Current Rheumatology Reviews

ISSN: 1573-3971

Current Rheumatology Reviews
Volume 3, Number 3, August 2007

Contents

Editorial Pp. 171


Review of In Vitro Models and Development and Initial Validation of a Novel Co-Culture Model for the Study of Osteoarthritis Pp. 172-182
James L. Cook, Keiichi Kuroki, Aaron Stoker, Heather Streppa and Derek B. Fox
[Abstract]


Extracellular Matrix Fragments as Regulators of Cartilage Metabolism in Health and Disease Pp. 183-196
Gene A. Homandberg, Lei Ding and Danping Guo
[Abstract]


The Impact of Coagulation and Fibrinolysis Cascades on the Development of Septic and Autoimmune Arthritis Pp. 197-204
Tao Jin, Maria Bokarewa and Andrej Tarkowski
[Abstract]


Central Nervous System Manifestations in Systemic Lupus Erythematosus Pp. 205-214
Simone Appenzeller, Lilian T.L. Costallat and Fernando Cendes
[Abstract]


Pregnancy and Postpartum Influences on Rheumatoid Arthritis Activity: Nature’s Model to Investigate Systemic Biological Mechanisms in the Disease Pp. 215-224
Alfonse T. Masi, Thomas J. Santoro and Jean C. Aldag
[Abstract]


Macrophage Activation Syndrome in Childhood Rheumatic Diseases Pp. 225-230
Angelo Ravelli, Alejandra Pringe, Clara Malattia, Ilaria Sala and
Alberto Martini
[Abstract]


Amyloid A Amyloidosis Secondary to Rheumatoid Arthritis: An Uncommon Yet Important Complication Pp. 231-241
Tadashi Nakamura
[Abstract]




Abstracts

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Editorial: At Long Last: A Viable Biomedical Model for Fibromyalgia

When I was a medical student, I became acquainted with a journal called Medical Hypotheses. This was a unique pub-lication, because at the time anybody (especially non physi-cians) could propose a novel theory and have it circulated with a minimal amount of peer review. It got so absurd that I still remember reading a parody of the journal in the April Fool’s edition of our medical school newspaper where an article entitled “Drinking water causes breast cancer” soberly concocted data to demonstrate a cause and effect relation-ship.

Rheumatic disease specialists are original thinkers, and some of their ideas are creative and innovative but not quite ready for prime time. Current Rheumatology Reviews has committed itself to allow some of the best and brightest to present hypotheses to stimulate and arouse the interest of investigators on a variety of topics. An example of this is the compelling article by Dr. Alfonse Masi and his associates. Dr. Masi has proposed that microvascular endothelial sys-tems and neuroendocrine immune systems have profound influences upon pregnancy and postpartum influences of rheumatoid arthritis. Preliminary data is presented, and pro-vocative ideas are presented for further study.

Over the last 6 months, CRR has solicited and received over 20 proposals for special issues or sections relating to important, but not commonly reviewed or discussed rheu-matic disease topics, which will appear in upcoming issues. We fill a niche of presenting quality work that might not fit the requirements and rigor of Arthritis and Rheumatism, but with the boost of CRR and its reader’s reactions will indeed achieve that benchmark. The international diversity and reach of CRR includes more countries with nationals as au-thors than almost any other rheumatology journal. Hope-fully, these initiatives will stimulate further international collaborative efforts which will improve the health and well being of rheumatic disease patients.


Address correspondence to Editor-in-Chief at the David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA;
E-mail:dwallace@ucla.edu


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Review of In Vitro Models and Development and Initial Validation of a Novel Co-Culture Model for the Study of Osteoarthritis
James L. Cook, Keiichi Kuroki, Aaron Stoker, Heather Streppa and Derek B. Fox

Objective: Provide an overview of models used for the study of osteoarthritis (OA) and describe a novel in vitro model of OA using synovial and cartilage explants from dogs which we compared to spontaneously occurring OA in dogs.

Design: Controlled laboratory study.

Methods: Articular cartilage and synovial explants were created from canine cadaveric tissues (n=38 dogs) or tissues excised during surgery on clinical canine patients (n=17 hips). Matched cartilage and synovial explant co-cultures were compared to articular cartilage explant culture. Four groups were created based on presence or absence of synovium and presence or absence of IL-1β: Cartilage Culture Control (n=48), Cartilage Culture OA (n=48), Co-Culture Control (n=76), Co-Culture OA (n=76). Explants and media were evaluated on days 1, 3, 6, 12, and/or 20 of culture. For comparison to spontaneously occurring OA, articular cartilage and synovial tissues from dogs that had no evidence of OA, Clinical Control, and dogs that had OA, Clinical OA, were evaluated. Outcome measures included molecular, biochemical, and histologic assessments.

Results: Gene expression levels in articular tissues correlated well between Co-Culture and Clinical Control and OA groups. GAG and collagen in normal and OA cartilage also corresponded well between Co-Culture and Clinical groups. Subjective histologic assessment revealed consistent similarities in cell and matrix characteristics between these groups. Changes in the media of the Co-Culture OA group were consistent with what has been reported for changes in synovial fluid of OA in dogs and humans.

Conclusions: This co-culture model allows for assessment of cartilage and synovium, and can be used to provide a relatively comprehensive picture of spontaneously occurring OA in dogs. This model may have advantages over other models of OA in that the influences of both synovium and articular cartilage can be investigated at many levels and initial validation of the model using tissues from spontaneously occurring OA in dogs as the gold standard has been performed.


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Extracellular Matrix Fragments as Regulators of Cartilage Metabolism in Health and Disease
Gene A. Homandberg, Lei Ding and Danping Guo

It is now firmly established that fragments of extracellular matrix (ECM) macromolecules that arise from the damaged ECM have the ability to regulate chondrocyte metabolism and enhance the degradative processes. Fibronectin fragments (Fn-fs), type II collagen fragments (Col-fs) and hyaluronan fragments (HA-fs) have all been shown to upregulate matrix metalloproteinases and cause extensive damage to the ECM, while Fn-fs have also been shown to enhance anabolic pathways. Since these ECM fragments are elevated in states of cartilage degeneration or in osteoarthritic cartilage, the ECM fragments likely play a role in either initiation or augmentation of degradative and anabolic pathways which collectively dictate the metabolic state of the damaged tissue. Retrospectively, the ability of ECM fragments to serve as the initial sensors of cartilage damage provides the most upstream signaling possible for effective cartilage repair/remodeling. Newer observations suggest that the perturbation of the matrix to chondrocyte interactions by ECM fragments may be the key initiating event in the catabolic pathways since this may indirectly affect matrix to receptor interaction and downstream signaling. It is conceivable that these fragment pathways either intersect or overlap and involve common players which might constitute common targets for therapeutic intervention.


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The Impact of Coagulation and Fibrinolysis Cascades on the Development of Septic and Autoimmune Arthritis
Tao Jin, Maria Bokarewa and Andrej Tarkowski

Intra-articular fibrin deposition in the inflamed joints is one of the hallmarks of rheumatoid arthritis (RA). This process is a result of local imbalance between coagulation and fibrinolysis. Proteins participating in the coagulation and fibrinolysis cascades play various roles in the process of inflammation. Chronic inflammation in joints induces activation of extrinsic coagulation cascade through the over-expression of tissue factor (TF). In addition, local fibrinolysis is greatly suppressed due to decreased tPA levels and significantly increased PAI-1. Importantly, many proteins in coagulation/fibrinolysis cascade including TF, TF/VIIa, thrombin, fibrin, plasminogen activators (uPA) display potent pro-inflammatory properties, which reinforces chronic inflammation and destruction in the engaged joints. Furthermore, co-agulation/fibrinolysis proteins may also interfere with acquired immune system. Therefore, approaches that focus on alleviating imbalance between coagulation and fibrinolysis might be beneficial in therapy of chronic arthritis.


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Central Nervous System Manifestations in Systemic Lupus Erythematosus
Simone Appenzeller, Lilian T.L. Costallat and Fernando Cendes

Neurologists and rheumatologist are often called to evaluate central nervous system (CNS) manifestations in patients with suspected or definite systemic lupus erythematosus (SLE). The manifestations are highly diverse and often have major prognostic consequences. The major difficulties are to determine if the given manifestation is primarily due to SLE activity in the brain, or a consequence of metabolic disturbances, infection, or corticosteroid use.

The true incidence of CNS manifestations attributable to SLE is not entirely clear, but several studies show prevalence rate between 15-75%, depending on different methods and classification criteria applied.

This paper has the objective to review the main clinical manifestations according to American College of Rheumatology (ACR) criteria, possible etiological mechanisms and neuroimaging features associated with these manifestations. We further discuss the most important tools that can help bedside diagnosis.


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Pregnancy and Postpartum Influences on Rheumatoid Arthritis Activity: Nature’s Model to Investigate Systemic Biological Mechanisms in the Disease
Alfonse T. Masi, Thomas J. Santoro and Jean C. Aldag

The hormonal, immunological, and microvascular endothelial (MVE) systems are believed to be important determinants of RA. These core systems interactions may influence clinical activity of this disease during pregnancy and postpartum. Notably, immunological adaptations have been documented during these periods of tightly programmed physiological changes. The neuroendocrine immune (NEI) systems of hormones and cytokines act in counter-regulatory networks and cascades. Hormones modulate immunological reactivity, and the NEI interactions complexly affect synovial and MVE target tissues. Such local joint effects may not be reflected well by cytokine or hormonal blood levels. Additionally, peripheral blood mononuclear cell cultures can provide valuable information on immunological activation. Cytokines and hormones interact as components of the complex multifactorial networks operating in the in vivo biological model. The highly programmed physiology of pregnancy and postpartum offers insights and examples of NEI and MVE relations, as they may influence clinical activity of RA. New dynamic concepts of immunological reactivity are reviewed in relation to contextual modulation during pregnancy and postpartum.

The concept of type1/type2 cytokine shift also provides a framework for interpreting immunological mechanisms and their respective interactions during pregnancy and postpartum. Deciphering interactive dynamics of these systems promises to reveal basic mechanisms of how pregnancy ameliorates some diseases like RA, but may worsen others like SLE. Risks of developing premenopausal onset RA are also inextricably linked to the biology of NEI and MVE systems inter-actions. Endorsing multisystems interactions during pregnancy and postpartum, the concluding section proposes resource protocols and models for future multidisciplinary investigations on fundamental mechanisms influencing the RA activity. Nature’s model of pregnancy and postpartum influences on activity of RA may offer the best opportunity to study integrative biology of this profoundly complex disease
.


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Macrophage Activation Syndrome in Childhood Rheumatic Diseases
Angelo Ravelli, Alejandra Pringe, Clara Malattia, Ilaria Sala and
Alberto Martini

Macrophage activation syndrome (MAS) is a life-threatening complication of systemic inflammatory disorders that is thought to be caused by the activation and uncontrolled proliferation of T lymphocytes and macrophages, leading to widespread hemophagocytosis and cytokine overproduction. Recent findings in hemophagocytic lymphohistiocytosis, a disease that is clinically very similar to MAS, highlight the possible pathogenetic role of a defective function of cytotoxic lymphocytes. Prompt diagnosis is important and recently preliminary diagnostic guidelines for the syndrome have been proposed. The recognition that MAS belongs to the secondary or reactive hemophagocytic syndromes has led to propose to rename it according to the contemporary classification of histiocytic disorders. Cyclosporine A has been found to be effective in patients with corticosteroid resistant MAS.


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Amyloid A Amyloidosis Secondary to Rheumatoid Arthritis: An Uncommon Yet Important Complication
Tadashi Nakamura

LAmyloid A (AA) amyloidosis secondary to rheumatoid arthritis (RA) is an uncommon yet important complication. There is both startling variation and different prevalence among different races in the frequency of AA amyloidosis worldwide and the fact that AA amyloidosis is not consistently related to length and severity of RA inflammation suggests the involvement of genetic factors. Serum amyloid A (SAA)1.3 allele, in particular homozygosity of this allele, has been revealed to be not only a risk factor for the association of AA amyloidosis but also a poor prognostic factor in survival of Japanese patients with RA. This leads us to the notion of clinical significance of SAA1.3 allele in the management of Japanese RA patients. Renal involvement is a pivotal clinical manifestation in the development of AA amyloidosis. Cyclophosphamide is superior to methotrexate in the medication of RA patients with AA amyloidosis. Etanercept showed an efficacy for patients with AA amyloidosis secondary to RA who carry SAA1.3 allele, suggesting a possibility of the drug as a tailor-made medicine. It is probable that SAA plays not only an important role in the development of AA amy-loidosis but also interacts as a factor closely involved in metabolic syndrome in health and disease.