1 and IGF-1 were added together. Morphometrical analysis indicated larger matrices produced by OA chondrocytes than by normal cells under the combined treatment. All tested matrix proteins were more abundant in the combination group. Type X collagen was detected only under the combined OP-1 and IGF-1 treatment and was present at very low levels. Type I collagen was found only in OA chondrocytes. CONCLUSIONS: The results obtained in the current study suggest that combined therapy with IGF-1 and OP-1 may have a greater potential in treating cartilage defects seen in OA than use of either growth factor alone.
Intact human adult articular cartilage is central for the functioning of the articulating joints. This largely depends on the integrity of its extracellular matrix, given the high loading forces during movements in particular in the weight-bearing joints. Unlike the first impression of a more or less static tissue, articular cartilage shows - albeit in the adult organism a slow--tissue turnover. Thus, one of the most important questions in osteoarthritis research is to understand the balance of catabolic and anabolic factors in articular cartilage as this is the key to understand the biology of cartilage maintenance and degeneration. Anabolic and catabolic pathways are very much intermingled in articular cartilage. The balance between anabolism and catabolism is titrated on numerous levels, starting from the mediator-synthesizing cells which express either catabolic or anabolic factors. Also, on the level of the effector cells (i.e. chondrocytes) anabolic and catabolic gene expression compete for a balance of matrix homeostasis, namely the synthesis of matrix components and the expression and activation of matrix-degrading proteases. Also, there are multiple layers of intracellular cross-talks in between the anabolic and catabolic signalling pathways. Maybe the most important lesson from this overview is the notion that the anabolic-catabolic balance as such counts and not so much sufficient net anabolism or limited catabolism alone. Thus, it might be neither the aim of osteoarthritis therapy to foster anabolism nor to knock down catabolism, but the balance of anabolic-catabolic activities as a total might need proper titration and balancing.
OBJECTIVE: To review the current knowledge of the mechanism of DNA methylation, its association with transcriptional silencing, possible mechanisms of hyper- and hypomethylation and how epigenetic changes may relate to the pathogenesis of osteoarthritis (OA). METHODS: Journal literature was searched using Pubmed. Since there are very few publications directly on epigenetic phenomena in OA, the search was extended to give an overview of epigenetic mechanisms as they relate to the molecular mechanisms of the disease. RESULTS: While the epigenetics of cancer cells have been intensively investigated, little attention has so far been paid as to whether epigenetic changes contribute to the pathology of non-neoplastic diseases such as OA. This review explains the mechanisms of DNA methylation, its role in transcriptional regulation, and possible demethylation mechanisms that may be applicable to OA. Preliminary evidence suggests that changes in DNA methylation, together with cytokines, growth factors and changes in matrix composition, are likely to be important in determining the complex gene expression patterns that are observed in osteoarthritic chondrocytes. CONCLUSION: Early evidence points to a role of epigenetics in the pathogenesis of OA. Since epigenetic changes, although heritable at the cellular level, are potentially reversible, epigenetics could be a new molecular target for therapeutic intervention, especially early in the disease.
AIM: To examine eosinophil infiltration and degranulation in 50 oesophageal biopsy specimens from 30 patients (21 men, 9 women; mean 39 years) with eosinophilic oesophagitis, by haematoxylin and eosin staining and immunohistochemistry. METHODS: Immunohistochemistry was carried out using a monoclonal antibody for human eosinophilic major basic protein (MBP). Eosinophils were counted in three high power fields (x40) and degranulation, as quantified by extracellular MBP immunostaining, was scored on a scale of 1-4. Morphological changes (basal cell hyperplasia, elongation of papillae and dilatation of intercellular spaces) were scored on a 1-4 scale on sections stained with haematoxylin and eosin. RESULTS: Numbers of intraepithelial eosinophils were significantly higher with MBP immunostaining than with haematoxylin and eosin staining (mean 109.6 v 80.6; p<0.001), whereas numbers of eosinophils were considerably correlated (r = 0.794). Eosinophil degranulation was higher in the distal oesophagus. Additionally, basic morphological changes were markedly associated with eosinophil infiltration. Extracellular deposition of eosinophil-MBP and eosinophil infiltration in subepithelial connective tissue, present in the biopsy specimens, were detected by immunohistochemistry. CONCLUSION: Numbers of eosinophils and degranulation are underestimated by haematoxylin and eosin staining. Immunohistochemistry detected up to two times more eosinophils than routine haematoxylin and eosin staining. Moreover, eosinophil-MBP immunoreactivity in extracellular regions indicates the release of toxic eosinophil granule proteins and gives further evidence for a causative role of eosinophils with regard to structural changes in eosinophilic oesophagitis. Immunohistochemistry may serve as a useful diagnostic tool to support the morphological differential diagnosis of eosinophilic oesophagitis and gastro-oesophageal reflux disease.
Osteoarthritis is first and foremost the ongoing destruction of the articular cartilages of joints. Therefore, the extracellular matrix and the cells of the articular cartilages are the primary targets of osteoarthritis therapy. This tries to inhibit enzymatic destruction of the extracellular cartilage matrix as well as the modification of the cellular phenotype of the chondrocytes: cell degeneration and cell death are alongside anabolic activation and stabilization of the cellular phenotype of major interest. However, apart from the cartilage and its cells, other tissues of the joints are also important for the symptoms of the disease, which basically all originate outside the articular cartilage. In addition, changes in the subchondral bone as well as the synovial capsule and membrane are important at least for the progression of the disease process. All the named tissues offer different directions and ways for therapeutic intervention.
Dysplasia epiphysealis hemimelica (DEH) and metachondromatosis (MC) are considered in the differential diagnosis of solitary and hereditary osteochondromas. Both are rare disorders with DEH demonstrating cartilaginous overgrowth of an epiphysis and MC exhibiting synchronous enchondromas and osteochondromas. Ten cases of DEH and two of MC were compared with osteochondromas at the histological and molecular level. Histologically, clumping of chondrocytes within a fibrillary chondroid matrix is characteristic of DEH, while osteochondromas and MC display the characteristic growth plate architecture. Using cDNA microarray analysis we demonstrate that DEH and MC cluster separately from osteochondromas and growth plates. The EXT genes, involved in the hereditary multiple osteochondromas syndrome, and downregulated in osteochondroma, were normally expressed in DEH and MC as shown by quantitative reverse transcriptase-polymerase chain reaction (qPCR). EXT is involved in heparan sulphate biosynthesis, important for Indian Hedgehog/ParaThyroid Hormone Like Hormone (IHH/PTHLH) growth plate signalling pathways. IHH/PTHLH signalling molecules were expressed in DEH and MC as shown by both qPCR and immunohistochemistry, suggesting that this pathway is active. This is in contrast to osteochondroma, in which PTHLH signalling is downregulated. Thus, lesions of DEH and MC are separate entities from osteochondroma as confirmed by their different cDNA and protein expression profiles. Downstream targets of EXT, which are downregulated in osteochondroma, are expressed in DEH and MC, suggesting that EXT signalling is not disturbed.
The occurrence of primary non-Hodgkin's lymphomas of the testes is described in just a few studies in the urological literature. The clinical symptomatology and especially the treatment concept for this relatively rare tumor entity are hardly discussed. Imaging diagnostics, e.g., with CT or MRI, play a decisive role in determining the diagnosis and whether a primary testicular disease is involved or a generalized systemic disease. In cases of primary B-cell lymphomas of the testes, a high inguinal orchiectomy should be performed for diagnostic and therapeutic purposes. The standard chemotherapy for aggressive non-Hodgkin's lymphomas is the CHOP regimen consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone. This article presents two adults aged 67 and 75 years with histologically proven B-cell lymphoma of the testes and discusses the characteristics of this relatively rare clinical picture as well as treatment and prognosis.
Degenerative arthropathy (osteoarthritis) is one of the most common diseases in modern western societies, in particular in the elderly. The classification and grading of changes during cartilage degeneration represent complex endeavors which are only of limited value in daily pathological practice. In general, the process of joint destruction can always be evaluated for the determining pathogenesis ("typing"), extent ("staging") and degree of the most extensive focal damage ("grading"). However, for routine use one might best restrict description and reporting to the most essential features. This is in particular true for specimens obtained from endoprosthetic surgery (hips and knees), because there is currently no specific clinical relevance for further evaluation. Only the identification of secondary types of degenerative changes, such as those due to unknown rheumatoid disease, gout or extensive osteonecrosis, is of particular interest to the clinical colleague (i.e. typing of the joint lesion).
Articular cartilage has poor reparative capacities, and once damaged cartilage lesions remain chronic and can lead to osteoarthritis. Over the last decade, several innovative therapies have been introduced to promote the regeneration of articular cartilage while sustaining sufficient mechanical stress and permitting a pain free motion. An important measure of outcome is the morphological characterization of the repair tissue in order to allow for cross-study evaluation. The International Cartilage Repair Society has developed a analogue visual scale to quantify repair tissue, which is described in this paper.
Bone morphogenetic protein-7 (BMP)-7 plays an important role during fetal kidney development. In the adult, BMP-7 is most strongly expressed in the kidney compared to other organs, but the exact expression pattern as well as the function of BMP-7 is unclear. The major aim of the present study was to define which parts of the human kidney do physiologically express BMP-7 and which cells appear to be targets of BMP activity by showing phosphorylated BMP-receptor-associated Smads 1, 5, or 8 and inhibitor of differentiation factor 1 (ID1) expression. BMP-7 expression was localized by immunohistology to the epithelia of the distal tubule as well as the collecting ducts (CDs). Phospho-Smads 1/5/8 and ID1 expression largely colocalized with BMP-7 and was also localized in the epithelia of the distal tubule and the CDs. This was confirmed by polymerase chain reaction-based mRNA expression analysis. In vitro, proximal tubular cells (PTCs) expressed BMP receptors and BMP-receptor-associated Smads and were reactive to BMP-7. Our data indicate that BMP-7 expression in the adult human kidney appears to be more restricted than in the fetal situation and predominantly found in the distal nephron. Also, evidence of in vivo BMP signalling (i.e. phospho-Smads and ID1 expression) was found there. These findings suggest that BMP-7 plays a physiological role mostly in this part of the kidney. Still, as reported previously, PTCs are responsive to BMP-7, but presumably not in an autocrine or paracrine mode in normal adult kidneys.
AIM: Chondroblastoma and clear cell chondrosarcoma are uncommon skeletal neoplasms that have a strong tendency to involve the epiphysis of long bones. They also share some overlapping histological features. Thus, it can be difficult both radiographically and histologically to distinguish these neoplasms. So far there are no immunohistochemical markers available that have been shown to be helpful in differentiating these neoplasms. METHODS: In our study of a series of clear cell chondrosarcomas (n = 15) and chondroblastomas (n = 35), S100, vimentin, aggrecan and collagen type II were detected by immunohistochemistry. RESULTS: We detected immunohistochemical evidence of type II collagen within both the extracellular matrix-rich (chondroid) and matrix-poor areas in all 15 cases of clear cell chondrosarcoma. In contrast, immunohistochemical analysis failed to show staining of collagen type II in any of the 35 chondroblastomas. Other markers, including S100 protein, vimentin and aggrecan proteoglycan were tested in parallel and found to be focally positive in both neoplasms. CONCLUSION: Therefore, our data show that in cases when clear cell chondrosarcoma and chondroblastoma pose a diagnostic challenge, the presence of type II collagen in the extracellular tumour matrix significantly supports the diagnosis of clear cell chondrosarcoma and aids in distinguishing it from chondroblastoma.
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AIMS: The introduction of clearly defined histopathological criteria for a standardised evaluation of the periprosthetic membrane, which can appear in cases of total joint arthroplasty revision surgery. METHODS: Based on histomorphological criteria, four types of periprosthetic membrane were defined: wear particle induced type (detection of foreign body particles; macrophages and multinucleated giant cells occupy at least 20% of the area; type I); infectious type (granulation tissue with neutrophilic granulocytes, plasma cells and few, if any, wear particles; type II); combined type (aspects of type I and type II occur simultaneously; type III); and indeterminate type (neither criteria for type I nor type II are fulfilled; type IV). The periprosthetic membranes of 370 patients (217 women, 153 men; mean age 67.6 years, mean period until revision surgery 7.4 years) were analysed according to the defined criteria. RESULTS: Frequency of histopathological membrane types was: type I 54.3%, type II 19.7%, type III 5.4%, type IV 15.4%, and not assessable 5.1%. The mean period between primary arthroplasty and revision surgery was 10.1 years for type I, 3.2 years for type II, 4.5 years for type III and 5.4 years for type IV. The correlation between histopathological and microbiological diagnosis was high (89.7%), and the inter-observer reproducibility sufficient (85%). CONCLUSION: The classification proposed enables standardised typing of periprosthetic membranes and may serve as a tool for further research on the pathogenesis of the loosening of total joint replacement. The study highlights the importance of non-infectious, non-particle induced loosening of prosthetic devices in orthopaedic surgery (membrane type IV), which was observed in 15.4% of patients.
Cartilage exerts many functions in different tissues and parts of the body. Specific requirements presumably also account for a specific biochemical composition. In this study, we investigated the presence and distribution pattern of matrix components, in particular collagen types in the major human cartilages (hyaline, fibrous, and elastic cartilage) by histochemical and immunohistochemical means. Macroscopically normal articular cartilages, menisci, disci (lumbar spine), epiglottal, and tracheal tissues were obtained from donors at autopsy. Aurical and nasal cartilages were part of routine biopsy samples from tumor resection specimens. Conventional histology and immunohistochemical stainings with collagen types I, II, III, IV, V, VI, and X and S-100 protein antibodies were performed on paraformaldehyde-fixed and paraffin-embedded specimens. The extracellular matrix is the functional component of all cartilages as indicated by the low cell densities. In particular major scaffold forming collagen types I (in fibrous cartilage) and II (in hyaline and elastic cartilages) as well as collagen type X (in the calcified layer of articular cartilages, the inner part of tracheal clips, and epiglottis cartilage) showed a specific distribution. In contrast, the "minor" collagen types III, V, and VI were found in all, collagen type IV in none of the cartilage subtypes. In this study, we present a biochemical profile of the major cartilage types of the human body which is important for understanding the physiology and the pathophysiology of cartilages.
OBJECTIVE: The objective of this study was to determine whether collagen type II breakdown products in synovial fluid (SF), detected by an enzyme-linked immunoassay, represent a useful marker for early events in osteoarthritis (OA) in the rabbit medial meniscectomy model. DESIGN: Complete medial meniscectomy was performed on the right knee joints of 32 rabbits. Balanced groups of rabbits were then sacrificed at 2, 4, 8, and 12 weeks post-surgery. An additional 8 unoperated and 11 sham-operated animals served as controls. SF lavages were performed on right and left knee joints of the same animals at sacrifice. The proteolytic epitope of type II collagen was monitored using an enzyme-linked immunoassay. RESULTS: Macroscopically visible surface fibrillation and focal erosions appeared as early as 2 weeks after meniscectomy in the femorotibial joint (P<0.01). OA developed gradually during the later observation period, and then predominantly on the medial tibial plateau and medial femur. Significant histological alterations in cartilage, including a loss of proteoglycans, surface irregularities, and clefts, were detected at 2 weeks after meniscectomy (P<0.01). Collagen type II epitope levels in SF lavage samples were elevated peaking at 2 weeks after meniscectomy (P<0.02). Levels decreased at later time points, but they were still raised at 12 weeks (P< or =0.05). Highly significant correlations were found between the SF collagen type II epitope levels and the macroscopic and microscopic scoring results (Spearman rho correlation coefficient, macroscopy-collagen type II epitope r=0.222, P=0.025; microscopy-collagen type II epitope r=0.436, P< or =0.01). CONCLUSION: In this rabbit model of medial meniscectomy, levels of type II collagen fragments in SF appear to provide a useful marker of the early degenerative changes.
OBJECTIVES: This review is focused on the influence of oxygen and derived reactive species on chondrocytes aging, metabolic function and chondrogenic phenotype. METHODS: A systematic computer-aided search of the Medline database. RESULTS: Articular cartilage is an avascular tissue, and consequently oxygen supply is reduced. Although the basal metabolic functions of the cells are well adapted to hypoxia, the chondrocyte phenotype seems to be oxygen sensitive. In vitro, hypoxia promotes the expression of the chondrogenic phenotype and cartilage-specific matrix formation, indicating that oxygen tension is probably a key parameter in chondrocyte culture, and particularly in the context of tissue engineering and stem cells transplantation. Besides the influence of oxygen itself, reactive oxygen species (ROS) play a crucial role in the regulation of a number of basic chondrocyte activities such as cell activation, proliferation and matrix remodeling. However, when ROS production exceeds the antioxidant capacities of the cell, an "oxidative stress" occurs leading to structural and functional cartilage damages like cell death and matrix degradation. CONCLUSIONS: This paper is an overview of the in vitro and in vivo studies published on the influence of oxygen and derived reactive species on chondrocyte aging, metabolic function, and the chondrogenic phenotype. It shows, that oxygen and ROS play a crucial role in the control of cartilage homeostasis and that at this time, the exact role of "oxidative stress" in cartilage degradation still remains questionable.