The progressive increase in life expectancy within the last century has led to the appearance of novel health related problems. Some of these are within the musculoskeletal field, for example diseases such as osteoporosis, osteoarthritis, rheumatoid arthritis and bone cancer, just to mention some of the most relevant. Other related problems are those that arise from serious injuries, often leading to non-recoverable critical joint-space defects. The therapies currently used to treat this type of diseases / injuries are based on the use of pharmaceutical agents and auto / allotransplant and synthetic materials. However, such solutions present a number of inconveniences.
The appearance of a novel field of science called tissue engineering brought some hope for arthritis sufferers. It is believed that by combining a 3D porous template scaffold with an adequate cell population, with osteo or chondrogenic potential, it will be possible to develop bone and cartilage tissue equivalents that when implanted in vivo ( back into the human body), could lead to the total regeneration of the affected area. This ideal cell population should have a series of properties, namely a high osteo and chondrogenic potential and at the same time, should be easily expandable, i.e. capable of self replicating and maintained in cultures for long periods of time. Due to their natural and intrinsic properties, stem cells are one of the best available cell types.
During the last 10 / 15 years, the scientific community witnessed and reported the appearance of several sources of stem cells with both osteo and chondrogenic potential. There are many different sources of adult stem cells (bone marrow, periosteum, adipose tissue, skeletal muscle and umbilical cord) for bone and cartilage regenerative medicine, namely those focusing on the differentiation potential of the latter, as well as in vivo proof of concept of their applicability.
Mesenchymal stem cells, the non-heamatopoietic progenitor cells found in various adult tissues, are characterized by their ease of isolation and their rapid growth in vitro while maintaining their differentiation potential, allowing for extensive culture expansion to obtain large quantities suitable for therapeutic use. These properties make mesenchymal stem cells an ideal candidate cell type to use as building blocks for tissue engineering efforts to regenerate replacement tissues and repair damaged structures as encountered in various arthritic conditions. Osteoarthritis (OA) is the most common arthritic condition and, like rheumatoid arthritis (RA), presents an inflammatory environment with immunological involvement. This has been an enduring obstacle that can potentially limit the use of cartilage tissue engineering, although clinical cases where allogeneic and autologous stem cell procedures were shown to ameliorate and potentially cure the arthritis are well documented. Phase I and Phase II clinical studies of stem cell treatments have established the feasibility, safety and efficacy of autologous stem cell mobilisation and transplantation.
Recent advances in our understanding of the functions of mesenchymal stem cells have shown that they also possess potent immunosuppression and anti-inflammation effects. In addition, through secretion of various soluble factors, mesenchymal stem cells can influence the local tissue environment and exert protective effects with an end result of effectively stimulating regeneration in arthritis. This function of mesenchymal stem cells can be exploited for their therapeutic application in degenerative joint diseases such as rheumatoid arthritis and osteoarthritis(1)
Although cartilage defects are common features of osteoarthritis and rheumatoid arthritis, current medical treatments can rarely restore the full function of native cartilage. Recent studies have provided new perspectives for cartilage engineering using multipotent mesenchymal stromal stem cells. Moreover, mesenchymal stromal stem cells have been used as immunosuppressant agents in autoimmune diseases and have tested successfully in animal models of arthritis.
Mesenchymal stromal stem cells extracted from the patient’s own bone marrow are sent for various laboratory tests and cell culture to grow sufficient cells, which are then used to stimulate cartilage regeneration via two techniques – an open or a minimally invasive procedure.
The open technique involves opening the knee joint and implanting the stem cells into the affected area. For the minimally invasive technique, cultured stem cells are injected into the knee three weeks after an initial arthroscopic microfacture, which is a surgical technique to treat damaged areas of the knee’s articular cartilage.
The advantages of stem cell transplantation and cartilage regeneration:
Cartilage defects have a poor healing capacity, and unresolved injury tends to progress to osteoarthritis. Until recently, the treatment for such problems was limited to surgical methods that involved the abrasion and drilling of the subchondral bone in the knee. This technique stimulates repair tissue, which unfortunately degenerates with time. Tissue engineering using stem cells for cartilage regeneration has been found to be promising.
Mesenchymal stem cells are able to grow into various mesenchymal cells, such as cartilage and secrete bioactive factors that help the healing process in the knee. Mesenchymal stem cells grow faster than cartilage cells, reducing the culture incubation period in the laboratory. This technique also averts the need to harvest cartilage, lowering donor site morbidity.
Mesenchymal stem cells from rheumatoid arthritis and osteoarthritis patients possess similar chondrogenic potential as mesenchymal stem cells isolated from healthy donors. Therefore, these cells may serve as a potential new prospect in cartilage replacement therapy.
Immunoablative therapy and heamatopoietic stem cell transplantation is an intensive treatment modality aimed at ‘resetting’ the dysregulated immune system of a patient with immunoablative therapy and allow outgrowth of a nonautogressive immune system from reinfused heamatopoietic stem cells, either from the patient (autologous stem cells) or a healthy donor (allogeneic stem cells).
Autologous stem cells have been shown to induce profound alterations of the immune system affecting B and T cells, monocytes, and natural killer cells and dendritic cells, resulting in elimination of autoantibody-producing plasma cells and in induction of regulatory T cells.
Most of the available data has been collected through retrospective cohort analyses of autologous stem cell treatments, case series, and translational studies in patients with refractory autoimmune diseases. Long-term and marked improvements of disease activity have been observed, notably in systemic sclerosis, systemic lupus erythematosus, and juvenile idiopathic arthritis, and treatment-related morbidity has improved due to better patient selection and modifications of transplant regimen.
Mesenchymal stem cells - isolated from various tissues in humans and other species - are one of the most promising adult stem cell types due to their availability and the relatively simple requirements for in vitro expansion. They have the capacity to differentiate into several tissues, including bone, cartilage, tendon, muscle and adipose, and produce growth factors and cytokines that promote hematopoietic cell expansion and differentiation. In vivo, mesenchymal stem cells are able to repair damaged tissue from kidney, heart, liver, pancreas and gastrointestinal tract. Furthermore, they also have anti-proliferative, immunomodulatory and anti-inflammatory effects, but evoke only little immune reactivity. Although the mechanism underlying the immunosuppressive effects of mesenchymal stem cells has not been clearly defined, their immunosuppressive properties have already been exploited in the clinical setting. Therefore, in the future, MSCs might have implications for treatment of allograft rejection, graft-versus-host disease, rheumatoid arthritis, autoimmune inflammatory bowel disease and other disorders in which immunomodulation and tissue repair are required
The word arthritis means joint inflammation. The term arthritis is used to describe more than 100 rheumatic diseases and conditions that affect joints, the tissues which surround the joint and other connective tissue. The pattern, severity and location of symptoms can vary depending on the specific form of the disease. Typically, rheumatic conditions are characterized by pain and stiffness in and around one or more joints. The symptoms can develop gradually or suddenly. Certain rheumatic conditions can also involve the immune system and various internal organs of the body.
Types of arthritis
A brief overview of the most common forms of arthritis will be discussed in this section.
In 2006, the combined data from the National Health Interview Survey years 2003–2005 Sample Adult Core estimated an average yearly prevalence of arthritis in American adults to be 21.6% (46.4 million). This disease is more common in women than in men and increases with age.
There is much disagreement among experts about definitions of childhood arthritis. At least three clinical classification schemes exist: juvenile rheumatoid arthritis (JRA), juvenile chronic arthritis (JCA), and juvenile idiopathic arthritis (JIA). All three schemes do not include many of the conditions considered as arthritis and other rheumatic conditions in adults. Also, a case counted in one classification system may not be a case in another system. However, all schemes define childhood arthritis as occurring in people younger than 16 years. The most common form of juvenile arthritis is juvenile rheumatoid arthritis (the term and classification system used most commonly in the United States). Juvenile rheumatoid arthritis involves at least 6 weeks of persistent arthritis in a child younger than 16 years with no other type of childhood arthritis. Juvenile rheumatoid arthritis has three distinct subtypes: systemic (10%), polyarticular (40%) and pauciarticular (50%). Each type has a unique presentation and clinical course and immunogenetic association. For the latter two types, girls are more commonly affected (3–5:1). In all three types about 40 – 45% still have active disease after 10 years. For the systemic type, the peak age of onset is 1 to 6 years old and about 50% of cases show very short stature in adulthood as a result. For the pauciarticular form, there are two distinct subtypes: early onset and late onset. Early onset is more common in girls, late onset is more common in boys. The genetics differ as do the clinical courses. In the polyarticular form, there are also two subtypes: rheumatoid factor (RF) positive and negative. RF positive usually affects girls with onset after 8 years of age and a poorer prognosis compared with RF negative children
Rheumatoid arthritis (RA), an autoimmune condition, is a chronic inflammatory polyarthritis.1
Natural history studies of RA suggests that RA follows one of three courses:
Another natural history study found that 75% of people with RA experienced remission after five years.
The current status of stem cell transplantation for treatment of rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus, and systemic sclerosis are varied. From a large European bone marrow transplant registry, a bird’s eye view of stem cell transplantation for autoimmune disease can be obtained. Among 43 rheumatoid arthritis patients, 35 juvenile chronic arthritis patients, 34 systemic lupus erythematosus patients and 58 systemic sclerosis patients who underwent stem cell transplantation, initial responses in most patients were good to excellent. In rheumatoid arthritis and systemic lupus erythematosus treatment, the criteria for patient selection are still not clear and the therapeutic regimens for stem cell transplantation (and whether follow-up treatment is necessary) are not fully defined. In juvenile chronic arthritis, responses are encouraging although little fully published data beyond that from the European Bone Marrow Transplant Registry exists.
Cellular immune therapy for severe autoimmune diseases can now be considered when such patients are refractory to conventional treatment. The use of autologous stem cell transplantation to treat human autoimmune diseases has been initiated following promising results in a variety of animal models. Anecdotal observations have been made of autoimmune disease remission in patients who have undergone allogeneic bone marrow transplantation as a result of coincidental haematological malignancies. The possibility of inducing immunological self-tolerance by autologous stem cells is particularly attractive as a means for treating juvenile idiopathic arthritis.
Mesenchymal stem cells are precursors of tissue of mesenchymal origin, but they also have the capacity to regulate the immune response by suppressing T and B lymphocyte proliferation in a non-major histocompatibility complex-restricted manner. Use of stem cells as immunosuppressant agents in autoimmune diseases has been proposed and successfully tested in animal models. The feasibility of using allogeneic mesenchymal stem cells as therapy for collagen-induced arthritis, a mouse model for human rheumatoid arthritis, has already been convincing. A single injection of mesenchymal stem cells prevented the occurrence of severe, irreversible damage to bone and cartilage. Mesenchymal stem cells induced hyporesponsiveness of T lymphocytes as evidenced by a reduction in active proliferation, and modulated the expression of inflammatory cytokines. In particular, the serum concentration of tumor necrosis factor alpha was significantly decreased. These results suggest an effective new therapeutic approach to target the pathogenic mechanism of autoimmune arthritis using allogeneic mesenchymal stem cells.
Osteoarthritis is a chronic joint disorder in which there is progressive softening and disintegration of articular cartilage, accompanied by new growth of cartilage and bone at the joint margins (osteophytes) and capsular fibrosis. The common cause of osteoarthritis are genetic conditions, metabolic,hormonal and mechanical injury. Most importantly, ageing degenerative joint disease is by far the commonest form of arthritis, characterized by focal and progressive loss of the hyaline cartilage of joints, underlying bony changes that are clearly identified on radiographic changes (joint space narrowing, osteophytes and bony sclerosis).
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Rheumatology Unit, Institute of Child Health, UCL and Great Ormond Street Hospital NHS Trust, London, UK. Email:
