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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 9, Number 10, October 2008
Contents
Thrombospondins
Guest Editor: Jack Lawler
Editorial Pp. 820-821
Thrombospondin-1 in von Willebrand Factor Function
Pp. 822-832
A. Bonnefoy and M.F. Hoylaerts
[Abstract]
Enhancing Cardiovascular Dynamics by
Inhibition of Thrombospondin-1/CD47 Signaling Pp.
833-841
J.S. Isenberg, W.A. Frazier, M.C. Krishna,
D.A. Wink and D.D. Roberts
[Abstract]
CD47 in the Immune Response: Role of
Thrombospondin and SIRP-α
Reverse Signaling Pp. 842-850
M. Sarfati, G. Fortin, M. Raymond and
S. Susin
[Abstract]
Thrombospondin and Apoptosis: Molecular
Mechanisms and Use for Design of Complementation Treatments
Pp. 851-862
Y. Mirochnik, A. Kwiatek and O.V.
Volpert
[Abstract]
Regulation of Thrombospondin1 by Extracellular
Proteases Pp. 863-868
M. Luisa Iruela-Arispe
[Abstract]
The Role of Cartilage Oligomeric Matrix
Protein (COMP) in Skeletal Disease Pp. 869-877
K.L. Posey and J.T. Hecht
[Abstract]
General Articles
Chemotherapy for Laryngeal Cancer - An Apoptotic Approach
Pp. 878-886
H.C. Liu, G.G. Chen, A.C. Vlantis, M.C.F.
Tong and C.A. van Hasselt
[Abstract]
Enkephalinase Inhibitors: Potential Agents
for the Management of Pain Pp. 887-894
V. Thanawala, V.J. Kadam and R.
Ghosh
[Abstract]
Fluorescence Imaging: Applications in
Drug Delivery Research Pp. 895-898
A. Agarwal, P.K. Tripathi, S. Tripathi and
N.K. Jain
[Abstract]
GPR40 Carboxylic Acid Receptor Family
and Diabetes: A New Drug Target Pp. 899-910
V.N. Telvekar and H.S. Kundaikar
[Abstract]
Glucagon Like Peptides-1 Modulators as
Newer Target for Diabetes Pp. 911-920
H.B. Vaidya and R.K. Goyal
[Abstract]
Abstracts
[Back to top]
Editorial: Thrombospondins
During tissue development and remodeling, cells obtain
informational cues from the proteins that comprise the extracellular
matrix. The thrombospondins are a family of extracellular,
calcium-binding proteins that modulate cellular proliferation,
migration and differentiation. At least one of the five members
of this gene family is expressed in virtually every tissue
of the body. The thrombospondins participate in embryonic
development, axon guidance, synaptogenesis, wound healing,
and angiogenesis. They are up-regulated and function in various
disease states including, diabetes, atherosclerosis, scleroderma
and tumor progression. The importance of the thrombospondins
in tissue remodeling is underscored by the observations that
mice that lack thrombospondin-1 (TSP-1) or -2 have significant
abnormalities in response to a wide range of challenges. In
addition, mutations in cartilage oligomeric matrix protein
(COMP or TSP-5) cause the human dwarfing conditions pseudoachondroplasia
and multiple epiphyseal dysplasia. The reviews in this series
focus on the importance of thrombospondins in various disease
states and discuss potential ways that the knowledge that
has been gained to date may be used to diagnose and treat
disease.
Recently, thrombospondin-1 has been shown to regulate thrombosis
by inhibiting the degradation of high molecular weight von
Willebrand factor. The review by Drs. Bonnefoy and Hoelerts
in this series describes the effect of TSP-1 on von Willebrand
factor function. TSP-1 binds to von Willebrand factor and
protects it from degradation by ADAMTS13 (A Disintegrin
And Metalloprotease with ThromboSpondin-1
repeat 13). In the absence of TSP-1, there is a decrease in
the formation of the long strands of von Willebrand factor
that support thombosis.
TSP-1 also profoundly affects the cardiovascular system through
the suppression of nitric oxide (NO). The review by Dr. Isenberg
and colleagues describes the molecular basis for the inhibition
of NO signaling by TSP-1, CD47 and CD36. TSP-1 limits NO function
in endothelial cells, smooth muscle cells and platelets. The
authors point out that therapeutic strategies that target
TSP-1 and/or CD47 would enhance the beneficial effects of
NO on blood flow and vascular remodeling.
The TSP-1/CD47 axis has also been shown to be involved in
the regulation of the immune response. The review by Dr. Sarfati
and colleagues explains how the interaction of TSP-1 with
CD47 suppresses dendritic and T cell function. This interaction
contributes to the maintenance of peripheral tolerance and
the cross talk between antigen presenting cells and T cells.
In adult tissue, the inhibition of angiogenesis in the tumor
microenvironment has received significant attention. The review
by Dr. Volpert and coworkers describes the molecular mechanisms
that underlie the inhibition of angiogenesis by TSP-1, with
particular focus on the induction of apoptosis. Like most
anti-angiogenic therapies, TSP-1-based therapies are well
tolerated and have limited activity as a monotherapy. The
review by Dr. Volpert and colleagues discusses the importance
of developing strategies for the use of TSP-1-based combination
therapies.
The thrombospondins regulate tissue genesis and remodeling
by modulating the structure of the extracellular matrix and
cellular behavior. They exert their effect on the extracellular
matrix in several ways. Through the activation of transforming
growth factor (TGF) β,TSP-1
can affect the composition of the extracellular matrix. TSPs
bind directly to other matrix proteins including laminin,
collagens, fibronectin and fibrinogen. The inclusion of TSP-1
into fibrin preparations decreases the fibril thickness. The
absence of TSP-2 results in abnormal collagen fibril assembly
in the skin. TSPs also modulate extracellular matrix structure
by inhibiting proteinases, including elastase, cathepsin G,
plasmin and urokinase. Proteases, in turn, may regulate TSP-1
function. The review by Dr. Iruela-Arispe describes the characterization
of proteases that cleave TSP-1. The members of the ADAMTS
family of extracellular proteases contain multiple copies
of the type 1 repeats (TSRs). Proteolytic cleavage of the
TSPs may have dramatic effects on the activity and bioavailability
of specific regions of the proteins during tissue remodeling.
Among the thrombospondins, TSP-1 is unique in that it has
the ability to activate TGFβ.
This activity requires the presence of the amino acid sequence
KRFK, which is between the first and second TSR. The TSRs
represent a novel β-stand
fold that is stabilized by cation-π
interactions between arginine and tryptophan residues. The
TSRs are present in approximately fifty genes in the human
genome. They have been reported to function in neurite outgrowth
and axon guidance as sites for integrin and proteoglycan binding.
Many abnormalities in the TSP-1-null mice relate to its ability
to activate TGFβ.
This is perhaps not surprising given that the ability to activate
TGFβ
is unique to TSP-1 among the TSP family members. Thus, other
TSPs can not substitute for TSP-1 in this function. The activation
of TGFβ
by TSP-1 has been shown to be involved in the response to
injury in a variety of experimental models in various tissues,
include the skin, heart, lung, liver and kidney. TSP-1 and
TGFβ
are often coordinately up-regulated in pathological conditions.
Thus, therapies that specifically target this axis may suppress
the pathologic activity of TGFβ
without perturbing its homeostatic functions.
Whereas the function of COMP is only partially understood,
it is clear that it interacts with other cartilage extracellular
matrix proteins and PGs, including fibronectin, collagen I,
II and IX, matrilin-3, and aggrecan. COMP has recently been
shown to promote collagen fibrilogenesis. The physiological
relevance of these interactions is supported by the fact that
COMP colocalizes with fibronectin and collagens in vivo.
The significance of the interaction of COMP with collagen
IX and matrilin-3 is underscored by the fact that mutations
in all three proteins result in multiple epiphyseal dysplasia,
as described by Drs. Posey and Hecht in this series. In this
review, the authors discuss the importance of COMP for growth
plate organization and highlight the use of COMP as a marker
of the joint destruction that is associated with osteoarthritis,
rheumatoid arthritis, joint trauma and intense activity.
Whereas our understanding of the biological functions of the
TSPs is still incomplete, it is already apparent that the
TSPs are potential targets for therapeutic development. The
concepts that are discussed in this review series highlight
the potential novel translational opportunities for regulation
of thrombosis, immune response, skin grafting, fibrosis, and
angiogenesis. In addition, COMP has been shown to be a very
useful marker of joint injury and disease.
Jack Lawler
[Back to top]
Thrombospondin-1 in von Willebrand Factor Function
A. Bonnefoy and M.F. Hoylaerts
Thrombospondin-1 (TSP1), expressed in many cells and
tissues is abundantly present in platelet α-granules,
from where it is released upon platelet activation. Murine
Tsp1-/- platelet studies
have revealed that TSP1 is redundant for platelet aggregation,
but that it reinforces platelet aggregate stabilization, especially
in a shear field. von Willebrand factor (VWF), synthesized
by megakaryocytes and endothelial cells is stored both in
platelet α-granules
and in endothelial Weibel-Palade bodies as ultralarge multimers.
When released from endothelial cells, these multimers are
temporarily retained on the endothelium, to be cleaved by
the plasma protease ADAMTS13 into smaller and hemostatically
less reactive multimers, released in plasma. This protease
shows partial sequence identity with the type 1 (TSR1) and
type 2 (TSR2) repeats of TSP1 and contains 1 TSR1 and 6 TSR2
repeats. TSP1, locally released by platelets, competes with
ADAMTS13 during VWF proteolysis and controls the degree of
VWF multimer processing. In addition, TSP1 and VWF both interact
with the platelet GPIb/V/IX membrane complex, primarily in
flow. These interactions control the recruitment of platelets
to (sub) endothelial VWF and TSP1, exposed to the circulation,
as a consequence of vascular inflammation and endothelial
injury. TSP1-VWF interactions do not strictly enhance platelet
recruitment and secreted TSP1 even weakly competes with the
dynamic platelet rolling and adhesion onto VWF. Hence, TSP1
and VWF show partially related hemostatic functions, the most
important one being the TSP1 role in the ADAMTS13 operated
VWF multimer processing, in pro-inflammatory and thrombogenic
conditions.
[Back to top]
Enhancing Cardiovascular Dynamics by
Inhibition of Thrombospondin-1/CD47 Signaling
J.S. Isenberg, W.A. Frazier, M.C. Krishna,
D.A. Wink and D.D. Roberts
Activation of soluble guanylate cyclase by nitric oxide
(NO) controls signaling pathways that play critical roles
in normal vascular physiology and in the pathogenesis of cardiovascular
disease. We have identified the secreted protein thrombospondin-1
as a key regulator of NO signaling. Thrombospondin-1 limits
the angiogenic activity of NO in endothelial cells, its vasodilator
activity in vascular smooth muscle, and its antithrombotic
activity in platelets. Loss of either thrombospondin-1 or
its receptor CD47 in transgenic mice results in hyperdynamic
responses to NO and reveals the importance of this pathway
in normal physiology. Thrombospondin-1 and CD47 null mice
show improved abilities to respond to ischemic stress, suggesting
that therapeutic targeting of this pathway could benefit patients
with a variety of ischemic conditions. We review the preclinical
development of therapeutics targeting thrombospondin-1 or
CD47 for improving survival of fixed ischemia, ischemia due
to aging and peripheral vascular disease, and skin grafting.
[Back to top]
CD47 in the Immune Response: Role of Thrombospondin and SIRP-α
Reverse Signaling
M. Sarfati, G. Fortin, M. Raymond and
S. Susin
The past decades have been marked by spectacular progress
towards understanding how dendritic cells (DCs) interact with
T cells to elicit protective immune responses to fight infectious
diseases and cancer. DCs that are lying at the interface between
innate and adaptive immunity, are educated in peripheral tissues
prior to their journey to the secondary lymphoid organs (SLO)
whereby they dictate different classes of T cell responses.
Uncontrolled or unwanted inflammatory responses are the price
to pay to eliminate pathogens. However, if not self-limited,
they may induce collateral damages that result in chronic
inflammation often associated with autoimmune disorders. CD47
and its two ligands, i.e. thrombospondin 1 (TSP-1) and SIRP-α,
were identified as a previously unappreciated inhibitory axis
of DC and T cell functions. TSP-1 is predominantly a negative
regulator of DC and T cell function while basal SIRP-α
ligation on APC by CD47 enforces tolerance. Yet, CD47/SIRP-α
interaction positively controls DC and innate cell transendothelial
migration. Due to the promiscuity of the protein interactions
for CD47 and its ligands, it is quite interesting to note
that deletion of the CD47 gene in mice largely agrees with
the in vitro data with human cells. In fact, the
well-conserved tissue distribution of CD47 and SIRP-α
across species may facilitate the transition from bench to
bedside. We thus propose CD47/TSP-1/SIRP-α
axis as an important sensor to maintain homeostasis and regulate
innate and adaptive immune responses.
[Back to top]
Thrombospondin and Apoptosis: Molecular Mechanisms and Use
for Design of Complementation Treatments
Y. Mirochnik, A. Kwiatek and O.V.
Volpert
Thrombospondin-1 is the first and most studied naturally
occurring protein inhibitor of angiogenesis. Its characteristic
multi-domain structure determines thrombospondin-1 divergent
functions, which include but are not limited to the regulation
of angiogenesis. Below we overview the structural determinants
and receptors expressed on the endothelial and other cell
types, that are at the root of thrombospondin-1 striking ability
to block neovascularization. We specifically emphasize thrombospondin-1
direct apoptotic action on the remodeling vascular endothelium
and summarize current knowledge of its pro-apoptotic signaling
and transcriptional networks. Further, we provide comprehensive
survey of the thrombospondin-based anti-angiogenic strategies
with special focus on the combination treatments. We convincingly
illustrate how precise knowledge of the pro-apoptotic events
and intermediates elicited by thrombospondin in the vascular
endothelial cells facilitates the design of the most effective
treatment combinations, where the efficacy of throm-bospondin-derived
compounds is maximized by the partner drug(s) (“complementation”
strategies) and provide examples of such fine-tuning of the
thrombospondin-based anti-angiogenic treatments.
[Back to top]
Regulation of Thrombospondin1 by Extracellular Proteases
M. Luisa Iruela-Arispe
The contribution of proteases to developmental, physiological
and pathological processes has been well accepted. Cleavage
of matrix proteins is a key requirement for cell migration
and remodeling of the extracellular environment. The constant
process of matrix turnover is dependent on the delicate balance
between degradation and synthesis. In addition, regulated
proteolysis also allows for the release and activation of
growth factors and cytokines. Similarly to other extracellular
matrix proteins, thrombospondins are also targets of proteolysis.
While in some cases enzymatic activity is associated with
degradation of the protein; in other situations, targeted
and selective cleavage offers the means to release polypeptides
with either alternative or enhanced function. Here, we provide
a summary of the published information related to thrombospondin
proteolysis within the context of how proteolysis of extracellular
matrix proteins impacts diversification of protein function.
We also discuss its biological relevance and potential therapeutic
value of thrombospondin proteolysis with particular emphasis
on angiogenesis.
[Back to top]
The Role of Cartilage Oligomeric Matrix Protein (COMP) in
Skeletal Disease
K.L. Posey and J.T. Hecht
Cartilage oligomeric matrix protein is a non-collagenous
extracellular matrix protein expressed primarily in cartilage,
ligament, and tendon. Cartilage oligomeric matrix protein
has been studied extensively because mutations in the gene
cause two skeletal dysplasias, pseudoachondroplasia and multiple
epiphyseal dysplasia. Pseudoachondroplasia is a disproportionate
dwarfing condition associated with joint abnormalities, while
multiple epiphyseal dysplasia is less severe. Both of these
skeletal dysplasias have a characteristic chondrocyte pathology
that consists of intracellular retention of cartilage oligomeric
matrix protein and other extracellular matrix proteins in
an enlarged rough endoplasmic reticulum. This toxic intracellular
retention of extracellular matrix proteins causes chondrocyte
cell death thereby decreasing linear bone growth. Additionally,
when cartilage oligomeric matrix protein and the other co-retained
proteins are not exported to the extracellular matrix, the
resulting matrix is abnormal and easily erodes with normal
physical activity. Cartilage oligomeric matrix protein is
also a marker for joint destruction associated osteoarthritis,
rheumatoid arthritis, joint trauma, and intense activity.
Serum cartilage oligomeric matrix protein levels are higher
in aggressive cases of arthritis and levels are used to predict
future disease progression. Recent studies have identified
molecular functions of cartilage oligomeric matrix protein
that may contribute to its role in skeletal disease. These
molecular functions include: binding other ECM proteins, catalyzing
polymerization of type II collagen fibrils, and regulation
of chondrocyte proliferation. Here, we review cartilage oligomeric
matrix protein’s role in skeletal disease and potential
molecular mechanisms.
[Back to top]
Chemotherapy for Laryngeal Cancer - An Apoptotic Approach
H.C. Liu, G.G. Chen, A.C. Vlantis, M.C.F.
Tong and C.A. van Hasselt
Laryngeal cancer is a common head and neck cancer. Despite
advances in treatment, improvement in survival and quality
of life of patients still remains a challenge. Chemotherapy
has become more and more important since this treatment is
able to preserve laryngeal function. There is increasing evidence
showing that many chemotherapeutic agents kill laryngeal tumor
cells via apoptotic mechanisms. The balance between
anti-apoptotic molecules and pro-apoptotic ones plays a critical
role in determining the sensitivity of the tumor cells to
chemotherapy. The commonly used chemotherapeutic agents for
laryngeal cancer include cisplatin, 5-fluorouracil and paclitaxel.
These three agents may target common apoptotic molecules,
but more importantly they have their own particular targets.
Systemically analysis of these targets will not only help
to optimize the treatment but also provide a rationale for
the best combination of two or more agents for the chemotherapy
of laryngeal cancer.
[Back to top]
Enkephalinase Inhibitors: Potential Agents for the Management
of Pain
V. Thanawala, V.J. Kadam and R.
Ghosh
Management of acute and chronic pain has always been
a key area of clinical research. Enkephalinase inhibitors
(EIs) seem to be promising as therapeutic agents having antinociceptive
action. They additionally possess anticraving, antidiarrhoeal
and antidepressant actions. The antinociceptive action of
EIs has been reported for over a decade however, their therapeutic
potential is yet to be effectively explored. EIs may be broadly
classified as endogenous and those that are obtained synthetically.
Endogenous EIs include peptides like spinorphin and opiorphin.
And compounds like RB 101, RB 120, RB 3007 constitute the
synthetically obtained EIs. Endogenous and synthetic inhibitors
enkephalin degrading enzymes have been studied in vivo
using standard animal models. The potential EI targets appear
to be APN (Aminopeptidase N), NEP (Neutral endopeptidase),
DPP-III (Dipeptidyl peptidase). EIs possess the advantage
that they lack the opioid side effects. This article reviews
the mechanisms by which EIs act and elucidates the pathways
involved.
[Back to top]
Fluorescence Imaging: Applications in Drug Delivery Research
A. Agarwal, P.K. Tripathi, S. Tripathi and
N.K. Jain
In the context of drug delivery it is crucial to gain
knowledge of nature of the cell's internal barriers, as well
as one needs to be aware of requirements for the study of
spatial and temporal interactions of drug delivery vehicles
with the cell. Fluorescent imaging technology can be a great
innovation in the field of science as far as study of live
cell imaging and dynamic events are concerned. The technique
has also demonstrated the ability to integrate the anatomic,
functional, and statistical data. The current review article
discusses various fluorescent techniques and also elaborates
the scope of fluorescent imaging in the field of drug delivery.
[Back to top]
GPR40 Carboxylic Acid Receptor Family and Diabetes: A New
Drug Target
V.N. Telvekar and H.S. Kundaikar
Type-2 diabetes is strongly linked to visceral obesity
and elevated levels of circulating free fatty acids. For years
this correlation of obesity to diabetes has intrigued the
minds of researchers and research in this direction has led
to a possible solution to this question. Human Genome project
has identified nearly 150 orphan GPCRs. The reverse pharmacology
approaches have identified free fatty acids as ligands for
the GPR40 family of orphan receptors. This review mainly emphasizes
on the role of GPR40 carboxylic acid receptor family in the
development of diabetes alongwith detailed coverage of each
receptor of the family. GPR40 family has provided an insight
into regulation of carbohydrate and lipid metabolism in vertebrates
and has further provided targets for the development of therapeutic
agents useful for treating or preventing disorders such as
Type-2 diabetes. This review also suggests where further research
and development could be beneficial.
[Back to top]
Glucagon Like Peptides-1 Modulators as Newer Target for Diabetes
H.B. Vaidya and R.K. Goyal
Diabetes mellitus (DM) has been recognized as a growing
world-wide epidemic by many health advocacy groups including
the World Health Organization (WHO). DM affects about 6% of
the North American population. A recent report estimated that
8.2% of adult population worldwide has impaired glucose tolerance.
Current treatment approaches include diet, exercise, and a
variety of pharmacological agents including insulin, biguanides,
sulfonylureas and thiazolidinediones. New therapies are still
needed to control metabolic abnormalities, and also to preserve
β-cell
mass and to prevent loss of β-cell
function. In many cases monotherapy gradually fails to improve
blood glucose control and combination therapy is employed.
The long-term success of these treatments varies substantially.
Thus, there is an imperative need for novel therapeutic approaches
for glycemic control that can complement existing therapies
and possibly attempt to preserve normal physiological response
to meal intake. Glucagon-like peptide 1 (GLP-1) is a drug
candidate which potentially fulfils these conditions. Glucoregulatory
actions of GLP-1 include glucose-dependent enhancement of
insulin secretion, inhibition of glucagon secretion, slowing
of gastric emptying and reduction of food intake. GLP-1 is
rapidly inactivated by amino peptidase, Dipeptidyl Peptidase-IV
(DPP-IV) and the utility of DPP-IV inhibitors are also under
investigation. There is a recent upsurge in the development
of GLP-1 mimetics and DPP-IV inhibitors as potential antidiabetic
agents. The present review summarizes the concepts of GLP-1
based therapy for type 2 diabetes and the current preclinical
and clinical development in GLP-1 modulators.
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