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Current
Rheumatology Reviews
ISSN: 1573-3971
Current Rheumatology Reviews
Volume 2, Number 1, February 2006
Contents
Editorial Pp. i
Hepatocyte Growth Factor in Normal and Diseased Bone
and Joint Tissues Pp. 1-7
Iannis E. Adamopoulos and Nicholas A. Athanasou
[Abstract]
Protein Kinase R: A Novel Mediator of Articular Cartilage
Degradation in Arthritis Pp. 9-21
Sophie J. Gilbert, Victor C. Duance and Deborah J. Mason
[Abstract]
Mechanisms of Beneficial Effects of High Molecular
Weight Hyaluronan on Cultured Cartilage Tissue Pp.
23-30
Gene A. Homandberg
[Abstract]
Wnt/β-Catenin Signaling in Chondrocyte Function
and Cartilage Matrix Disruption Pp. 31-38
Motomi Enomoto-Iwamoto, Tomohiro Otani, Tatsuya Koike
and Masahiro Iwamoto
[Abstract]
High Resolution Molecular Analysis as Tool for Evaluation
of Arthritis Pathology Pp. 39-45
Elena Neumann, Tarner Ingo, Steffen Gay and Ulf Müller-Ladner
[Abstract]
Role of Bone Marrow in the Pathogenesis of Rheumatoid
Arthritis Pp. 47-54
Shunsei Hirohata
[Abstract]
Ankylosing Spondylitis, HLA-B27 and Klebsiella
- An Overview: Proposal for Early Diagnosis and Treatment
Pp. 55-68
Alan Ebringer, Taha Rashid,Clyde Wilson, Teresa
Ptaszynska and Mark Fielder
[Abstract]
The DREAM of Pain Relief Pp. 69-82
Nataša Reisch, André Aeschlimann,Steffen Gay and
Haiko Sprott
[Abstract]
Scleroderma Subsetting Pp. 83-87
Gabriele Valentini and Clodoveo Ferri
[Abstract]
Autonomic Nervous System Dysfunction in Sjögren’s
Syndrome Pp. 89-94
Stamatis-Nick C. Liossis and Andrew P. Andonopoulos
[Abstract]
Phosphocitrate, A Potential Therapeutic Agent for
Calcium Crystal Deposition Diseases Pp. 95-99
John D. Sallis, Konstantinos D. Demadis and Herman S. Cheung
[Abstract]
Familial Mediterranean Fever Pp.
101-108
Esra Baskin and Umit Saatci
[Abstract]
Abstracts
[Back to top]
Editorial
Welcome to the second volume of Current Rheumatology Reviews.
The purpose of this publication is to review the latest advances
in rheumatology. An Editorial Advisory Board of 115 prominent
rheumatologists from over 25 countries emphasizes the mission
of this effort. First, the international nature of the initiative
and the means by which the editors and publishers invite submissions
differentiates it from other rheumatology publications. Many
prominent rheumatic disease experts are shy or reluctant to
submit manuscripts or have ideas which have been overlooked
or underemphasized and need to be invited to share their ideas.
Current Rheumatology Reviews allows these individuals the
opportunity to present potentially important insights that
can move clinical and basic research forward in specific disease
subsets as well as a variety of disciplines associated with
rheumatology.
In the current issue, 12 articles emanating from authors
in 8 countries cover Sjogren’s, familial Mediterranean
fever, osteoarthritis, crystal induced arthritis, rheumatoid
arthritis, scleroderma, chronic pain, cell signaling, growth
factors and the use of hyaluronans as a therapy. The concise
reviews focus on basic concepts but those which are also under
appreciated . For example, the topic of autonomic dysfunction
in Sjogren’s syndrome has never been reviewed before
in a thorough, concise, and accessible way even though this
complication is not uncommonly observed in clinical practice.
We also emphasize translational work. For example, Dr. Sprott
explores the possible implications of a protein in pain physiology
which most rheumatologists who manage patients with fibromyalgia,
for example, are largely unaware of, but which might have
significant implications in the future. It is hoped that the
reader will find Current Rheumatology Reviews to be a valuable
resource and a necessary part of their medical library.
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]
Hepatocyte Growth Factor in Normal and Diseased Bone
and Joint Tissues
Iannis E. Adamopoulos and Nicholas A. Athanasou
Hepatocyte Growth Factor (HGF) is a multifunctional growth
factor which, like its receptor c-Met, is widely expressed
in osteoarticular tissues. HGF has profound effects on cell
motility and differentiation and tissue morphogenesis and
angiogenesis. HGF plays an important role in normal bone and
cartilage turnover. Changes in HGF/c-Met have also been linked
to pathophysiological changes in several bone and joint disorders.
HGF has been implicated in the pathogenesis of inflammatory
changes in rheumatoid synovium and in degenerative changes
in osteoarthritis. HGF also influences bone remodelling and
has significant effects on the proliferation and differentiation
of osteoclast precursors, osteoclast activity and survival.
A therapeutic role of HGF also has been proposed in the regeneration
of osteoarticular tissues.
[Back to top]
Protein Kinase R: A Novel Mediator of Articular Cartilage
Degradation in Arthritis
Sophie J. Gilbert, Victor C. Duance and Deborah J. Mason
The protein kinase PKR is a key regulator of stress signalling
pathways. We found that the PKR activating
protein (PACT) is up-regulated in cartilage at the onset of
osteoarthritis. PACT activates PKR in response to various
cellular stresses such as TNF-α
and IL-1. TNF-α
also activates PKR via the sphingolipid second messenger,
ceramide. Recent studies have shown that ceramide-induced
activation of PKR inhibits protein synthesis as a prelude
to cell death. TNF-α
and ceramide stimulate cartilage degradation and we have demonstrated
a role for PKR in TNF-α
and ceramide-induced increases in the expression and activation
of degradative enzymes in articular cartilage. The known role
of PKR in cytokine-induced signalling pathways, together with
our data showing cytokine regulation of PKR in chondrocytes,
reveals a novel mechanism of cartilage degradation that may
be important in the pathogenesis of arthritis. Elucidation
of this pathway may enable more subtle control of cytokine-mediated
degradation of cartilage and improve upon the efficacy of
anti-TNF treatments in arthritis. This review will summarise
the known activities of PKR and provide evidence for the involvement
of this signalling pathway in cartilage breakdown.
[Back to top]
Mechanisms of Beneficial Effects of High Molecular
Weight Hyaluronan on Cultured Cartilage Tissue
Gene A. Homandberg
The efficacy of high molecular weight hyaluronan (HA) in
reversing cartilage damage in patients with joint degeneration
has not yet been clearly demonstrated, although there is compelling
evidence of reduction in parameters of pain. The rationales
as to why HA may be beneficial to cartilage structure are
diverse and are largely based on studies of in vitro
models of cartilage damage. However, there are few studies
in these models showing a linkage between effects of HA on
cartilage metabolism to an outcome more closely related to
osteoarthritis, such as cartilage matrix degradation. Thus,
while HA may have a myriad of effects on chondrocytes, perhaps
not all of these explain its potential chondroprotective activity.
This review discusses selected studies and question whether
there is a common explanation for efficacy of HA. It is concluded
and proposed that HA may be a weak catabolic mediator that
stimulates anabolic processes in cartilage. Thus, the efficacy
of HA may be explained by the linkage of catabolic events
to subsequent anabolic reparative responses, a newer theme
supported by numerous studies.
[Back to top]
Wnt/β-Catenin Signaling in Chondrocyte Function
and Cartilage Matrix Disruption
Motomi Enomoto-Iwamoto, Tomohiro Otani, Tatsuya Koike
and Masahiro Iwamoto
A fine balance between cartilage matrix synthesis and degradation
is critical both for the maintenance of articular cartilage
function and skeletal development and growth. Disruption of
this balance causes abnormalities in skeletal formation and
growth and leads to degenerative cartilage diseases, including
osteoarthritis and rheumatoid arthritis. Previous studies
from this and other laboratories have indicated that Wnt proteins
regulate chondrocyte function and behavior and also play important
roles in cartilage development and skeletogenesis, from the
initial steps of chondrogenesis to the final steps during
which calcified cartilage is replaced by bone. Inhibition
of Wnt/β-catenin
signaling suppresses chondrocyte maturation and endochondral
ossification, while activation both inhibits cartilage matrix
synthesis and accumulation and impairs growth plate organization
and tissue integrity. We found that activation of Wnt/β-catenin
signaling strongly stimulated proteoglycan loss from chondrocyte
cultures and cartilage explants while up-regulated the expression
of genes responsible for cartilage matrix degradation. Furthermore,
β-catenin
accumulates in chondrocytes located in osteoarthritic articular
cartilage in a manner similar to that normally occurring in
growth plate hypertrophic chondrocytes, suggesting that Wnt/β-catenin
signaling is activated in regions where active matrix degradation
occurs; thus, Wnt/β-catenin
signaling may be a common pathway regulating matrix disruption
during endochondral ossification and pathological degeneration
of cartilage.
[Back to top]
High Resolution Molecular Analysis as Tool for Evaluation
of Arthritis Pathology
Elena Neumann, Tarner Ingo, Steffen Gay and Ulf Müller-Ladner
Evaluation of differentially regulated genes is essential
for the development of novel therapeutic approaches in multifactorial
diseases such as rheumatoid arthritis (RA). The analysis of
the pathophysiology of RA requires also a functional understanding
of the interactions between different cell types, the cell
matrix, intracellular signaling pathways, often also called
‘functional genomics’, as well as between the
different tissues in the joint such as cartilage, bone, adipose
tissue, and the synovium.
In addition, the identification of disease- or treatment-specific
genes has become an important tool in arthritis research to
determine novel molecular markers for diagnosis and monitoring
of RA, and to elucidate the exact mode of operation and the
potential target molecules for therapeutic intervention.
Current approaches to analyze gene expression in arthritis
are based on RNA isolated from cultured synovial cells or
from synovial tissues and biopsies. Other approaches are directed
to cultured cells such as RA synovial fibroblasts, one of
the key players in inflammation and cartilage destruction,
chondrocytes, macrophages or lymphocytes to characterize molecular
changes and pathomechanisms in the RA synovium, especially
at sites of adhesion and invasion of the synovium into the
adjacent cartilage and bone.
In this review, different methods to analyze gene expression
of cells and tissues from patients with arthritides ranging
from RNA fingerprinting to cDNA array are presented and discussed.
In addition, a special focus is addressing the pitfalls resulting
in over- or misinterpretation of the data obtained by these
sensitive techniques.
[Back to top]
Role of Bone Marrow in the Pathogenesis of Rheumatoid
Arthritis
Shunsei Hirohata
Rheumatoid arthritis (RA) is characterized by hyperplasia
of synovial lining cells, consisting of macrophage-like type
A synoviocytes and fibroblast-like type B synoviocytes. Type
A synoviocytes, also called intimal macrophages, have been
found to be derived from monocyte precursors in the bone marrow.
Accordingly, the spontaneous generation of CD14+ cells from
bone marrow CD14- progenitor cells is accelerated in RA, resulting
in the facilitated entry of such CD14+ cells into the synovium.
Whereas type B synoviocytes, also called fibroblast-like synoviocytes,
are thought to arise from the sublining tissue or other support
structures of the joint, they might be also derived from bone
marrow progenitor cells. Thus, RA bone marrow CD34+ cells
show abnormal responses to TNF-α,
resulting in their accelerated differentiation into fibroblast-like
cells producing MMP-1. On the other hand, persistent neovascularization
is crucial for continuous synovial proliferation through delivery
of nutrients and recruitment of inflammatory cells. In this
regard, RA bone marrow CD34+ cells differentiate into endothelial
cells much more effectively than control subjects, suggesting
that bone marrow CD34+ cells might play a role in the synovial
hyperplasia in RA through mobilization of endothelial progenitor
cells that contribute to vasculogenesis. Taken together, these
results support the hypothesis that the bone marrow, rather
than the synovium, might be the primary-lesion site of RA.
[Back to top]
Ankylosing Spondylitis, HLA-B27 and Klebsiella
- An Overview: Proposal for Early Diagnosis and Treatment
Alan Ebringer, Taha Rashid,Clyde Wilson, Teresa
Ptaszynska and Mark Fielder
Ankylosing spondylitis (AS) is a potentially disabling rheumatic
disease for which no curative treatment has yet been discovered.
An extensive computer-based and manual search was undertaken
to evaluate the role of microbes in the pathogenesis of AS.
All together 147 papers were scrutinised. A total of 24 studies
carried out on 1330 AS patients and 1191 healthy controls
involving 15 different countries showed significantly elevated
Klebsiella antibodies in AS patients when compared
to controls. Molecular analysis has shown that Klebsiella
microbes possess antigens, which cross-react with self-antigens,
such as HLA-B27 and spinal collagens.
Diagnostic criteria have been developed in which a person
who is HLA-B27 positive and has clinical and laboratory evidence
of an inflammatory backache for at least three months is proposed
to have pre-AS. A specific elevation of anti-Klebsiella
antibodies would confirm the diagnosis. A proposal for an
early treatment using anti-Klebsiella measures is
suggested.
So far, apart from Klebsiella no other microbes
have been shown to have a link with the development of AS.
It is suggested that identifying and treating patients with
Klebsiella reactive arthritis/pre-AS could involve
the use of anti-Klebsiella measures, such as antibiotics
and low starch diet together with immunosuppressive drugs
in an endeavour to prevent the irreversible sequelae of established
AS.
[Back to top]
The DREAM of Pain Relief
Nataša Reisch, André Aeschlimann,Steffen Gay and
Haiko Sprott
Chronic pain has manifested itself as an independent disease.
Different molecules acting in nociceptive pathways in the
periphery and the nervous system are currently under investigation.
Recently the multifunctional protein DREAM (Downstream
Regulatory Element Antagonist
Modulator)/calsenilin/KChIP3 has been implicated
to play a role in the mechanisms of pain modulation and the
hypothesis “No DREAM - No pain” was raised. In
addition to the binding to DRE (Downstream
Regulatory Element) sequences,
DREAM/calsenilin/KChIP3 was shown to interact with presenilin,
a protein thought to be a key molecule in Alzheimer’s
disease, and Kv4alpha-subunits assembling potassium channels.
DREAM/calsenilin/KChIP3 has been described as a Ca2+-dependent
transcriptional repressor, which is targeted to the regulatory
DNA sequence of the prodynorphin gene. By actively
suppressing gene expression of the endogenous opioid receptor
ligand dynorphin, DREAM/calsenilin/KChIP3 is modulating the
kappa opioid receptor system, which mediates analgesia. DREAM
knock-out mice showed elevated levels of dynorphin and consequently
displayed attenuated chemical induced and inflammatory pain.
The data derived from the DREAM knock-out model led to the
identification of a novel target in chronic pain management.
[Back to top]
Scleroderma Subsetting
Gabriele Valentini and Clodoveo Ferri
Patients with Systemic Sclerosis [SSc] present great variability
in the extent of skin sclerosis, internal organ involvement
and prognosis. These aspects have long prompted clinical investigators
to differentiate SSc into subsets. The most widely used subsetting
schema was proposed by Carwile LeRoy et al. in 1988.
The schema differentiates two main subgroups (i.e., limited
cutaneous SSc -lcSSc- and diffuse cutaneous SSc -dcSSc-) characterized
by different extent of skin sclerosis, autoantibody profile
and pattern of internal organ involvement. This schema, however,
is based on a Delphy technique (i.e. a consensus among experts).
The other available schema, which differentiates three subsets
according to skin sclerosis (i.e. lc-SSc characterized by
sclerodactyly alone, intermediate cutaneous SSc-ic-SSc where
the limbs are also involved, and dc-SSc with trunk skin sclerosis)
has been demonstrated to have a greater prognostic power,
but lacks any reference to other prognostically relevant items
. A prospective multicenter study devoted to improve the three
subsetting schema by adding such items could help the clinical
investigator to better differentiate SSc subsets.
[Back to top]
Autonomic Nervous System Dysfunction in Sjögren’s
Syndrome
Stamatis-Nick C. Liossis and Andrew P. Andonopoulos
Peripheral nervous system dysfunction is well documented
in Sjögren’s syndrome (SS), whereas central nervous
system involvement is a matter of significant controversy.
On the other hand, autonomic nervous system (ANS) dysfunction
is not even mentioned in extensive reviews of the disease
in classic rheumatology textbooks. Despite isolated reports,
attention to such involvement in the rheumatologic literature
has only been noted over the last six years, following a controlled
prospective study that suggested significant autonomic cardiovascular
neuropathy in these patients.
Since then, few studies, on relatively small numbers of Sjögren’s
patients, have yielded conflicting results, including two
that claim no abnormality in autonomic nervous system function.
A variety of factors may be blamed for these discrepancies,
including bias on patient selection but mainly differences
in employed methodology, i.e. conventional cardiovascular
reflex tests and baroreflex sensitivity vs 24 hour
heart rate variability. In any case, besides isolated case
reports describing severe autonomic dysfunction, usually manifested
by postural hypotension, the majority of studies that indicate
the presence of ANS abnormalities in SS, have detected that
only by applying objective tests and specific questionnaires.
On the other hand, ANS dysfunction, implying defective innervation
of exocrine glands, and the presence of muscarinic receptor
antibodies have been blamed, partially at least, for the decreased
secretory function of exocrine glands in this disease.
More importantly, ANS dysfunction has been reported to result
in increased mortality in diabetics, post myocardial infarction
patients and the elderly. If such a possibility exists for
patients with SS, the need for prospective, controlled and
long follow up studies on large cohorts is imperative.
[Back to top]
Phosphocitrate, A Potential Therapeutic Agent for
Calcium Crystal Deposition Diseases
John D. Sallis, Konstantinos D. Demadis and Herman S. Cheung
The deposition of calcium-containing crystals in articular
tissues is probably an under-recognized event. Clinical observations
indicate that exaggerated and uniquely distributed cartilage
degeneration is associated with these deposits. Perhaps the
most compelling argument favoring a role for crystals in Osteoarthritis
(OA) stems from their in vitro effects on articular
tissues. Therapeutic options are limited and of compromised
value for controlling and/or eliminating calcium crystal salt
diseases. This review highlights past and present studies
related to phosphocitrate (PC), a relatively unheralded compound
with an ability to inhibit crystal nucleation, growth and
aggregation of calcium salts, including basic calcium phosphate
(a term including carbonate-substitute apatite, octacalcium
phosphate, and tricalcium phosphate) and calcium pyrophosphate
dihydrate. In addition, cell culture studies reveal that specific
calcium phosphate-induced cellular events associated with
osteoarthritis also are retarded by PC. Interest in the tetra-sodium
PC form and the new Calcium/Sodium/PC (CaNaPC) salt has stemmed
from their chemical characteristics and biological actions.
In two instances, the CaNaPC has displayed superior inhibitory
properties to that of the tetra-sodium salt. Using a calcergy
animal model, a chemically-induced calcifying skin plaque
in rats has been ameliorated while in cell culture studies,
strong inhibition of calcium phosphate-DNA co-precipitates
induced cell death has been noted. The assessed data indicate
that either of the PC salts through their modes of action,
could be useful as adjunct therapeutic treatment of crystal
associated OA.
[Back to top]
Familial Mediterranean Fever
Esra Baskin and Umit Saatci
Familial Mediterranean fever (FMF) is an autosomal recessive
disease characterized by recurrent self-limited febrile episodes.
The hallmarks of a typical attack are fever, peritonitis,
pleuritis, arthritis and/or erysipelas-like erythema that
resolve within hours or days. The disease primarily affects
Sephardic Jews, Armenians, Turks and North African Arabs.
The frequency of the attacks can vary and the inciting factors
are not always clear. Almost half of all patients with FMF
have arthritis of the ankle, knee or hip, and there are increasing
reports of vasculitic features. The first episode of FMF typically
occurs during childhood or adolescence, but the disease may
be evident even in infancy. By age 20, approximately 90% of
patients have had their first attack.
FMF is caused by a defect in the gene that encodes pyrin,
a protein that affects the actions of neutrophils and monocytes
during the inflammatory response. This “MEFV gene”
is located on the short arm of chromosome 16, and 89 MEFV
variants have been described to date. The most common MEFV
mutations are M694V, M680I, V726A and M694I (all located in
exon 10) and E148Q (located in exon 2). Genotype-phenotype
correlations in FMF are not yet clear.
The most important complication of this illness is development
of secondary amyloid A-type amyloidosis. Amyloid fibrils are
deposited in the patient’s kidneys, gastrointestinal
tract, liver, adrenal glands and spleen. Proteinuria is usually
the first laboratory finding that indicates renal involvement
and, in most cases, this progresses to end-stage renal failure.
The incidence rates of FMF-related amyloidosis in different
ethnic groups vary widely. Several risk factors for more severe
FMF or development of FMF-related amyloidosis have been identified:
homozygosity for the M694V mutation and for the complex V726A-E148Q
allele of MEFV, male gender, family history of FMF, and the
α/α
genotype for the serum amyloid A1 gene. However, results in
the literature are conflicting with respect to possible relationships
between the M694V mutation and the severity of FMF or development
of FMF-related amyloidosis.
Colchicine effectively reduces the frequency and duration
of attacks in most FMF patients, and is the mainstay of treatment
for this condition. This agent also helps prevent or arrest
the development of amyloidosis in FMF patients.
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