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Mosaic chromosomal aberrations in synovial fibroblasts of patients with rheumatoid arthritis, osteoarthritis, and other inflammatory joint diseases
Raimund W Kinne, Thomas Liehr, Volkmar Beensen, Elke Kunisch, Thomas Zimmermann, Heidrun Holland, Robert Pfeiffer, Hans-Detlev Stahl, Wolfgang Lungershausen, Gert Hein, Andreas Roth, Frank Emmrich, Uwe Claussen, Ursula G Froster
Arthritis Research & Therapy , 2001, DOI: 10.1186/ar322
Abstract: Human rheumatoid arthritis (RA) is characterized by chronic inflammation and destruction of multiple joints, perpetuated by an invasive pannus tissue. Activated synovial fibroblasts (SFB), whether reversibly stimulated by the inflammatory microenvironment [1,2,3,4,5,6,7,8] or irreversibly transformed [2,3,4,5,6,7,9,10,11], are a major component of the pannus and contribute to the joint destruction by secretion of proinflammatory cytokines and tissue-degrading enzymes [1].While specific chromosomal aberrations (e.g. mosaic trisomy/polysomy 7; +7) are of particular interest with regard to malignant transformation and biological behavior of cells, (for example invasiveness, by analogy with observations in hematological malignancies and solid tumors [12]), recent evidence indicates that chromosomal abnormalities may also be of biological relevance in nontrans-formed cells, including synovial cells derived from patients with RA [13,14,15,16,17,18].To date, analyses of +7 have been carried out either in nonseparated synovial cells (including contaminating inflammatory cells) or in passaged SFB [13,14,15,16,17,18,19]. Thus, the main goals of the present study were: i) to identify the full extent of structural and numerical chromosomal aberrations (see below) in primary-culture (P-0) synovial cells (collagenase digest), and early passages of isolated SFB (98% enrichment; P-1, P-4); ii) to compare these alterations in matched peripheral blood, synovial membrane, and skin of RA patients; iii) to analyze the specificity of the aberrations for RA by comparison with other rheumatic diseases (inflammatory/degenerative) and normal joints or joints that had undergone trauma; and iv) within synovial and skin fibroblasts (FB), to differentiate in vivo alteration from in vitro growth selection.Patients with RA (n = 21), OA (n = 24), or spondylarthropathies (n = 3; consisting of one case of ankylosing spondylitis and two of psoriatic arthritis), villonodular synovitis; systemic lupus e
Defining and Computing Topological Persistence for 1-cocycles  [PDF]
Dan Burghelea,Tamal K. Dey,Du Dong
Mathematics , 2010,
Abstract: The concept of topological persistence, introduced recently in computational topology, finds applications in studying a map in relation to the topology of its domain. Since its introduction, it has been extended and generalized in various directions. However, no attempt has been made so far to extend the concept of topological persistence to a generalization of `maps' such as cocycles which are discrete analogs of closed differential forms, a well known concept in differential geometry. We define a notion of topological persistence for 1-cocycles in this paper and show how to compute its relevant numbers. It turns out that, instead of the standard persistence, one of its variants which we call level persistence can be leveraged for this purpose. It is worth mentioning that 1-cocyles appear in practice such as in data ranking or in discrete vector fields.
Quiescent Fibroblasts Are More Active in Mounting Robust Inflammatory Responses Than Proliferative Fibroblasts  [PDF]
Bo-Rui Chen, Huei-Hsuan Cheng, Wei-Chung Lin, Kai-Hsuan Wang, Jun-Yang Liou, Pei-Feng Chen, Kenneth K. Wu
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049232
Abstract: Quiescent cells are considered to be dormant. However, recent studies suggest that quiescent fibroblasts possess active metabolic profile and certain functional characteristics. We previously observed that serum-starved quiescent fibroblasts respond to proinflammatory stimuli by robust expression of cyclooxygenase-2 (COX-2), which declines after the quiescent fibroblasts are driven to proliferation. In this study, we elucidated the underlying signaling and transcriptional mechanism and identified by microarray genes with similar differential expression. By using pharmacological inhibitors coupled with gene silencing, we uncovered the key role of protein kinase C δ (PKCδ) and extracellular signal regulated protein kinase 1/2 (ERK1/2) signaling in mediating COX-2 expression in quiescent cells. Surprisingly, COX-2 expression in proliferative cells was not blocked by PKCδ or ERK1/2 inhibitors due to intrinsic inhibition of PKCδ and ERK1/2 in proliferative cells. Restrained COX-2 transcription in proliferative cells was attributable to reduced NF-κB binding. Microarray analysis identified 35 genes whose expressions were more robust in quiescent than in proliferative cells. A majority of those genes belong to proinflammatory cytokines, chemokines, adhesive molecules and metalloproteinases, which require NF-κB for transcription. Quiescent fibroblasts had a higher migratory activity than proliferative fibroblasts as determined by the transwell assay. Selective COX-2 inhibition reduced migration which was restored by prostaglandin E2. As COX-2 and inflammatory mediators induce DNA oxidation, we measured 8-hydroxydeoxyguanosine (8-OHdG) in quiescent vs. proliferative fibroblasts. PMA-induced 8-OHdG accumulation was significantly higher in quiescent than in proliferative fibroblasts. These findings indicate that quiescent fibroblasts (and probably other quiescent cells) are at the forefront in mounting inflammatory responses through expression of an array of proinflammatory genes via the PKCδ/ERK1/2 signaling pathway.
High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts
Heidi W?h?maa, Hanna Schierbeck, Hulda S Hreggvidsdottir, Karin Palmblad, Anne-Charlotte Aveberger, Ulf Andersson, Helena Harris
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3450
Abstract: Synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients were stimulated with HMGB1 alone or in complex with LPS, IL-1α or IL-1β. Tumour necrosis factor (TNF) production was determined by enzyme-linked immunospot assay (ELISPOT) assessment. Levels of IL-10, IL-1-β, IL-6 and IL-8 were measured using Cytokine Bead Array and matrix metalloproteinase (MMP) 3 production was determined by ELISA.Stimulation with HMGB1 in complex with LPS, IL-1α or IL-1β enhanced production of TNF, IL-6 and IL-8. HMGB1 in complex with IL-1β increased MMP production from both RASF and OASF. The cytokine production was inhibited by specific receptor blockade using detoxified LPS or IL-1 receptor antagonist, indicating that the synergistic effects were mediated through the partner ligand-reciprocal receptors TLR4 and IL-1RI, respectively.HMGB1 in complex with LPS, IL-1α or IL-1β boosted proinflammatory cytokine- and MMP production in synovial fibroblasts from RA and OA patients. A mechanism for the pathogenic role of HMGB1 in arthritis could thus be through enhancement of inflammatory and destructive mechanisms induced by other proinflammatory mediators present in the arthritic joint.The highly conserved protein high mobility group box protein 1 (HMGB1) exerts vital functions in the nucleus of all eukaryotic cells. When tissue injury is inflicted and inflammation is induced, HMGB1 can be released extracellularly and can then convey inflammatory functions. Extracellular HMGB1 may induce cytokine production, up-regulation of adhesion molecules on endothelial cells and activation of dendritic cells and T cells [1-11]. The reported presence of extracellular HMGB1 in multiple inflammatory conditions and the beneficial effects of HMGB1 blockade in preclinical models of inflammatory diseases have thus led to the acknowledgement of HMGB1 as an inflammatory mediator with pathogenic functions in several inflammatory diseases (reviewed in [12]).HMGB1 interacts with th
Persistence of Inflammatory Response to Intense Exercise in Diabetic Rats  [PDF]
José Ricardo Bortolon,Antonio José de Almeida Silva Junior,Gilson Masahiro Murata,Philip Newsholme,Rui Curi,Tania Cristina Pithon-Curi,Elaine Hatanaka
Journal of Diabetes Research , 2012, DOI: 10.1155/2012/213986
Abstract: In this study we evaluated the onset and resolution of inflammation in control and streptozotocin-induced diabetic rats subjected to a single session of intense exercise. The following measurements were carried out prior to, immediately after, and 2 and 24 hours after exercise: plasma levels of proinflammatory cytokines (TNF- , IL- , IL-6, CINC- , MIP-3 , and IL-6), immunoglobulins (IgA and IgM), acute phase proteins (CRP and C3), and creatine kinase (CK) activity. We also examined the occurrence of macrophage death by measurements of macrophages necrosis (loss of membrane integrity) and DNA fragmentation. An increase was observed in the concentration of IL- (3.3-fold) and TNF- (2.0-fold) and in the proportion of necrotic macrophages (4.5-fold) in diabetic rats 24 hours after exercise, while the control group showed basal measurements. Twenty-four hours after the exercise, serum CK activity was elevated in diabetic rats but not in control animals. We concluded that lesion and inflammations resulting from intense exercise were greater and lasted longer in diabetic animals than in nondiabetic control rats. 1. Introduction Moderate and regular aerobic exercise reduces insulin resistance and improves antioxidant and immune capacities, preventing the onset and progression of chronic diseases that present low-grade systemic inflammation (e.g., diabetes mellitus) [1–5]. On the other hand, high-intensity exercise imposes major acute endocrine, metabolic, and immune changes that may persist for a period of several hours after the exercise and may be detrimental to the health of diabetic patients [6]. The American College of Sports Medicine (ACSM), the American Diabetes Association (ADA), the European Association for the Study of Diabetes (EASD), and the American Heart Association (AHA) recommend regular aerobic and resistance exercising for patients with diabetes without major complications [7–10]. However, their guidelines do not specify the intensity or the most suitable type of physical exercise to maximize the benefits of exercise with minimal risk while ensuring the proper regulation of immune function and inflammatory control. Furthermore, there are no studies that have determined the time required for diabetic patients to recover from exercise-induced skeletal muscle injury. Strenuous physical exercise can result in muscle injury, promoting the release of skeletal muscle enzymes creatine kinase (CK) and lactate dehydrogenase (LDH) [11]. Inflammatory response begins by infiltration of fluid, plasma proteins, and leukocytes (e.g., macrophages) into the
The effect of the pro-inflammatory cytokine tumor necrosis factor-alpha on human joint capsule myofibroblasts
Stefan G Mattyasovszky, Alexander Hofmann, Christoph Brochhausen, Ulrike Ritz, Sebastian Kuhn, Jochen Wollst?dter, Hendrik Schulze-Koops, Lars P Müller, Bernhard Watzer, Pol M Rommens
Arthritis Research & Therapy , 2010, DOI: 10.1186/ar2902
Abstract: In this study, we examined the impact of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α) on cellular functions of human joint capsule MFs. MFs were challenged with different concentrations of TNF-α with or without both its specifically inactivating antibody infliximab (IFX) and cyclooxygenase-2 (COX2) inhibitor diclofenac. Cell proliferation, gene expression of both alpha-smooth muscle actin (α-SMA) and collagen type I, the synthesis of prostaglandin derivates E2, F1A, and F2A, as well as the ability to contract the extracellular matrix were assayed in monolayers and in a three-dimensional collagen gel contraction model. The α-SMA and COX2 protein expressions were evaluated by immunofluorescence staining and Western blot analysis.The results indicate that TNF-α promotes cell viability and proliferation of MFs, but significantly inhibits the contraction of the extracellular matrix in a dose-dependent manner. This effect was associated with downregulation of α-SMA and collagen type I by TNF-α application. Furthermore, we found a significant time-dependent upregulation of prostaglandin E2 synthesis upon TNF-α treatment. The effect of TNF-α on COX2-positive MFs could be specifically prevented by IFX and partially reduced by the COX2 inhibitor diclofenac.Our results provide evidence that TNF-α specifically modulates the function of MFs through regulation of prostaglandin E2 synthesis and therefore may play a crucial role in the pathogenesis of joint capsule contractures.Post-traumatic joint stiffness is a common complication that occurs primarily after injuries of the upper extremities involving articular structures [1,2]. In the majority of cases, loss of function after trauma is due to adhesions and contractions as well as to scar formation within capsulo-ligamentous structures. Upon injury, fibroblasts of the surrounding tissue become activated, start to proliferate, and undergo a phenotypic differentiation into contractile myofibroblasts (MFs) [3].
Inhibition of protein geranylgeranylation induces apoptosis in synovial fibroblasts
Alison M Connor, Stuart Berger, Aru Narendran, Edward C Keystone
Arthritis Research & Therapy , 2006, DOI: 10.1186/ar1968
Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory disease causing progressive joint destruction, deformity and disability. The pathogenesis of the rheumatoid joint involves hyperplasia of the synovial lining cells, mononuclear cell infiltration and new blood vessel formation within the synovium as well as the destruction of cartilage and underlying bone as a consequence of pro-inflammatory cytokines and proteases [1]. Much of the pathology is thought to be driven by cytokines, particularly tumor necrosis factor α (TNF-α) [2].Synovial tissue consists primarily of two distinct cell types: the macrophage-like synoviocytes and synovial fibroblasts. The synovial fibroblasts are important in all aspects of the pathogenesis of arthritis. Hyperplasia of the synovial lining in RA is due primarily to increases in the number of synovial fibroblasts. Although the reason for this increase is currently unknown, impaired apoptosis or senescence has been proposed to explain their increased numbers [3].The RA synovial fibroblast response to the macrophage-derived cytokines TNF-α and IL-1 includes elevated expression of adhesion molecules, cytokines and chemokines. RA synovial fibroblasts also secrete angiogenesis-promoting molecules such as vascular endothelial growth factor A and several proteases, including matrix metalloproteinases, aggrecanases and cathepsins, that mediate extracellular matrix degradation [4].TNF-α is capable of signaling both cell-survival and cell-death signals. The response of a cell to TNF-α depends on specific adaptors and downstream signaling molecules [5]. The addition of TNF-α to RA synovial fibroblasts results in resistance to apoptosis and hence to increased survival as well as proliferation [6]. Recent reports have indicated that it is possible to reverse the survival response of RA synovial fibroblasts to TNF-α by inhibiting the translocation of nuclear factor κB to the nucleus [7], or ectopically expressing TIMP (tissue inhibitor of metalloprotein
Treatment of Joint Inflammatory Diseases in the Lame Backyard Chickens with NSAIDs
M.M. Hadipour,M.R. Hadipourfard, M.B. Vakili, N. Shayanpour and F. Azad
International Journal of Animal and Veterinary Advances , 2011,
Abstract: The effects of several Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) were determined in 200 mature backyard chickens with clinical signs of lameness. The NSAIDs, diclofenac, carprofen, ketoprofen and meloxicam with doses 0.5, 1, 2, 3 and 4 mg/kg were used in these groups, orally. Chickens were monitored on a daily basis for general condition, joint inflammation reduction and mortality. Diclofenac, carprofen and ketoprofen were associated with mortality. In contrast, there were no reported mortalities for the NSAID, meloxicam in this study. Results of the current study revealed that the meloxicam was the drug of choice with relative safety for treatment of joint inflammatory diseases in chickens.
Some Peculiarities of Bone Tissue Remodelling at Hip Joint Inflammatory and Degenerative Diseases  [PDF]
E.V. Karyakina,E.A. Persova
Saratov Journal of Medical Scientific Research , 2009,
Abstract: During the assessment of peculiarities of bone tissue remodelling in inflammatory and non inflammatory lesions of hip joint, according to the levels of biochemical indices in the blood serum, some unilateral changes of bone tissue metabolism have been revealed in advanced rheumatoid arthritis and osteoarthrosis. More severe disturbances of bone remodelling in case of rheumatoid arthritis are obviously connected with peculiarities of the rheumatoid inflammation pathogenesis.
Transcriptional Program Induced by Wnt Protein in Human Fibroblasts Suggests Mechanisms for Cell Cooperativity in Defining Tissue Microenvironments  [PDF]
Zach Klapholz-Brown, Graham G. Walmsley, Ysbrand M. Nusse, Roel Nusse, Patrick O. Brown
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000945
Abstract: Background The Wnt signaling system plays key roles in development, regulation of stem cell self-renewal and differentiation, cell polarity, morphogenesis and cancer. Given the multifaceted roles of Wnt signaling in these processes, its transcriptional effects on the stromal cells that make up the scaffold and infrastructure of epithelial tissues are of great interest. Methods and Results To begin to investigate these effects, we used DNA microarrays to identify transcriptional targets of the Wnt pathway in human lung fibroblasts. Cells were treated with active Wnt3a protein in culture, and RNA was harvested at 4 hours and 24 hours. Nuclear accumulation of ?-Catenin, as shown by immunofluorescence, and induction of AXIN2 demonstrate that fibroblasts are programmed to respond to extracellular Wnt signals. In addition to several known Wnt targets, we found many new Wnt induced genes, including many transcripts encoding regulatory proteins. Transcription factors with important developmental roles, including HOX genes, dominated the early transcriptional response. Furthermore, we found differential expression of several genes that play direct roles in the Wnt signaling pathway, as well as genes involved in other cell signaling pathways including fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signaling. The gene most highly induced by Wnt3a was GREMLIN2, which encodes a secreted BMP antagonist. Conclusions Elevated expression of GREMLIN2 suggests a new role for Wnt signals in the maintenance of stem cell niches, whereby Wnt signals induce nearby fibroblasts to produce a BMP antagonist, inhibiting differentiation and promoting expansion of stem cells in their microenvironment. We suggest that Wnt-induced changes in the gene expression program of local stromal cells may play an important role in the establishment of specialized niches hospitable to the self-renewal of normal or malignant epithelial stem cells in vivo.
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