Current Rheumatology Reviews - Volume 4, Issue 3, 2008

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.

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.

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.

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.

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.

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.

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 tissues 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.

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.

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 description 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.

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.

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 peroxisome 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.

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.

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.