The Division of Rheumatic Diseases at Case Western Reserve
University/University Hospitals of Cleveland has deeply invested
in the care of patients with osteoarthritis (OA), rheumatoid
arthritis (RA) and related disorders. Investigations on cartilage
and chondrocytes biology, autoimmunity, T cell biology and animal
models of RA and OA are the cornerstone of our research program.
We plan to build on this and to introduce a new program on the
modulation of immune response/inflammation by dietary constituents.
Another area, which we would like to develop, is the signal
transduction in lymphocytes/chondrocytes.
Primary research interests of the Members of the Division of
Rheumatic Diseases are:
Donald D. Anthony, M.D., Ph.D.
Research Interests: Hepatitis C virus, T cell biology and rheumatic
diseases.
Dr. Anthony’s primary research interests are in the T
cell mediated immune mechanisms of human disease. Current work
focuses on hepatitis C virus specific CD4 and CD8 T cell immunity
in the infected host and how this immunity is related to the
clinical manifestations and disease progression, as well as
response to therapy. Experiments are aimed at exploring the
relationship between the control or resolution of hepatitis
C related diseases and the frequency, cytokine producing quality,
and the fine antigen specificity of the cellular immune response
in infected host.
From this brief description it is evident that members of our
faculty are internationally recognized for their work in cartilage
homeostasis and degradation, immunogenetics, animal models of
RA and OA, and T cell biology.
Ali D. Askari, M.D.
Research Interests: Myopathies, rheumatoid arthritis and sjogren’s
syndrome.
Current research is being done on specific case studies of
patients with myopathy where Dr. Askari is scheduled to present
at the 68th Annual American College of Rheumatology (ACR) Scientific
meeting in San Antonio, TX in October 2004.
Another area of focus is rheumatoid arthritis in which Dr.
Askari is involved with a pilot study with Chris Winkelman,
R.N. of the CWRU School of Nursing and Alan Levine, Ph.D. to
determine whether moderate levels of physical activity contribute
to the decrease in pro-inflammatory cytokines.
Dr. Askari is also involved in another study with the CWRU
School of Dentistry where he and Drs. Nabil Bissada, and Alkatman
Khaldoun of the CWRU School of Dentistry, are conducting a study
regarding periodontal disease in patients with active and controlled
rheumatoid arthritis.
Dr. Askari’s study on Neuromuscular Complications of
Sjogren’s syndrome (presented at the VII International
Symposium on Sjogren’s Syndrome May 2002), is being prepared
for publication with participation from Dr. Jon Ryan.
A DYSAutonomia study is being conducted involving patients
with fibromyalgia, Chronic Fatigue Syndrome (CFS) and Raynauds.
This study is being spearheaded by Dr. Thomas Chelimsky, Director
of Autonomic Disorders and the Pain Center, and includes participation
from the Division of Rheumatology (Drs. Askari and Malemud)
as well as doctors from various disciplines.
Tariq M. Haqqi, Ph.D.
Research Interests: Inflammation in Cartilage/chondryte homeostasis
and redox-regulation of signal
transduction; animal models of arthritis.
Patients with degenerative and age-related diseases generally
display a low antioxidant status. Imbalances in the cellular
levels of prooxidants and antioxidants induces oxidative stress,
which is a contributor to the etiology of various degenerative
diseases. Another characteristic feature of degenerative diseases
is the persistence of pro-inflammatory cytokines such as tumor
necrosis factor-a (TNF-a) and interleukin-1 (IL-1) at the affected
sites. These pro-inflammatory cytokines induce the expression
of several genes, e.g. matrixmetalloproteinases (MMPs), whose
products initiate or accelerate the degradation of extracellular
matrix (ECM), cellular leakage and cell death in the affected
tissue. There is ample evidence that both TNF-a and IL-1 also
induce the excessive production of nitric oxide (NO), which
is a source of free radicals, which can oxidize protein side
chains resulting in enzyme, receptor and carrier dysfunction.
Lipid peroxidation leads to alterations in the functional properties
of membranes and delivery of lipids to tissues. Scavenging of
oxygen and nitrogen free radicals by low molecular mass antioxidants,
such as vitamins C and E and enzymes such as superoxide dismutase,
prevent the buildup of prooxidants such as NO, which is a potent
inducer of apoptosis in human chondrocytes. Evidence is emerging
that consumption of diet rich in antioxidants or use of dietary
supplements, such as ascorbate, tocopherols, tea polyphenols,
and ß-carotene, has beneficial health effects for humans
and in particular for the prevention and or inhibition of degenerative
joint and other diseases. Our studies are designed to analyze
the mechanism of action of dietary antioxidants both in vivo
and in vitro. Currently we are exploring the role of green tea
polypheols on signal transduction and the regulation of the
production of mediators of cartilage degradation by human chondrocytes
in vitro and mouse synovium in vivo. These studies are currently
supported by an RO1 application.
Micronutrients present in edible plants are known to possess
anti-carcinogenic properties because epidemiological studies
have suggested that consumption of fruits and vegetables may
prevent against many cancer types. This approach of chemoprevention
of cancer has practical implications in reducing cancer risk
because unlike the carcinogenic environmental factors that are
difficult to control, individuals can make decisions to modify
their choice for the food and beverage they consume. Tea, a
preparation from the dried leaves of Camellia sinensis, is a
widely and popularly consumed beverage in the world. Extensive
studies from several laboratories over the last ten years, have
verified cancer chemo preventive effects of a polyphenolic mixture
derived from green tea [hereafter referred to as green tea polyphenols
(GTP)] in many animal tumor bioassay systems. However, the anticarcinogenic
potential of green tea against hard tissue tumors (osteosarcomas
or chondrosarcomas) has not been extensively explored. We have
found that GTP induces apoptosis in osteosarcoma cells SA-OS2.
The central hypothesis to be tested in this proposal is that
green tea induces apoptosis in osteosarcoma cells by modulating
the cell cycle- and apoptotic- machinery of SA-OS2 cells. Therefore,
in this developmental application we are studying the modulation
of survival and apoptotic signaling pathways by green tea in
an osteosarcoma cell line in vitro. These studies are focused
on determining (1) whether GTP induce apoptosis in SA-OS2 cells
by modulating the constitutively active NF-?B; (2) whether GTP
induce apoptosis in SA-OS2 cells through cell cycle arrest by
up-regulating the expression of p21; and (3) whether GTP induce
apoptosis in SA-OS2 cells by altering the Bax/Bcl2 ratio. This
project is supported by the award of an R21 grant from NIH/NCCAM.
Another area, which we have developed sufficiently to submit
an RO1 application, is focusing on peroxisome proliferator activated
receptors (PPARs) in chondrocytes. PPARs are also expressed
in bone and cartilage and PPAR agonists inhibit IL-1ß
induction of both NO and MMP-13 in human chondrocytes. Interleukin-1ß
(IL-1ß) and tumor necrosis factor-a (TNF-a) are important
mediators of inflammation and play a pivotal role in inflammatory
and degenerative joint diseases such as rheumatoid arthritis
(RA) and osteoarthritis (OA). One mechanism through which these
inflammatory cytokines exert their effects is by inducing connective
tissue cells, including chondrocytes and synoviocytes, to produce
inflammatory mediators such as nitric oxide (NO) and matrix
metalloproteinases (MMPs). Recent advances in the understanding
of the pathogenesis of these diseases at the molecular level
have revealed the existence of a family of nuclear hormone receptors,
which link the cytokine signals to the control of gene expression
in connective tissue cells. These molecules, termed peroxisome
proliferator activated receptors (PPARs) are also expressed
in bone and cartilage and PPAR agonists inhibit IL-1ß
induction of both NO and MMP-13 in human chondrocytes. Given
that we have shown that green tea polyphenol epigallocatechin-3-gallate
(EGCG) is a potent inhibitor of IL-1ß-induced NO and MMP-13
in chondrocytes. Recently a laminin has been identified as a
receptor for EGCG (EGCGR) and our preliminary studies show that
it is expressed on human chondrocytes. Therefore, it is reasonable
to ask if cross talk may exist between EGCGR and PPAR mediated
transcriptional regulation in human chondrocytes. This proposal
will test the hypothesis that EGCG repress inflammatory genes
transcription by activating PPARs in human chondrocytes. This
application is likely to be submitted in October 04/February05.
Raymond Hong, M.D.
Research Interests: Assessment of intrinsic cell surface complement-inhibitor
upregulation after
Captopril and Atorvastatin Administration in healthy human subjects.
Dr. Hong is currently involved in a study with Drs. Michael
Strainic, Jeffrey Blumer and M. Edward Medof using healthy human
volunteers with hypothesis that volunteers receiving captopril
or atorvastatin will increase the expression of DAF, MCP and
CD59 on their blood cell surfaces. Because the upregulation
of complement inhibitors could have differing risk and benefit
profiles dependent on underlying disease processes, the studies
are potentially important. Autoimmune diseases, such as lupus
nephritis, in which complement activation causes renal and vascular
damage could have decreased end organ damage if upregulation
is achieved. In contrast, similar upregulation on tumor cells
possibly could lead to tumor expansion as a result of enhanced
resistance to immune elimination. The implications of the results,
if they apply in vivo in humans, is that they could help clinicians
judiciously choose medications for comorbid conditions in patients
with diseases that would be expected to respond to complement
activation or inactivation.
Charles J. Malemud, Ph.D.
Research Interests: Apoptotic chondrocyte death; Cartilage
homeostasis.
Apoptosis may be one of the earliest pathophysiological alterations
in human cartilage resulting in osteoarthritis (OA). Our studies
are designed to explore the mechanism of induction of apoptosis
in human chondrocytes in vitro by cytokines and hydrostatic
pressure. The regulatory mechanism resulting in hydrostatic
pressure-induced apoptosis involve multiple pathways including
the up-regulation of p-53 and c-myc gene expression and protein
synthesis and suppression of bcl-2 gene expression and protein
synthesis. The relationship between induction of apoptosis and
extra cellular matrix gene expression are also being studied.
Jon P. Ryan, D.O.
Research Interests: Systemic Lupus Erythematosus
Dr. Ryan, Chief Fellow in the Division, is currently involved
in regarding a retrospective analysis of four patients in the
treatment of resistant SLE with Rituximab administered without
cycolophosphamide. An abstract regarding this study will be
presented by Dr. Ryan at the 68th Annual American College of
Rheumatology (ACR) Scientific meeting in San Antonio, TX October
2004.
Johnny G. Su, M.D.
Research Interests: Osteoporosis
Dr. Su is involved in two projects regarding Osteoporosis.
The first project is in collaboration with Dr. Heather Gillespie,
first year fellow in the Division, to investigate the association
between homocystiene levels and bone mineral density to determine
whether high homocysteine levels are predictive of low BMD resulting
in increased risk of osteopathic fracture. An association between
high homocysteine levels and increased risk of fracture has
shown in two separate studies published in the
New England Journal of Medicine in 2004. However, it is unclear
whether this association holds true for BMD.
The second project is to investigate the impact of intermittent
intra-articular steroids on bone mineral density. It has long
been proven that systemic steroids increase risk of osteoporosis
and fracture. However, it is unclear whether the frequency and
cumulative dose of intra-articular steroids affect bone mineral
density with increased risk of fracture as a result of low BMD.
Dr. Su is also in the process of completing a project with
the National Databank of Rheumatic Diseases under the auspices
of the CHORD Fellowship to look at predictors of osteoporosis
in men with rheumatic diseases.
Carlos E. Zevallos, D.O.
Research interests: Sjogren’s Syndrome
Dr. Zevallos is a first year fellow in the Division. His focus
is on establishing an international database that will consist
of approximately 350 patients with Sjogren’s syndrome.
He will specifically looking at validating modified European
criteria vs. the criteria based on consensus expert opinion
in 1998.
In addition, studies are also planned for a limited clinical
trial to test the efficacy of an extract of green tea in Juvenile
Rheumatoid Arthritis (JRA) in combination with current therapeutic
regimen. Discussions will be initiated with the NIH funded Clinical
Research Center (CRC) upon the return of Dr. Singer from leave.
We expect these studies to start in spring/summer of 2003.
Future Plans: Our broad long term objectives remain to pursue
these areas of research as well as to expand into the molecular
basis of the anti-inflammatory effects and modulation of degenerative
diseases by dietary interventions. As you are aware that degenerative
and inflammatory joint diseases such as osteoarthritis (OA)
and rheumatoid arthritis are the most common joint disorders
in the aging population and a significant health challenge.
No effective therapeutic option is currently available to inhibit
the disease progression and the compound that has shown some
promise in inhibiting cartilage degradation, glucosamine, is
a commonly used dietary supplement. Rheumatoid arthritis (RA)
is an autoimmune disorder but only little information about
its etiology is available. Cellular immune response to the self-antigens
is the primary problem in RA and inhibition of this response
is the target of many drugs, which are under development. Another
problem is that many patients develop treatment related complications
including various types of cancer. Thus another area, which
can be developed as a complementary approach to this problem,
is to focus on strategies that would minimize, if not abolish,
the secondary complications (e.g. inhibition of cancer) through
dietary interventions. This is not an all inclusive list, but
should provide evidence that there are areas in which there
is active ongoing research at the interface between pharmaceutical
sciences, nutrition and cartilage/chondrocyte biology. One of
the key issues is how these programs would be funded. In this
regard both NIAMS and NCCAM have shown heightened interest in
funding this area of research. An avenue to be pursued would
be a Program Project Grant on some aspects of nutrition and
autoimmune diseases, which could be funded by NIAMS/NCCAM.
