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Current
Rheumatology Reviews
ISSN: 1573-3971
Current Rheumatology Reviews
Volume 4, Number 3, August 2008
Contents
Stem Cells and Osteoarthritis
Guest Editors: Nicolai Miosge and Mary B. Goldring
Editorial Pp. 135
Regulatory Mechanisms of Chondrogenesis and Implications
for Understanding Articular Cartilage Homeostasis
Pp. 136-147
Chisa Hidaka and Mary B. Goldring
[Abstract]
Biology of Mesenchymal Stem Cells Pp.
148- 154
Franz Jakob, Catarina Limbert, Tatjana Schilling, Peggy
Benisch, Lothar Seefried and Regina Ebert
[Abstract]
Mesenchymal Stem Cells and Their Cell Surface
Receptors Pp 155- 160
Denitsa Docheva, Florian Haasters and Matthias Schieker
[Abstract]
Adult Stem Cells for Cartilage Tissue Engineering
and Regeneration Pp.161-170
Faye H. Chen and Rocky S. Tuan
[Abstract]
Migration of Local Progenitor Cells as Therapeutic
Target in Knee Osteoarthritis Pp. 171- 174
Rolf E. Brenner and Jorg Fiedler
[Abstract]
Animal Models of Osteoarthritis Pp.
175-182
Christopher B. Little and Margaret M. Smith
[Abstract]
Knock-Out Mice in Osteoarthritis Research
Pp. 183-193
Aurelia Raducanu and Attila Aszódi
[Abstract]
Clinical Aspects of Autologous Chondrocyte Transplantation
Pp. 193-196
Hans-Michael Klinger and Mike H. Baums
[Abstract]
Current Concepts in Meniscus Tissue Engineering
Pp. 196-201
Anja Drengk, Klaus Michael Stürmer and Karl-Heinz
Frosch
[Abstract]
Does Osteoblast to Adipocyte Differentiation
Play a Role in Osteoarthritis? Pp. 202-205
Heide Siggelkow
[Abstract]
Angiogenesis in Osteoarthritis Pp. 206-209
Norbert Schütze
[Abstract]
The Role of Progenitor Cells in Osteoarthritis
Pp. 210-213
Jenny Kruegel, Nicolai Miosge and Sebastian Koelling
[Abstract]
Abstracts
[Back to top]
Editorial
In recent years, hopes have been raised, not only
by the scientific community, that stem cells might be a therapeutic
alternative for the treatment of degenerative diseases like
Alzheimer’s or osteoarthritis. In this issue, we have
combined a series of reviews to elucidate various aspects
of stem cell biology that may be applicable to our understanding
of the pathogenesis of osteoarthritis and development of novel
therapeutic approaches.
The synovial joint is a complex organ that is composed of
tissues other than cartilage, and we must consider the whole
joint when considering therapeutic options. Although cartilage
is the most obvious tissue undergoing destruction during the
course of osteoarthritis, the synovium, the meniscus, and
the subchondral bone are also involved in the disease process.
Chisa Hidaka and Mary Goldring introduce this review series
with a profound essay on the mechanisms underlying chondrogenesis
and chondrocyte homeostasis. In general, the knowledge of
developmental processes provides a basis for the understanding
of disease processes; this is particularly true for osteoarthritis.
This leads to a concise summery by Franz Jakob et al.
on the current developments in mesenchymal stem cell biology.
Following the elegant introductory reviews is the article
by Denitsa Docheva et al. describing the various
cell surface receptors of mesenchymal stem cells and emphasizing
the need to understand the role of cell surface markers, especially
in the light of scaffold-based approaches in tissue engineering
of cartilage defects. Faye H. Chen and Rocky S. Tuan present
a broad review on the role of adult stem cells for cartilage
tissue engineering and set the stage for the subsequent reviews
dealing with more specialized aspects of stem cells and osteoarthritis.
Rolf E. Brenner and Jörg Fiedler highlight the role of
migration processes for stem cell recruitment as one of the
cornerstones for future cell based therapies for osteoarthritis.
Christopher B. Little and Margaret Smith write about the importance
of the selection of the appropriate animal model to answer
questions related to stem cells as means to treat osteoarthritis.
Large animal models will be essential in the evaluation of
the safety of new treatment options. Aurelia Raducanu and
Attila Aszódi remind us of the wealth of information
derived from transgenic and knock-out mice. Hans-Michael Klinger
and Mike H. Baums provide a concise, critical overview of
clinical aspects of autologous chondrocyte transplantation,
perhaps one of the few examples of cell-based therapeutic
approaches already integrated into medical practice. Anja
Drengk et al. describe current concepts of meniscus
tissue engineering, a still highly experimental procedure
with broad implications for future regenerative therapies,
as osteoarthritis is a disease that affects tissues other
than the articular cartilage tissue of the synovial joint.
Heide Siggelkow describes the role of osteoblast and adipocyte
differentiation and Norbert Schütze provides a concise
review on the role of angiogenesis for the pathogenesis of
osteoarthritis. Finally Jenny Kruegel et al. report
on the role of chondrogenic progenitor cells found in the
diseased tissue itself as a promising starting point for interventions
in late-stage osteoarthritis.
Overall, this section highlights interesting developments
in the field of stem cell biology and stem cell based treatment
possibilities that will lead in the first place to a better
understanding of the pathophysiology of osteoarthritis and
eventually towards cell biological therapies for this disease.
However, a large amount of additional knowledge is necessary
before we can apply any cell-based therapeutic approach to
degenerative joint diseases in general and osteoarthritis
in particular.
Nicolai Miosge
Tissue Regeneration Work Group
Medical Faculty
Department of Prosthodontics
Georg August University
Abteilung Prothetik im Zentrum ZMK
Robert-Koch-Str. 40
D-37075 Goettingen
Germany
E-mail: nmiosge@gwdg.de
Mary B. Goldring
Tissue Engineering Regeneration and Repair Program
Research Division
Caspary 528
Hospital for Special Surgery
535 East 70th Street
NY 10021
USA
E-mail: goldringm@hss.edu
[Back to top]
Regulatory Mechanisms of Chondrogenesis and Implications for
Understanding Articular Cartilage Homeostasis
Chisa Hidaka and Mary B. Goldring
Studies of chondrogenesis and embryonic limb development
offer a wealth of knowledge regarding signals that regulate
the behavior of chondrocytes. Many such chondrogenic regulators
are upregulated in osteoarthritis-affected chondrocytes, suggesting
a role in pathogenesis. Yet, some of the same factors also
support adult articular cartilage homeostasis, and enhance
neo-cartilage tissue formation in experimental models. In
this review, we summarize many of the important regulatory
mechanisms involved in chondrogenesis and examine how their
disruption may contribute to functional changes in articular
cartilage during osteoarthritis or aging.
[Back to top]
Biology of Mesenchymal Stem Cells
Franz Jakob, Catarina Limbert, Tatjana Schilling, Peggy
Benisch, Lothar Seefried and Regina Ebert
Mesenchymal stem cells (MSC) are derived from mesodermal
precursor and are committed towards mesenchymal differentiation.
They are scattered all over the organism, situated in bone,
cartilage, adipose tissue and accompany organs for tissue
regeneration and structural and functional support. MSC populations
are not homogenous, their signature is variable according
to their localization. A process called “epithelial
mesenchymal transition” is fundamental for the development
of mesoderm. Epithelial-mesenchymal interactions specify MSC
and this may influence their regeneration potential. Multipotent
adult MSC are used for research in tissue regeneration and
engineering. Crude mixtures of bone marrow-derived MSC are
clinically applied for tissue healing, but complex transplantable
tissue engineered constructs are still under development.
The role and regeneration potential of MSC in inflammation
and ageing organisms remains to be characterized. The establishment
of reprogrammed homogenous MSC cultures of high plasticity
might allow developing these cells towards multiple cell-based
therapeutic strategies. Many applications can be envisioned,
e.g. regeneration of bone, cartilage and tendon or engineering
of beta cells and neurons. Since homogenous MSC with high
plasticity represent a promising tool for the treatment of
many diseases, research in this area of adult stem cells should
be supported with high priority.
[Back to top]
Mesenchymal Stem Cells and Their Cell Surface Receptors
Denitsa Docheva, Florian Haasters and Matthias Schieker
Daily increasing evidence indicates that stem cells can
be found in nearly every tissue. Mesenchymal stem cells (MSCs)
are adult stem cells, which reside in the bone marrow and
other mesenchymal tissues. MSCs can be expanded to large numbers
and can be driven into diverse mesenchymal cell lineages,
including chondrocytes. Therefore, MSCs have attracted the
attention of the biomedical community as very promising tools
for repair of joint tissues, such as articular cartilage.
This review will outline the MSC surface receptors and will
focus on receptors that deliver important signals for chondrogenic
differentiation of MSCs.
[Back to top]
Adult Stem Cells for Cartilage Tissue Engineering and Regeneration
Faye H. Chen and Rocky S. Tuan
Osteoarthritis (OA) is the most common joint disease
and the leading cause of disability in the developed countries.
Its clinical manifestations include pain and impairment to
movement, and often affect surrounding tissues with symptoms
of local inflammation. It is a progressively debilitating
disease that is often associated with injury and aging. However,
current pharmacological and surgical treatment modalities
ultimately fail to stall the progression of OA. Viable treatment
options are in need, and current effort of cartilage tissue
engineering and regeneration, especially using chondroprogenitor
cells, such as adult mesenchymal stem cells (MSCs), has offered
hope of eventual success. First, ex vivo MSC cartilage tissue
engineering can potentially produce effective replacement
constructs for focal cartilage defects to prevent the progression
to OA. This paper will review the factors important for cartilage
tissue engineering, including cells, scaffold, and environment,
as well as current problems and areas that await more research.
Secondly, MSCs possess the capacity to function as a systematic
regulator, to influence the local environment, via
direct or indirect interactions, including soluble factors.
Through these functions, MSCs can enhance local progenitor
cell mediated regeneration, confer immunomodulation and anti-inflammatory
effects, which can prove to be critically important in the
setting of cell therapy for OA, a degenerative disease with
associated local inflammation. Taken together, MSCs, used
either as a structural substitute in a tissue engineered construct,
or in cell therapy utilizing their modulating functions, or
both, present promise in the treatment of OA, although clearly
more research is needed to achieve this ultimate goal.
[Back to top]
Migration of Local Progenitor Cells as Therapeutic Target
in Knee Osteoarthritis
Rolf E. Brenner and Jorg Fiedler
The identification of mesenchymal progenitor cells in
bone marrow and various joint related tissues like cartilage
or synovial tissue renders the cell-biologic systems on which
the pathogenetic concepts of osteoarthritis have been developed
more complicated by introducing a novel cellular player. The
progenitor cells could have different implications in the
osteoarthritic process but their precise role is not known
so far. For bone marrow derived mesenchymal stromal cells
(MSC) the capacity to migrate in response to various chemoattractive
factors and to differentiate into the chondrogenic phenotype
has been shown. Their potential role in tissue repair may
further include the secretion of trophic factors and a certain
immunomodulatory function. Migration activity of cartilage-derived
cells has also been shown by different approaches. The emerging
concept of motile chondroprogenitor cells present within synovial
joints might lead to novel therapeutic strategies. Therefore,
local mesenchymal progenitor cells may become a future therapeutic
target in patients with early stage degenerative joint disease.
[Back to top]
Animal Models of Osteoarthritis
Christopher B. Little and Margaret M. Smith
The complex pathobiologic changes of human joint disease,
particularly osteoarthritis (OA), normally take several decades
to develop and may be influenced by a multitude of genetic
and environmental factors. The need to clarify the molecular
events that occur in joint tissues at the onset and during
the progression of OA has necessitated the use of models,
which, although imperfect, can exhibit many of the pathologic
features that characterize the human disease. In vitro
studies have proven invaluable in defining specific molecular
and cellular events in degradation of joint tissues such as
cartilage. However, to fully understand the complex inter-relationship
between the different disease mechanisms, joint tis-sues and
body systems, studying OA in animal models is necessary. Models
of inflammatory arthropathies have proven predictive of clinical
efficacy, with therapies that are beneficial in animals having
significant benefit in treatment of rheumatoid arthritis in
humans. While none of the available animal models of OA can
truly be said to be predictive, as no anti-OA therapies have
yet proven to be disease modifying in human trials, this approach
represents a cornerstone for discovery of new anti-OA therapeutic
targets and drugs. In this paper the available species and
models of OA are reviewed and their potential utility discussed.
[Back to top]
Knock-Out Mice in Osteoarthritis Research
Aurelia Raducanu and Attila Aszódi
Osteoarthritis (OA) is the most common degenerative disorder
of the joints with an etiology involving genetic and environmental
factors. Although various animal models have been used to
elucidate the pathogenesis of OA, in the past decade gene
targeting in mice has become one of the most powerful tools
to dissect the molecular mechanisms of the disease. The generation
of knockout mice has enormously accelerated the identification
of the key genetic players in articular cartilage homeostasis
and made a significant contribution to further our understanding
of OA pathology. In this review, we will outline the phenotypes
of the currently available mouse strains, carrying either
engineered or spontaneous gene mutations, which provide insight
into the processes of articular cartilage destruction. The
analysis of these mice reveals a complex interaction among
cytokines, proteases, transcription factors, extracellular
matrix, cell surface and signaling molecules during the initiation
and progression of OA and, in some cases, suggests new therapeutic
interventions for the disease.
[Back to top]
Clinical Aspects of Autologous Chondrocyte Transplantation
Hans-Michael Klinger and Mike H. Baums
Despite its highly specialized nature, articular cartilage
has a poor reparative capability. Therefore chondral and osteochondral
lesions remain a difficult problem for the patient and the
physician. Autologous Chondrocyte Transplantation was first
reported 1994 by Brittberg et al. as an alternative for the
treatment of these injuries. Since the original de-scription
of Autologous Chondrocyte Transplantation many new techniques
and technique modifications have been reported. Autologous
Chondrocyte Transplantation today is the only reliable biological
reconstruction method for localised cartilage defects of more
than 4 cm², especially for symptomatic defects in the
knee. However, Autologous Chondrocyte Transplantation is a
relatively costly procedure, since it requires two interventions
and cell culturing in vitro. Current literature and
techniques of Autologous Chondrocyte Transplantation are reviewed
and a treatment algorithm is presented.
[Back to top]
Current Concepts in Meniscus Tissue Engineering
Anja Drengk, Klaus Michael Stürmer and Karl-Heinz
Frosch
After partial or total meniscus resection, cartilage
degeneration can be observed in many knee joints, frequently
culminating in osteoarthritic changes. Therefore, a meniscus
preserving therapy should be performed whenever possible.
However, despite improved surgical techniques and new treatment
strategies, meniscal tissue resection cannot always be avoided.
Currently, only few treatment options are available after
total meniscectomy, a dissatisfying situation considering
that many patients presenting with meniscal injuries are young
patients. Transplantation of allogenous menisci has been valuable
only in particular cases and does not seem to prevent degenerative
changes in the affected knee joint. Because of the unsatisfactory
clinical progression after resection of meniscal tissue, new
tissue engineering concepts are eagerly sought after. A first
step towards a meniscus replacement therapy has been achieved
with the development of a collagen meniscus implant (CMI),
which has recently been approved for clinical application
in Europe. This review will give a short overview about actual
meniscus replacement therapies. Current experimental research
concepts for meniscus tissue engineering and new perspectives
for clinical treatment strategies will also be presented.
Additionally, we will report about successful experimental
application of new scaffolds and scaffolding materials, the
use of different cell types and gene therapy approaches.
[Back to top]
Does Osteoblast to Adipocyte Differentiation Play a Role in
Osteoarthritis?
Heide Siggelkow
The plasticity of mesenchymal stem cells (MSC) is of
major interest for diagnosis and therapy of bone diseases.
Interactions between osteoblasts and adipocytes seem to be
involved in the pathogenesis of osteoporosis. This review
is intended to elucidate a link between osteoarthritis and
the differentiation of MSCs towards the adipocytic or osteoblastic
lineage. Viewing osteoarthritis as a systemic disease, recent
data underline the importance of the nuclear receptor perox-isome
proliferator activated receptor gamma (PPARγ)
in its pathogenesis. In contrast to the increase in fat mass
in osteoporosis, in OA, there is evidence of a decrease in
PPARγ
signaling with increasing severity of OA. Therefore, not the
differentiation of osteoblasts to adipocytes, but the development
from adipocytes to osteoblasts might be a mechanism relevant
to the pathogenesis of osteoarthritis.
[Back to top]
Angiogenesis in Osteoarthritis
Norbert Schütze
Articular cartilage is essentially avascular and in recent
years the role of blood vessel formation in osteoarthritis
has been increasingly recognized. Therefore, healthy cartilage
most likely actively prevents vessel in growth although the
underlying mechanisms have not been uncovered to date. Further,
the role of inflammation in the degradative processes in osteoarthritis
is increasingly recognized. An inflammation dependent angiogenesis
is clearly involved in the pathophysiology of osteoarthritis.
Vascular endothelial growth factor (VEGF) has evolved as a
dominant mediator of angiogenesis. In addition an angiopoietin
(Ang)-dependent signalling system as well as processes like
hypoxia contribute to a complex signalling network that stimulates
ingrowth of blood vessels and degradative processes in the
cartilage tissue itself. It can be expected that additional
players related to angiogenesis in osteoarthritis and/or antiangiogenesis
in healthy cartilage will emerge in the future such as the
CCN-family proteins. The cysteine rich protein 61 (CYR61/CCN1)
represents an angiogenic inducer whereas the WNT1 inducible
signalling pathway protein 3 (WISP3/CCN6) appears to be an
antiangiogenic factor. The inhibition of inflammation dependent
angiogenesis or solely angiogenesis appears to be a promising
strategy in osteoarthritis. However, studies targeting angiogenesis
(e.g. VEGF) are missing to date.
[Back to top]
The Role of Progenitor Cells in Osteoarthritis
Jenny Kruegel, Nicolai Miosge and Sebastian Koelling
It remains a great challenge to enhance the regeneration
potential of hyaline cartilage tissue. Tissue degeneration
activities initiated after major injury or due to age-related
processes override the generally limited self-renewal capacity
of this tissue. Numerous catalytic enzymes lead to chondrocyte
apoptosis and extracellular matrix deterioration. During early
embryonic development, some of the embryonic stem cells of
the inner cell mass of the blastocyst will turn into the mesoderm.
This will be the founder of the mesenchymal cells in connective
tissues of adult life, such as bone, tendon, muscle, and cartilage.
Some of these embryonic mesenchymal cells are believed not
to differentiate, but to reside in each of the tissues. These
are now collectively described as adult mesenchymal stem cells,
which are thought to be capable of repairing injured tissue.
To date, various populations of bone marrow stroma cells,
one of the various populations of adult stem cells, have been
described and have been experimentally differentiated into
cartilage tissue in vivo and in vitro. In
this review, we will briefly summarize the current knowledge
about stem cell related cells in cartilage tissue that are
potentially involved in regeneration processes in osteoarthritis.
Our unpublished results indicate that a cell population already
present in the diseased cartilage tissue might be a starting
point for a regenerative therapy for osteoarthritis.
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