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Current
Rheumatology Reviews
ISSN: 1573-3971
Current Rheumatology Reviews
Volume 2, Number 2, May 2006
Contents
Editorial Pp. i
Glucose Sensing in Chondrocytes via GLUT1
and GLUT3: Implications for Articular Cartilage and Intervertebral
Disc Metabolism Pp. 109-121
Ali Mobasheri, Mehdi Shakibaei, Reza Mobasheri, Stephen
Richardson and Judith A. Hoyland
[Abstract]
Biomechanics and Knee Osteoarthritis Pp.
123-129
David J. Hunter and Fabian E. Pollo
[Abstract]
Imaging Modalities in the Outcome Assessment of Knee
Osteoarthritis Pp. 131-136
Andrew J. Teichtahl, Flavia M. Cicuttini and
Anita E. Wluka
[Abstract]
Chondroitin Sulfate and Sulfur Contain-ing Chondroprotective
Agents: Is there a Basis for their Pharmacological Action?
Pp. 137-149
Marcel E. Nimni, Fabiola Cordoba, Basil Strates and Bo
Han
[Abstract]
Is the Vasculature a Potential Therapeutic Target
in Arthritis? Pp. 151-158
Peter C. Taylor and Ewa M. Paleolog
[Abstract]
Human Parvovirus B19: An Infectious Agent with the
Potential to Induce and Trigger Rheumatic Disease Pp.
159-175
Hartwig W. Lehmann and Susanne Modrow
[Abstract]
Expression and Function of Cytokines and Chemokines
in Neuropsychiatric Related Systemic Lupus Erythematosus Pp.
177-185
Tsuyoshi Kasama, Takeo Isozaki, Tsuyoshi Odai, Mizuho
Matsunawa and Nobuyuki Yajima
[Abstract]
Update on the Therapies of Severe Lupus Nephritis
Pp. 186-190
Chi Chiu Mok
[Abstract]
Recent Advances in Neuro-Endocrine-Immune Interactions
in the Pathophysiology of Rheumatoid Arthritis Pp.
191-205
Hideshi Yoshikawa, Kazuhiko Nara and Noboru Suzuki
[Abstract]
Gastrointestinal Involvement in Children and Adolescents
with Rheumatic Diseases Pp. 207-213
Peter Weber, Bolz Dieter and Klaus-Peter Zimmer
[Abstract]
Pathogenesis and Biomarkers in Spondyloarthritis:
Clues from Microarray Analyses Pp. 215-218
David Tak Yan Yu
[Abstract]
Abstracts
[Back to top]
Editorial
We are poised for a major advance in the treatment of lupus
nephritis. Prior to 1960, the mortality rate for renal involvement
was 80% within two years. After the availability of dialysis,
this steadily improved. Nevertheless, by 1980, half with nephritis
(and two-thirds with nephrotic syndrome) succumbed within
10 years. Between 1980 and the millennium, cyclosporine and
mycophenolate mofetil became available. Along with advances
in new antihypertensive agents (especially angiotensin converting
enzyme inhibitors), improved antibiotics to treat infections,
and transplant immunology, half with nephritis now survived
20 years. As pointed out by Dr. Mok in his update on the therapies
for severe lupus nephritis in this issue, we still have a
long way to go. More patients are surviving the initial onslaught
of renal inflammation only to experience complications from
chronic corticosteroid therapy and renal scarring (e.g., hypertension,
hyperlipidemia, hyperglycemia). Over the last few years, lupus
specialists have begun networking through collaborative groups
(e.g., SLICC, the LCTC), forming registries, and following
cohorts. This has led to publications showing that efforts
to educate patients, eliminate nonadherence, increase access
to lupus specialists, exercise programs, osteoporosis prevention
measures, promotion of smoking cessation, weight reduction
regimens, and aggressive proactive preventive efforts relating
to accelerated atherogenesis can improve survival and quality
of life without even considering the effects of anti-inflammatory
regimens. The improvements in quality of life experienced
by our lupus patients in the last few years has been bolstered
by new insights into the etiopathogenesis of antiphospholipid
syndrome as it relates to the kidney (e.g., using antiplatelet
regimens in at risk patients), an improved classification
system for nephritis (the ISN) which can better predict prognosis
and the discovery of pro-inflammatory HDL in nephritis patients.
Nevertheless, as reinforced in Dr Mok’s review, using
the “gold standard”, cyclophosphamide, for proliferative
lupus nephritis is still associated with a 50% risk of evolving
end stage renal disease within 10 years if one considers “all
comers”. As briefly mentioned in his article, the advent
of biologics have arrived. No fewer than 14 biologics are
in clinical trials for SLE. Within the next year, nephritis
studies evaluating abatacept and rituximab will join LJP 394
trials already underway. The publication of preliminary industry
guidelines by the United States Food and Drug Administration
and monitoring nephritis trials by the American College of
Rheumatology further underscore the seriousness of these efforts.
Hopefully, ten years from now when we reread Dr Mok’s
review, it will lead us to be thankful that new therapies
being evolved at the present time were so much more effective.
Daniel J. Wallace
(Editor-in-Chief)
David Geffen School of Medicine at UCLA
Los Angeles
CA
USA
E-mail: dwallace@ucla.edu
[Back to top]
Glucose Sensing in Chondrocytes via GLUT1
and GLUT3: Implications for Articular Cartilage and Intervertebral
Disc Metabolism
Ali Mobasheri, Mehdi Shakibaei, Reza Mobasheri, Stephen
Richardson and Judith A. Hoyland
Glucose is an essential source of energy for embryonic growth
and fetal development. Glucose is vital for chondroblasts
during chondrogenesis and for articular and growth plate chondrocytes
during post-natal development. Glucose also plays a key role
in extracellular matrix synthesis as a precursor for glycosaminoglycans.
The quantity of glucose available to cells in avascular connective
tissues such as articular cartilage and intervertebral disc
is normally significantly lower than plasma and synovial fluid.
Glucose concentrations in cartilage can fluctuate depending
on age, physical activity and endocrine status. Chondrocytes
are glycolytic cells and must be able to sense the amount
of glucose available to them in the extracellular matrix and
respond appropriately by adjusting cellular metabolism. Studies
are currently in progress to identify glucose sensors in tissues
that carry out bulk glucose fluxes (intestine, kidney and
liver) where the sodium dependent glucose transporter (SGLT1)
has been proposed to be involved. GLUT2 and hexokinase have
been identified as important components of the glucose sensing
apparatus in the pancreas. Chondrocytes do not appear to express
GLUT2 or SGLT1 and glucose sensing in these cells is likely
to involve other facilitative glucose transporters. In this
article we review selected literature on glucose sensing in
the yeast, and in pancreas, kidney, brain and gut in an attempt
to understand how different cells sense and respond to alterations
in extracellular glucose. We present a new hypothesis that
implicates the hypoxia responsive GLUT1 and GLUT3 glucose
transporters and the hypoxia-inducible transcription factor
(HIF-1α)
in glucose sensing in chondrocytes.
[Back to top]
Biomechanics and Knee Osteoarthritis
David J. Hunter and Fabian E. Pollo
This narrative review focuses on the influence of biomechanics
on the etiology of knee osteoarthritis, and on the therapies
that may ameliorate these forces. The etiopathogenesis of
osteoarthritis is widely believed to be the result of local
mechanical factors acting within the context of systemic susceptibility.
For knee osteoarthritis knee alignment, and the stance-phase
adduction moment are key determinants of the disproportionate
medial transmission of load and may play a role in knee symptoms.
Since involvement of the medial compartment of the knee is
especially frequent, interventions whose goal is to realign
the knee so as to reduce transarticular loading on the medial
compartment, such as valgus bracing are sometimes used clinically.
Two therapies that have attempted to modify these forces are
knee braces and heel wedges. Greater attention to the important
role of mechanical factors in OA etiopathogenesis and their
modification is required if we are to find ways of reducing
the public health impact of this condition.
[Back to top]
Imaging Modalities in the Outcome Assessment of Knee
Osteoarthritis
Andrew J. Teichtahl, Flavia M. Cicuttini and
Anita E. Wluka
Knee radiography is the current “gold standard”
for assessing the severity of knee osteoarthritis (OA) in
clinical and research settings. Nevertheless, radiographic
evaluation of OA is an insensitive and unreliable measure
for quantifying disease severity and change over relatively
short periods of time. The failure of knee radiographs to
provide a sensitive outcome measure may be one factor that
has contributed to the limited progress that has been achieved
in developing effective treatments to slow or stop the progression
of knee OA. Emerging evidence suggests that measurement of
articular cartilage volume using magnetic resonance imaging
(MRI) is valid, reproducible and sensitive to change in both
normal subjects and those with OA. This review discusses the
issues related to joint imaging using radiographs and MRI
in the outcome assessment of knee OA.
[Back to top]
Chondroitin Sulfate and Sulfur Contain-ing Chondroprotective
Agents: Is there a Basis for their Pharmacological Action?
Marcel E. Nimni, Fabiola Cordoba, Basil Strates and Bo
Han
Chondroitin sulfate, glucosamine sulfate and other sulfur
containing compounds are widely used by individuals afflicted
with joint pains. In spite of their incremental use, neither
their efficacy nor their mode of action has been defined.
Metabolic studies indicate that these compounds are degraded
prior to absorption or shortly thereafter into their fundamental
constituents: simple carbohydrates and inorganic sulfate.
Polysaccharides cannot be reutilized as such, and inorganic
sulfate can only be incorporated into cartilage glycosaminoglycans
(GAG) following de novo activation. The carbohydrate
moiety of GAG can, under normal circumstances, be readily
synthesized by cells.
If these compounds, rich in sulfur, are exhibiting any pharmacological
effects, they are most likely doing so solely because of their
ability to contribute this important element to our organism.
Sulfur is normally derived from methionine and cysteine in
proteins. Very little is derived from other dietary sources.
The minimal daily requirements for this important mineral
have never been established in spite that in addition to being
essential for GAG synthesis, it is a structural component
of glutathione and other key enzymes, coenzymes and metabolites
that play fundamental roles in cellular homeostasis and control
of inflammation. It is therefore not unlikely that any beneficial
effect of these dietary supplements results from their ability
to supplement our diet with a source of inorganic sulfur.
[Back to top]
Is the Vasculature a Potential Therapeutic Target
in Arthritis?
Peter C. Taylor and Ewa M. Paleolog
The vasculature fulfils a gatekeeper role in cell recruitment,
through expression of leukocyte activators and chemoattractants,
as well as adhesion molecules. Endothelial cells also play
a role in the growth of new blood vessels (‘angiogenesis’),
which are vital for efficient supply of oxygen and nutrients
to tissue. It is therefore unsurprising that the endothelium
contributes to the initiation and maintenance of pathologies
such as rheumatoid arthritis (RA). The expansion of RA synovium
necessitates an increase in the vascular supply to the synovium,
to cope with the increased requirement for oxygen and nutrients.
Although many pro-angiogenic factors have been demonstrated
to be expressed in RA synovium, the potent pro-angiogenic
cytokine vascular endothelial growth factor (VEGF) has been
demonstrated to a have a central involvement in the angiogenic
process in RA. Several studies have shown that targeting angiogenesis
in animal models of arthritis ameliorates disease. Thus blockade
of angiogenesis - and especially VEGF - looks to be a promising
avenue for the future treatment of RA.
The focus of this review is to discuss the role of the vasculature
in RA, particularly in the light of observations using therapies
such as anti-tumour necrosis factor α
(TNFα)
biologicals, and on the potential for development of vascular-targeted
therapies for treatment of RA. Furthermore, the potential
of approaches targeting VEGF, or other angiogenic factors,
will be discussed.
[Back to top]
Human Parvovirus B19: An Infectious Agent with the
Potential to Induce and Trigger Rheumatic Disease
Hartwig W. Lehmann and Susanne Modrow
Erythema infectiosum is the main manifestation of human
parvovirus B19 infections. Further B19-related diseases commonly
associated with the acute infection are flue-like symptoms,
transient aplastic crisis, transient arthralgias, leukopenia
and thrombocytopenia, spontaneous abortion and hydrops fetalis
in pregnant women. Hepatitis, myocarditis, meningitis, encephalitis
as well as pure red cell anemia may occur occasionally. In
addition parvovirus B19 infections have been frequently described
as cause or trigger of various forms of autoimmune diseases
affecting all blood cell lines, joints, connective tissue,
uvea, large and small vessels. In some autoimmunopathias the
data are conflicting. Despite these controversial results
recent research revealed insights that may explain the molecular
mechanisms for the observed autoimmune phenomena. The viral
transactivator protein NS1 induces enhanced TNFα
and IL-6 production and activates mitochondria related and
TNFα-induced
apoptosis. The viral phospholipase A2-like
(PLA2)
activity exerted by the capsid protein VP1 contributes to
the generation of elevated amounts of inflammatory eicosanoids
such as prostaglandins and leukotrienes during acute and peristent
infection. Additional phenomena may be caused by the formation
and deposition of immunocomplexes. Molecular mimicry may contribute
to the appearance of autoimmune antibodies, f.e. antiphospholipid
and anti-neutrophil cytoplasmic antibodies as well as antinuclear
antigens. All these mechanisms implicated in the pathogenesis
of parvovirus B19 triggered autoimmune diseases will be discussed
in this review.
[Back to top]
Expression and Function of Cytokines and Chemokines
in Neuropsychiatric Related Systemic Lupus Erythematosus
Tsuyoshi Kasama, Takeo Isozaki, Tsuyoshi Odai, Mizuho
Matsunawa and Nobuyuki Yajima
Systemic lupus erythematosus (SLE) is an autoimmune disease
characterized by multi-organ damage, and the neuropsychiatric
complications of SLE (NPSLE) are associated with increased
morbidity and mortality. In general, the diagnosis of NPSLE
is difficult, because no single laboratory marker or imaging
modality has been found which can serve as a gold standard,
and the diagnosis is thus primarily clinical. The pathogenesis
of NPSLE has not been fully elucidated. Focal symptoms are
thought to more likely result from vascular lesions, whereas
diffuse manifestations are more likely related to autoantibody-
or cytokine-mediated impairment of neuronal function. However
recent progress has provided evidence that a number of cytokines
and chemokines, as well as autoantibodies, may be involved
in the neuropsychiatric manifestations of SLE, because certain
repertoires of cytokines/chemokines are detectable in the
central nervous system of NPSLE patients during active disease.
In addition, we have recently shown elevated levels of the
soluble form of fractalkine, which is a newly described membrane-bound
CX3C chemokine, in the cerebrospinal fluid of patients with
active NPSLE. This review will discuss the involvement of
cytokines and chemokines in the pathogenesis of NPSLE and
the evaluation of their significance as a useful laboratory
parameter of active neuropsychiatric disease.
[Back to top]
Update on the Therapies of Severe Lupus Nephritis
Chi Chiu Mok
Therapy of lupus nephritis should target at symptomatic
control, preservation of renal function, reduction of renal
flares, prevention of complications and treatment-related
toxicities. Despite the emergence of newer modalities, cyclophosphamide
(CYC) remains the most commonly prescribed therapy. This is
because of the considerable experience with this agent and
the availability of long-term data beyond 10 years. Modification
of CYC-containing regimens or early substitution with a less
toxic immunosuppressive agent in good responders may help
to reduce toxicities. Alternative induction regimens using
newer agents such as mycophenolate mofetil (MMF) and the calcineurin
inhibitors may also be considered in selected patients without
poor prognostic factors. Recalcitrant lupus nephritis carries
a high risk of renal function deterioration. Newer and more
aggressive therapies, including experimental agents, such
as immunoablative CYC, immunoadsorption and the biological
response modifiers may be considered on an individual basis.
[Back to top]
Recent Advances in Neuro-Endocrine-Immune Interactions
in the Pathophysiology of Rheumatoid Arthritis
Hideshi Yoshikawa, Kazuhiko Nara and Noboru Suzuki
Rheumatoid arthritis (RA) is an autoimmune disorder resulting
from the combination of several predisposing factors, including
hormonal influences and immune responses. Stress response
system, including hypothalamic-pituitary-adrenal/gonadal axes
and sympathetic nervous system plays important roles for its
pathophysiology. Proinflammatory cytokines secreted by synovial
cells and activation of inflammatory cells provoke systemic
as well as local inflammatory stresses in RA. However, the
decreased secretion of adrenal androgens and gonadal testosterone,
and the decreased number of sympathetic nerve fibers (norepinephrine)
in the synovial tissue are observed in RA, and eventually
leading to the Th1 dominant immune aberration. These suggest
a loss of the stress-induced feedback regulation in endocrine-immune
and neuro-immune interactions, leading to acceleration of
chronic inflammation in RA. The local nociceptive input and
sensitization of corresponding segments of spinal cord, resulted
in continuous pain with stabilization of afferent sensory
fibers and continuous release of proinflammatory neuropeptides,
including substance P. Thus, inappropriate secretion of hormones
and neuropeptides contributes to vicious cycle in progression
of inflammatory responses. In this review, we discuss the
recent advances of immunological aberrations and neuro-endocrine-immune
interactions in pathophysiology of RA.
[Back to top]
Gastrointestinal Involvement in Children and Adolescents
with Rheumatic Diseases
Peter Weber, Bolz Dieter and Klaus-Peter Zimmer
Pediatric rheumatic diseases are often associated with gastrointestinal
symptoms. Abdominal pain is the most frequently reported complaint.
In this review, we discuss the gastrointestinal manifestations
of chronic rheumatic syndromes: motility disorders of collagenosis,
mixed connective tissue disease and Sjögren’s syndrome
associated with the risk of esophagitis due to gastro-esophageal
reflux. Furthermore, we summarize data about non-steroidal
anti-inflammatory drug-induced gastroduodenal lesions in childhood
and adolescence. The relevance of co-medication with steroids
for the pathogenesis of these lesions is controversial. Further
prospective studies are necessary to examine which sensitivities
and specifics are raised by invasive and non-invasive procedures
such as endoscopy, testing of intestinal and gastric permeability,
fecal α1-antitrypsin
excretion, and fecal occult blood testing to indicate gastrointestinal
lesions in pediatric rheumatic diseases.
[Back to top]
Pathogenesis and Biomarkers in Spondyloarthritis:
Clues from Microarray Analyses
David Tak Yan Yu
Two areas of spondyloarthritis (SpA) are subjects of intense
research: pathogenesis and identification of biomarkers of
disease activity. Concerning pathogenesis, it is commonly
accepted that HLA-B27 is an essential gene for a prototype
of SpA called ankylosing spondylitis (AS). Although a MHC
class I molecule, studies of HLA-B27 have revealed biology
unusual for other HLA class I alleles. The latest surprise
is that this protein has a slow rate of biogenesis inside
the endoplasmic reticulum (ER), and hence might in certain
circumstances potentially lead to generation of the ER unfolded
protein response. First demonstrated with cultured cell lines,
this hypothesis has found fortuitous support during microarray
screening of synovial fluid cells derived from SpA patients.
Preliminary experiments based on microarray analyses suggest
that the targets of the ER responses are cells of the macrophage
lineage. Previous research on AS has been focused almost exclusively
on T lymphocytes. These microarray results provide investigators
with new target cells for future studies. Concerning biomarkers
of disease activity, microarray analyses have also provided
support for a previously suspected candidate: metalloproteinase-3
(MMP-3). The potential usefulness of serum levels of this
biomarker has now been demonstrated in cohorts of patients
derived from three different countries. If reproducible in
additional cohort studies, it might become a tool in clinical
practice.
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