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Claus W Heizmann - One of the best experts on this subject based on the ideXlab platform.
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Differential expression of S100A2 and S100A4 in lung adenocarcinomas: clinicopathological significance, relationship to p53 and identification of their target genes.
Cancer science, 2005Co-Authors: Daisuke Matsubara, Claus W Heizmann, Toshiro Niki, Shumpei Ishikawa, Akiteru Goto, Etsuko Ohara, Takehiko Yokomizo, Hiroyuki Aburatani, Sachiko Moriyama, Hirokazu MoriyamaAbstract:Previous studies suggest that some S100 proteins are involved in the progression of certain types of cancer. However, no comprehensive data is currently available on the expression of S100 family genes in lung adenocarcinomas. Oligonucleotide array, quantitative reverse transcription–polymerase chain reaction and western blot analyses of lung adenocarcinoma cell lines and bronchiolar epithelial cells (SAEC and NHBE) revealed that S100A2 and S100A4 were the most strikingly downregulated and upregulated members of the S100 family, respectively. Immunohistochemical analyses of 94 primary lung adenocarcinomas showed that positive S100A2 expression (33/94, 35.1%) was significantly associated with lymphatic invasion (P = 0.0233) and positive S100A4 expression (19/94, 20.2%) with vascular invasion (P = 0.0454). Interestingly, a strong inverse relationship was found between S100A4 and p53 expression (P = 0.0008). Survival analyses showed that S100A4 positivity was associated with poor patient prognosis (P = 0.042). S100A2 positivity was not associated with patient survival when the whole patient group was analyzed; however, S100A2 positivity was a favorable prognostic indicator in patients with p53-negative tumors (P = 0.0448). Finally, we used oligonucleotide array analyses and identified potential S100A2 and S100A4 target genes involved in cancer progression: S100A2 induced RUNX3 and REPRIMO; S100A4 induced EZRIN, RUNX1 and WISP1; S100A2 repressed EGFR, NFKB2 and RELA2; and S100A4 repressed ANXA10 and IL1RN. Thus, the present study demonstrates involvement of S100A2 and S100A4 in the progression of lung adenocarcinomas and an inverse association between S100A4 and p53 expression, and provides a list of targets regulated by S100A2 and S100A4. (Cancer Sci 2005; 96: 844–857)
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Expression analysis of S100 proteins and RAGE in human tumors using tissue microarrays
Biochemical and biophysical research communications, 2003Co-Authors: Hsiao-ling Hsieh, Beat W Schafer, Nobuyuki Sasaki, Claus W HeizmannAbstract:Microarray technology provides important information for diagnostic, prognostic, and even therapeutic applications. Several S100 proteins have been proposed to play important roles in tumor progression and are recognized as potential tumor markers. To substantiate these limited earlier findings, we screened hundreds of tumor specimens from patients of eight different tumor types using tissue microarrays. The results validated the expression of S100A4, S100A6, and S100B in specific tumor types. A significant S100A2 expression was observed in lymphoma biopsies, which implies a possible link between this S100 protein and lymphoma development. In contrast, S100A5 and S100A12 were not significantly expressed in any of the tumor tissues tested. Interestingly, expression of RAGE (receptor for advanced glycation end products) was found in breast and lung tumor tissues where abundant S100A4 and S100A6 expression was also observed. This suggests a possible role of RAGE-mediated signal transduction in the development of these particular cancers.
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s100 proteins in corpora amylacea from normal human brain
Brain Research, 2000Co-Authors: Daphne Hoyaux, Beat W Schafer, Christine Decaestecker, Isabelle Salmon, Thomas Vogl, Claus W Heizmann, Robert Kiss, Roland PochetAbstract:Corpora amylacea (C.A.) also named polyglucosan bodies (P.B.) are one of the hallmarks of normal brain aging. Although their functions are not yet clear, C.A. increase in number in patients suffering from neurodegenerative diseases. C.A. contain 88% of hexoses and 4% of proteins. Most of the proteins in C.A. are aging or stress proteins such as heat shock proteins, ubiquitinated proteins and advanced glycation end products which are also proinflammatory products. Stimulated by the potential role played by some S100 proteins in the inflammatory process which may be triggered in C.A., we investigated, by immunohistochemistry, the presence of different S100 proteins (S100A1, S100A2, S100A3, S100A4, S100A5, S100A6, S100A8, S100A9, S100A12 and S100B) in C.A. from normal human brain. Among the ten S100 proteins analyzed, nine (S100A) were detected in C.A. Three S100 proteins (S100A8, S100A9, S100A12) which are highly expressed in activated macrophages and used as inflammatory markers were detected in C.A. S100A8 was, in addition, found in thick neuronal processes from the pons. One (S100B) could not be found in C.A. although it was highly expressed in astrocytes. In C.A., the staining intensity was estimated by computer-assisted microscopy and gave the following order: S100A1 congruent withS100A8 congruent with S100A9>S100A5> or =S100A4>S100A12>S100A6> S100A2=S100A3. The potential inflammatory role played by S100 proteins in C.A. is discussed.
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expression pattern of s100 calcium binding proteins in human tumors
International Journal of Cancer, 1996Co-Authors: Beat W Schafer, Claus W HeizmannAbstract:The S100 Ca2+-binding proteins recently became of major interest because of their differential expression in neoplastic tissues, their involvement in metastatic processes, and the clustered organization of at least 10 S100 genes on human chromosome 1q21, a region frequently rearranged in several tumors. As a first attempt towards a specific and differentiated immunohistochemical classification of human tumors, we produced, purified and characterized a number of human recombinant S100 proteins and raised specific polyclonal antibodies. Their distinct cellular and intracellular localization was examined by immunohistochemical methods in normal and cancerogenic human tissues and cell lines. S100A1 and S100A2 can be detected in a few normal tissues only, whereas S100A4, S100A6, and S100B are expressed at higher levels in cancer tissues. In the future, these S100 antibodies will potentially be of great value in cancer diagnosis and therapy. © 1996 Wiley-Liss, Inc.
Philippe A Tessier - One of the best experts on this subject based on the ideXlab platform.
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S100A8 and S100A9 induce cytokine expression and regulate the NLRP3 inflammasome via ROS-dependent activation of NF-κB(1.).
PLoS ONE, 2013Co-Authors: Jean-christophe Simard, Annabelle Cesaro, Julie Chapeton-montes, Mélanie Tardif, Francis Antoine, Denis Girard, Philippe A TessierAbstract:S100A8 and S100A9 are cytoplasmic proteins expressed by phagocytes. High concentrations of these proteins have been correlated with various inflammatory conditions, including autoimmune diseases such as rheumatoid arthritis and Crohn's disease, as well as autoinflammatory diseases. In the present study, we examined the effects of S100A8 and S100A9 on the secretion of cytokines and chemokines from PBMCs. S100A8 and S100A9 induced the secretion of cytokines such as IL-6, IL-8, and IL-1β. This secretion was associated with the activation and translocation of the transcription factor NF-κB. Inhibition studies using antisense RNA and the pharmacological agent BAY-117082 confirmed the involvement of NF-κB in IL-6, IL-8, and IL-1β secretion. S100A8- and S100A9-mediated activation of NF-κB, the NLR family, pyrin domain-containing 3 (NLRP3) protein, and pro-IL-1β expression was dependent on the generation of reactive oxygen species. This effect was synergistically enhanced by ATP, a known inflammasome activator. These results suggest that S100A8 and S100A9 enhance the inflammatory response by inducing cytokine secretion of PBMCs.
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blockade of antimicrobial proteins s100a8 and s100a9 inhibits phagocyte migration to the alveoli in streptococcal pneumonia
Journal of Immunology, 2008Co-Authors: Marieastrid Raquil, Nadia Anceriz, Pascal Rouleau, Philippe A TessierAbstract:We investigated the roles of the potent, chemotactic antimicrobial proteins S100A8, S100A9, and S100A8/A9 in leukocyte migration in a model of streptococcal pneumonia. We first observed differential secretion of S100A8, S100A9, and S100A8/A9 that preceded neutrophil recruitment. This is partially explained by the expression of S100A8 and S100A9 proteins by pneumocytes in the early phase of Streptococcus pneumoniae infection. Pretreatment of mice with anti-S100A8 and anti-S100A9 Abs, alone or in combination had no effect on bacterial load or mice survival, but caused neutrophil and macrophage recruitment to the alveoli to diminish by 70 and 80%, respectively, without modifying leukocyte blood count, transendothelial migration or neutrophil sequestration in the lung vasculature. These decreases were also associated with a 68% increase of phagocyte accumulation in lung tissue and increased expression of the chemokines CXCL1, CXCL2, and CCL2 in lung tissues and bronchoalveolar lavages. These results show that S100A8 and S100A9 play an important role in leukocyte migration and strongly suggest their involvement in the transepithelial migration of macrophages and neutrophils. They also indicate the importance of antimicrobial proteins, as opposed to classical chemotactic factors such as chemokines, in regulating innate immune responses in the lung.
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blockade of s100a8 and s100a9 suppresses neutrophil migration in response to lipopolysaccharide
Journal of Immunology, 2003Co-Authors: Karen Vandal, Pascal Rouleau, Carle Ryckman, Annie Boivin, Marieve Talbot, Philippe A TessierAbstract:Recently, proinflammatory activities had been described for S100A8 and S100A9, two proteins found at inflammatory sites and within the neutrophil cytoplasm. In this study, we investigated the role of these proteins in neutrophil migration in vivo in response to LPS. LPS was injected into the murine air pouch, which led to the release of S100A8, S100A9, and S100A8/A9 in the pouch exudates that preceded accumulation of neutrophils. Passive immunization against S100A8 and S100A9 led to a 52% inhibition of neutrophil migration in response to LPS at 3 h postinjection. Injection of LPS was also associated with an increase in peripheral blood neutrophils and the presence in serum of S100A9 and S100A8/A9. Intravenous injection of S100A8, S100A9, or S100A8/A9 augmented the number of circulating neutrophils and diminished the number of neutrophils in the bone marrow, demonstrating that S100A8 and S100A9 induced the mobilization of neutrophils from the bone marrow to the blood. Finally, passive immunization with anti-S100A9 inhibited the neutrophilia associated with LPS injection in the air pouch. These results suggest that S100A8 and S100A9 play a role in the inflammatory response to LPS by inducing the release of neutrophils from the bone marrow and directing their migration to the inflammatory site.
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role of s100a8 and s100a9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air pouch model of acute gouty arthritis
Arthritis & Rheumatism, 2003Co-Authors: Carle Ryckman, Shaun R Mccoll, Karen Vandal, Rinaldo De Medicis, A Lussier, Patrice E Poubelle, Philippe A TessierAbstract:Objective To examine the role of chemokines, S100A8, and S100A9 in neutrophil accumulation induced by the causative agent of gout, monosodium urate monohydrate (MSU) crystals. Methods MSU crystal–induced neutrophil migration was studied in the murine air-pouch model. Release of chemokines, S100A8, S100A9, and S100A8/A9 in response to MSU crystals was quantified by enzyme-linked immunosorbent assays. Recruited cells were counted following acetic blue staining, and the subpopulations were characterized by Wright-Giemsa staining of cytospins. Results MSU crystals induced the accumulation of neutrophils following injection in the air pouch, which correlated with the release of the chemokines CXCL1, CXCL2, CCL2, and CCL3. However, none of these was found to play an important role in neutrophil migration induced by MSU crystals by passive immunization with antibodies directed against each chemokine. S100A8, S100A9, and S100A8/A9 were also found at high levels in the pouch exudates following injection of MSU crystals. In addition, injection of S100A8, S100A9, or S100A8/A9 led to the accumulation of neutrophils in the murine air pouch, demonstrating their proinflammatory activities in vivo. Passive immunization with anti-S100A8 and anti-S100A9 led to a total inhibition of the accumulation of neutrophils. Finally, S100A8/A9 was found at high concentrations in the synovial fluid of patients with gout. Conclusion S100A8 and S100A8/A9 are essential to neutrophil migration induced by MSU crystals. These results suggest that they might be involved in the pathogenesis of gout.
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proinflammatory activities of s100 proteins s100a8 s100a9 and s100a8 a9 induce neutrophil chemotaxis and adhesion
Journal of Immunology, 2003Co-Authors: Carle Ryckman, Pascal Rouleau, Karen Vandal, Marieve Talbot, Philippe A TessierAbstract:S100A8 and S100A9 are small calcium-binding proteins that are highly expressed in neutrophil and monocyte cytosol and are found at high levels in the extracellular milieu during inflammatory conditions. Although reports have proposed a proinflammatory role for these proteins, their extracellular activity remains controversial. In this study, we report that S100A8, S100A9, and S100A8/A9 caused neutrophil chemotaxis at concentrations of 10−12–10−9 M. S100A8, S100A9, and S100A8/A9 stimulated shedding of L-selectin, up-regulated and activated Mac-1, and induced neutrophil adhesion to fibrinogen in vitro. Neutralization with Ab showed that this adhesion was mediated by Mac-1. Neutrophil adhesion was also associated with an increase in intracellular calcium levels. However, neutrophil activation by S100A8, S100A9, and S100A8/A9 did not induce actin polymerization. Finally, injection of S100A8, S100A9, or S100A8/A9 into a murine air pouch model led to rapid, transient accumulation of neutrophils confirming their activities in vivo. These studies 1) show that S100A8, S100A9, and S100A8/A9 are potent stimulators of neutrophils and 2) strongly suggest that these proteins are involved in neutrophil migration to inflammatory sites.
Charlotta Enerbäck - One of the best experts on this subject based on the ideXlab platform.
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S100A7 psoriasin highly expressed in ductal carcinoma in situ dcis is regulated by ifn gamma in mammary epithelial cells
BMC Cancer, 2007Co-Authors: Stina Petersson, Anna Bylander, Maria Yhr, Charlotta EnerbäckAbstract:Background The aim of the present work was to explore signal transduction pathways used in the regulation of S100A7 (psoriasin). Members of the S100 gene family participate in many important cellular functions. Psoriasin, S100A8 (calgranulin A) and S100A9 (calgranulin B) are expressed in ductal carcinoma in situ (DCIS), as well as in the hyperproliferative skin disease, psoriasis. In the latter condition, a disturbance in the STAT pathway has recently been reported. This pathway is implicated in the regulation of IFN-gamma, widely recognized as a key cytokine in psoriasis. IFN-gamma also exerts anti-tumor action in a number of tumor cell types, including breast cancer. We therefore examined the effect of IFN-gamma and STAT-signaling on the psoriasin expression.
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Cluster analysis of S100 gene expression and genes correlating to psoriasin (S100A7) expression at different stages of breast cancer development.
International journal of oncology, 2005Co-Authors: Hanna Carlsson, Stina Petersson, Charlotta EnerbäckAbstract:Gene expression patterns in ductal carcinoma in situ (DCIS) and invasive and metastatic breast tumors have been determined using serial analysis of gene expression (SAGE). The purpose of this approach was to identify biologically and clinically meaningful subgroups of DCIS with a high risk of progression to invasive disease. The analyses have led to the identification of several differentially expressed genes, such as HIN-1, dermcidin and S100A7 (psoriasin). The aim of the present study was further to delineate the expression profile of S100 genes using information from 22 breast epithelial SAGE libraries. We demonstrated the down-regulation of S100A6 and S100A10 in breast cancer, irrespective of pathological stage. S100P and S100Z were both up-regulated in cancer; whereas S100A7, S100A8 and S100A9 were strongly up-regulated only in DCIS. The hierarchical clustering of S100 gene expression in these 22 libraries revealed two major groups with distinguishable S100 gene expression profiles. One of them was characterized by the high concomitant expression of S100A7, S100A8 and S100A9. Using SAGE informatics, we found 21 genes with a high positive correlation to S100A7 expression in libraries representing different categories of tissues archived at SAGE Genie, suggesting a function of psoriasin that is not tissue specific. Like S100A7, several of these genes displayed cation-binding properties. We also report the strong correlation in the breast epithelial SAGE libraries between the expression of S100A7 and genes reported as being up-regulated in DCIS, as well as in the inflammatory skin disorder, psoriasis; including RGS5, UPK1A, TMPRSS3, S100A9, p53, SCCA1, SCCA2 and KRT17.
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Expression patterns of S100A7 (psoriasin) and S100A9 (calgranulin-B) in keratinocyte differentiation.
Experimental dermatology, 2005Co-Authors: Hanna Martinsson, Maria Yhr, Charlotta EnerbäckAbstract:S100 proteins are involved in many biological processes. S100A7 and S100A9 have been shown to be markedly upregulated both in ductal carcinoma in situ of the breast and in psoriasis. We have examined the relationship between keratinocyte differentiation and the expression of the two proteins. Using Western blot analysis and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), both S100A7 and S100A9 were shown to be induced in normal primary keratinocytes (HEKn), when differentiation was promoted by high extracellular calcium, loss of contact with extracellular matrix and confluent conditions, as previously reported for S100A7 in mammary epithelial cells. Differentiation was confirmed by using RT-PCR for the differentiation marker keratin-1. Using immunohistochemistry with monoclonal antibodies, we compared the expression of the two proteins in a spectrum of conditions of dysregulated keratinocyte differentiation. We found a strikingly similar distribution of the proteins. Their expression correlated with the degree of keratinocyte differentiation. They were both absent in undifferentiated basalioma and strongly expressed in carcinoma in situ, as well as in keratoacanthoma and differentiated squamous cell carcinoma. In normal epithelium, they were expressed in the superficial, differentiated region of the epithelium rather than in the basal region. These findings support the hypothesis that these two S100 proteins are involved in keratinocyte differentiation.
Johannes Roth - One of the best experts on this subject based on the ideXlab platform.
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alarmins s100a8 s100a9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis
Annals of the Rheumatic Diseases, 2016Co-Authors: R.f. Schelbergen, W. De Munter, M.h. Van Den Bosch, Annet W. Sloetjes, Johannes Roth, Thomas Vogl, W.b. Van Den Berg, Peter M Van Der Kraan, Floris P J G Lafeber, Arjen B. BlomAbstract:OBJECTIVE: Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study, we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and whether S100A8/A9 predicts osteophyte progression in early human OA. METHODS: OA was elicited in S100A9-/- mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN neoepitope was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA participants of the Cohort Hip and Cohort Knee (CHECK) cohort study and osteophytes measured after 2 and 5 years. RESULTS: Osteophyte size was drastically reduced in S100A9-/- mice in ligaments and at medial femur and tibia on days 21 and 42 of collagenase-induced OA, in which synovial activation is high. In contrast, osteophyte size was not reduced in S100A9-/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of matrix metalloproteinases during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA participants of the CHECK study with osteophyte progression after 2 and 5 years had elevated S100A8/A9 plasma levels at baseline, while C-reactive protein, erythrocyte sedimentation rate and cartilage oligomeric matrix protein were not elevated at baseline. CONCLUSIONS: S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte progression in early symptomatic human OA.
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Alarmins S100A8/S100A9 aggravate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human symptomatic osteoarthritis
Annals of the Rheumatic Diseases, 2014Co-Authors: R.f. Schelbergen, W. De Munter, M.h. Van Den Bosch, Annet W. Sloetjes, Johannes Roth, Thomas Vogl, W.b. Van Den Berg, Peter M Van Der Kraan, Floris P J G Lafeber, Arjen B. BlomAbstract:OBJECTIVE: Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study, we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and whether S100A8/A9 predicts osteophyte progression in early human OA. METHODS: OA was elicited in S100A9-/- mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN neoepitope was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA participants of the Cohort Hip and Cohort Knee (CHECK) cohort study and osteophytes measured after 2 and 5 years. RESULTS: Osteophyte size was drastically reduced in S100A9-/- mice in ligaments and at medial femur and tibia on days 21 and 42 of collagenase-induced OA, in which synovial activation is high. In contrast, osteophyte size was not reduced in S100A9-/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of matrix metalloproteinases during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA participants of the CHECK study with osteophyte progression after 2 and 5 years had elevated S100A8/A9 plasma levels at baseline, while C-reactive protein, erythrocyte sedimentation rate and cartilage oligomeric matrix protein were not elevated at baseline. CONCLUSIONS: S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte progression in early symptomatic human OA.
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OP0146 Alarmins S100a8/S100a9 Aggravate Osteophyte Formation in Experimental Osteoarthritis and PREDICT Osteophyte Progression in Early Human Osteoarthritis in the Dutch CHECK Cohort
Annals of the Rheumatic Diseases, 2014Co-Authors: R.f. Schelbergen, W. De Munter, M.h. Van Den Bosch, Annet W. Sloetjes, Johannes Roth, Thomas Vogl, W.b. Van Den Berg, Peter M Van Der Kraan, Floris P J G Lafeber, Arjen B. BlomAbstract:Background The main pathological feature of osteoarthritis (OA) is degradation of the articular cartilage. Other important hallmarks include subclinical inflammation of the synovium and ectopic formation of new bone and cartilage at the ligaments or joint margins, termed osteophytes. Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (1) (OA). Objectives In the current study we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and if S100A8/A9 predicts osteophyte progression in early human OA. Methods OA was elicited in S100A9 -/- and wild-type C57Bl/6 mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN expression was measured on histology. Chondrogenesis was induced in murine mesenchymal stem cells (MSCs) in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA patients of the CHECK cohort study and osteophyte size measured at baseline and after 2 and 5 years. Results S100A8 and S100A9 protein levels in the synovial lining and serum coincide with osteophyte development in collagenase-induced OA (CIOA), in which synovial activation is high. Osteophyte size was drastically reduced in S100A9 -/- mice on day 21 and 42 of CIOA, in the medial collateral ligaments (58% and 93% reduction) and at medial femur and tibia (62% and 67% reduction). In contrast, osteophyte size was not reduced in S100A9 -/- mice during destabilized medial meniscus OA, in which synovial activation is scant. One explanation for the reduced osteophyte size in S100A9-/- mice may be a direct effect of S100-proteins on chondrogenesis. During in vitro chondrogenesis using murine MSCs, S100A8 caused a marked increase in MMP-3 mRNA and VDIPEN expression (as measure for MMP activity) as well as a strongly altered morphology, indicating increased remodeling allowing for larger osteophytes. Interestingly, early symptomatic OA patients of the CHECK study with osteophyte progression after two and five years had significantly elevated S100A8/A9 plasma levels at baseline, while CRP, COMP and ESR were not higher. Conclusions S100A8/A9 aggravate osteophyte formation in experimental OA with high synovial activation and may be used to predict osteophyte formation in early human OA. References van Lent PL, Blom AB, Schelbergen RF, Sloetjes A, Lafeber FP, Lems WF, et al. Active involvement of alarmins S100A8 and S100A9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis. Arthritis and rheumatism. 2012 May; 64(5):1466-1476 Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3178
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A5.11 alarmins S100A8/S100A9 stimulate osteophyte formation in experimental osteoarthritis and predict osteophyte progression in early human osteoarthritis
Annals of the Rheumatic Diseases, 2014Co-Authors: R.f. Schelbergen, W. De Munter, M.h. Van Den Bosch, Annet W. Sloetjes, Johannes Roth, Thomas Vogl, W.b. Van Den Berg, Peter M Van Der Kraan, Floris P J G Lafeber, Arjen B. BlomAbstract:Background and Objectives The main pathological feature of osteoarthritis (OA) is degradation of the articular cartilage. However, other important hallmarks include subclinical inflammation of the synovium and ectopic formation of new bone and cartilage at the ligaments or joint margins, termed osteophytes. Selective depletion of synovial macrophages prevents development of osteophytes in collagenase induced OA. Alarmins S100A8 and S100A9 are major products of activated macrophages regulating cartilage damage and synovial activation during murine and human osteoarthritis (OA). In the current study we investigated whether S100A8 and S100A9 are involved in osteophyte formation during experimental OA and if S100A8/A9 predicts osteophyte progression in early human OA. Materials and Methods OA was elicited in S100A9 -/- and wild-type C57Bl/6 mice in two experimental models that differ in degree of synovial activation. Osteophyte size, S100A8, S100A9 and VDIPEN expression was measured histologically. Chondrogenesis was induced in murine mesenchymal stem cells in the presence of S100A8. Levels of S100A8/A9 were determined in plasma of early symptomatic OA patients of the CHECK cohort study at baseline and development of osteophytes measured after 2 and 5 years. Results S100A8 and S100A9 protein levels in the synovial lining and serum coincide with osteophyte development in collagenase-induced OA (CIOA), in which synovial activation is high. Osteophyte size was drastically reduced in S100A9 -/- mice on day 21 and 42 of CIOA, in the medial collateral ligaments (58% and 93% reduction) and at medial femur and tibia (62% and 67% reduction). In contrast, osteophyte size was not reduced in S100A9 -/- mice during destabilised medial meniscus OA, in which synovial activation is scant. S100A8 increased expression and activation of MMPs during micromass chondrogenesis, thereby possibly increasing cartilage matrix remodelling allowing for larger osteophytes. Interestingly, early symptomatic OA patients of the CHECK study with osteophyte progression after two and five years had significantly elevated S100A8/A9 plasma levels at baseline, while CRP, COMP and ESR were not higher. Conclusions S100A8/A9 stimulate osteophyte formation in experimental OA with high synovial activation and may be used as a marker to predict osteophyte formation in early human OA.
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active involvement of alarmins s100a8 and s100a9 in the regulation of synovial activation and joint destruction during mouse and human osteoarthritis
Arthritis & Rheumatism, 2012Co-Authors: Peter L E M Van Lent, R.f. Schelbergen, Annet W. Sloetjes, Johannes Roth, Arjen B. Blom, Thomas Vogl, Floris P J G Lafeber, W F Lems, Hans Cats, W.b. Van Den BergAbstract:Objective To investigate whether alarmins S100A8 and S100A9 are involved in mediating cartilage destruction during murine and human osteoarthritis (OA). Methods Two different murine models of OA that differed in terms of synovial activation were compared. Cartilage destruction was measured histologically. Synovial biopsy and serum samples from OA patients were derived from the Cohort Hip and Cohort Knee (CHECK) patients with symptomatic early OA. Expression of mediators in the synovium was measured by reverse transcription–polymerase chain reaction analysis and immunolocalization. Results In collagenase-induced OA, which showed marked synovial activation, interleukin-1β was expressed at significant levels only during the early stages of disease, whereas S100A8 and S100A9 expression remained high for a prolonged period of time (up to day 21 after induction). In S100A9-knockout mice, we found a major impact of S100A8 and S100A9 on synovial activation (62% inhibition) and OA cartilage destruction (45–73% inhibition) as compared to wild-type controls. In contrast, in the surgically induced destabilized medial meniscus model, in which synovial involvement is scant, we found no role of S100A8 and S100A9 in the focal OA cartilage destruction. Examination of arthroscopic synovial biopsy samples from patients in the early symptomatic OA CHECK cohort revealed substantial levels of S100A8 and S100A9 messenger RNA and protein, which correlated significantly with synovial lining thickness, cellularity in the subintima, and joint destruction. Levels of S100A8/A9 serum protein were significantly enhanced (19%) at baseline in patients who had pronounced progression of joint destruction after 2 years. Conclusion Our data suggest that the S100A8 and S100A9 proteins are crucially involved in synovial activation and cartilage destruction during OA and that high levels may predict joint destruction in humans with OA.
Beat W Schafer - One of the best experts on this subject based on the ideXlab platform.
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Expression analysis of S100 proteins and RAGE in human tumors using tissue microarrays
Biochemical and biophysical research communications, 2003Co-Authors: Hsiao-ling Hsieh, Beat W Schafer, Nobuyuki Sasaki, Claus W HeizmannAbstract:Microarray technology provides important information for diagnostic, prognostic, and even therapeutic applications. Several S100 proteins have been proposed to play important roles in tumor progression and are recognized as potential tumor markers. To substantiate these limited earlier findings, we screened hundreds of tumor specimens from patients of eight different tumor types using tissue microarrays. The results validated the expression of S100A4, S100A6, and S100B in specific tumor types. A significant S100A2 expression was observed in lymphoma biopsies, which implies a possible link between this S100 protein and lymphoma development. In contrast, S100A5 and S100A12 were not significantly expressed in any of the tumor tissues tested. Interestingly, expression of RAGE (receptor for advanced glycation end products) was found in breast and lung tumor tissues where abundant S100A4 and S100A6 expression was also observed. This suggests a possible role of RAGE-mediated signal transduction in the development of these particular cancers.
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s100 proteins in corpora amylacea from normal human brain
Brain Research, 2000Co-Authors: Daphne Hoyaux, Beat W Schafer, Christine Decaestecker, Isabelle Salmon, Thomas Vogl, Claus W Heizmann, Robert Kiss, Roland PochetAbstract:Corpora amylacea (C.A.) also named polyglucosan bodies (P.B.) are one of the hallmarks of normal brain aging. Although their functions are not yet clear, C.A. increase in number in patients suffering from neurodegenerative diseases. C.A. contain 88% of hexoses and 4% of proteins. Most of the proteins in C.A. are aging or stress proteins such as heat shock proteins, ubiquitinated proteins and advanced glycation end products which are also proinflammatory products. Stimulated by the potential role played by some S100 proteins in the inflammatory process which may be triggered in C.A., we investigated, by immunohistochemistry, the presence of different S100 proteins (S100A1, S100A2, S100A3, S100A4, S100A5, S100A6, S100A8, S100A9, S100A12 and S100B) in C.A. from normal human brain. Among the ten S100 proteins analyzed, nine (S100A) were detected in C.A. Three S100 proteins (S100A8, S100A9, S100A12) which are highly expressed in activated macrophages and used as inflammatory markers were detected in C.A. S100A8 was, in addition, found in thick neuronal processes from the pons. One (S100B) could not be found in C.A. although it was highly expressed in astrocytes. In C.A., the staining intensity was estimated by computer-assisted microscopy and gave the following order: S100A1 congruent withS100A8 congruent with S100A9>S100A5> or =S100A4>S100A12>S100A6> S100A2=S100A3. The potential inflammatory role played by S100 proteins in C.A. is discussed.
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expression pattern of s100 calcium binding proteins in human tumors
International Journal of Cancer, 1996Co-Authors: Beat W Schafer, Claus W HeizmannAbstract:The S100 Ca2+-binding proteins recently became of major interest because of their differential expression in neoplastic tissues, their involvement in metastatic processes, and the clustered organization of at least 10 S100 genes on human chromosome 1q21, a region frequently rearranged in several tumors. As a first attempt towards a specific and differentiated immunohistochemical classification of human tumors, we produced, purified and characterized a number of human recombinant S100 proteins and raised specific polyclonal antibodies. Their distinct cellular and intracellular localization was examined by immunohistochemical methods in normal and cancerogenic human tissues and cell lines. S100A1 and S100A2 can be detected in a few normal tissues only, whereas S100A4, S100A6, and S100B are expressed at higher levels in cancer tissues. In the future, these S100 antibodies will potentially be of great value in cancer diagnosis and therapy. © 1996 Wiley-Liss, Inc.