Stem cells and osteoarthritis
Published on 01 April 2010
Stem cell treatments are often in the media as offering exciting new possible treatments for many conditions. Arthritis Research UK research manager Dr Lisa Croucher takes a look at what progress is being made in osteoarthritis.
Osteoarthritis – a complex problem
We have come a long way in our understanding of the causes and consequences of osteoarthritis (OA) but so far, translation of this knowledge into new drug treatments that might delay diseasprogression and the need for joint replacement surgery has been disappointing. Over the last 15 years, Arthritis Research UK-funded scientists have contributed significantly to a new and burgeoning field of research that holds great promise for sufferers of degenerative joint disease – tissue engineering.
Tissue engineering – a new approach
Tissue engineering applies the knowledge we have gained about the body’s natural biological processes to replace or support tissues that have been damaged or lost through injury or disease. In practice, this usually means growing (culturing) and manipulating cells and molecules outside of the body to form new tissue that copies the design and function of the original. Highly complex and intricate, tissue engineering research for diseases as varied as cancer, heart disease and liver disease is already well advanced.
A relatively simple tissue with only one type of cell, joint cartilage lends itself well to a tissue engineering approach, and promising therapies for OA and other musculoskeletal diseases are now under investigation by centres around the world, including the UK.
ACI for cartilage repair
The only tissue engineering technique currently used routinely for cartilage repair in the UK is autologous chondrocyte implantation (ACI). Used primarily to repair small cartilage injuries in young patients, the procedure is relatively simple. A small piece of healthy cartilage is surgically removed from the patient’s own joint. In the laboratory, the cartilage-producing cells, the chondrocytes, are isolated from their surrounding tissue and then cultured to replicate many times over. The new cells are implanted back into the joint, where they set about making new cartilage to fill the injury, eventually restoring function to the joint. Orthopaedic surgeon Professor James Richardson and his team at the Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, have run an ACI programme since 1996, treating between 30 and 50 patients per year. Success rates are high, and although the recovery period can be lengthy, most patients regain full use of the affected joint.
Arthritis Research UK has funded several projects over the years to more fully understand the processes at work in ACI, helping to find ways to improve the technique and to monitor the progress of patients who have undergone the procedure. The Oswestry team in particular are working towards refining ACI in the hope that it may be used to treat the more extensive cartilage damage seen in established OA. For this large and growing population of patients, scientists are also looking increasingly towards alternative techniques and sources of cells. Tissue engineering approaches using stem cells are beginning to look promising.
Stem cells – a new treatment for osteoarthritis?
Stem cells are the early precursor cells that give rise to all of the other cells in the body, the ‘blank slates’ from which a whole adult human is formed. We begin life as a fertilised embryo, the first and most primitive stem cell. As the embryo divides and divides again, its growing number of new cells progressively moves towards specialisation. In this way, adult human beings gradually acquire skin cells, brain cells, liver cells, chondrocytes – all of the highly specialised cell types that the body requires, each with its own precise job to do.
By the time a human is fully developed, the ‘super’ stem cells of the embryo are gone forever. But adults hold within their tissues small populations of potentially very useful stem cells that, whilst still open to manipulation, are a little closer to maturity. These ‘repair kits’ are used to replenish mature cells and repair tissues as needed throughout our lives. Primed to fulfil their destiny as specialised cells, all they need is a trigger to complete the maturation process.
Adult stem cells may lack the limitless potential of embryonic stem cells, but their availability makes them very attractive to researchers looking for tissue regeneration solutions. The trick is knowing how to harness and manipulate their huge potential.
Mesenchymal stem cells
Current research efforts for stem cell therapy for OA are focussed primarily on the mesenchymal stem cell (MSC), resident primarily in the bone marrow and possessing the capacity to form many different mature cell types, including cartilage-producing chondrocytes and bone cells. Once isolated in the laboratory, bone marrow MSCs can be stimulated to renew themselves almost without limit, and cultured on membrane ‘scaffolds’ for several weeks, will mature into chondrocytes capable of producing three-dimensional cartilage.
There is still some way to go before evidence-based treatments using MSCs are routinely available to patients with OA, but there are signs that the technology is beginning to move out of the laboratory and into the clinic.
At the Robert Jones and Agnes Hunt Orthopaedic Hospital, Professor Sally Roberts and Professor Richardson are planning a ground-breaking clinical trial to extend the group’s highly successful ACI programme to patients with the more extensive cartilage damage typical of OA. With funding of £500,000 from Arthritis Research UK, the team will investigate whether adding MSCs to the mature chondrocytes conventionally used in ACI results in a better outcome for patients than using either chondrocytes or MSCs alone. More details of this research will appear in the July edition of Arthritis Today. Patients taking part in this trial will be recruited from orthopaedic departments around the UK.
Meanwhile, Professor Anthony Hollander (pictured left), Arthritis Research UK Professor of Rheumatology and Tissue Engineering at Bristol University, is building on his extensive fundamental work to understand the behaviour of MSCs to develop a new stem cell treatment specifically designed to repair tears to the meniscus – a small, ‘C’-shaped piece of cartilage that helps the knee joint to cope with the extreme stresses that it encounters in everyday activities. Meniscal tears are a common sports injury in young people, often triggering the development of premature OA. With his colleague Dr Wael Kafienah, Professor Hollander has pioneered a technique to encourage the integration of implants engineered from bone marrow MSCs into the injured meniscus, and improve the ‘knitting’ between the meniscus tissue and the new implant. Dubbed the ‘cell bandage’ the technique is now undergoing testing for safety and effectiveness in animal models, and trials to test the therapy in humans may begin in early 2011.
Stem cells from cartilage
There is no doubt that bone marrow MSCs offer exciting prospects for the treatment of degenerative joint disease, but the use of these cells is not without problems. The cartilage that they form sometimes has a tendency to calcify and turn into a bone-like tissue – indeed, bone marrow MSCs have been used successfully to assist fracture healing and to treat some metabolic bone diseases.
With support from Arthritis Research UK, Professor Charlie Archer and his team at Cardiff University are attempting to circumvent this problem with their work on a stem cell derived not from bone marrow, but from adult cartilage. Forming an authentic, permanent cartilage tissue in the laboratory that does not turn into bone, cartilage stem cells have even been identified in the cartilage of elderly individuals. Studies in animals to test the effectiveness and safety of these cells for cartilage repair are due to start this year, a necessary prerequisite to clinical trials in humans.
Embryonic stem cells
With their huge proliferative capacity, embryonic stem cells offer the possibility of an extraordinarily high-volume production of cartilage cells. Human embryonic stem cells are usually taken from unused embryos donated after IVF treatment. These cells can be manipulated to form almost any type of mature cell, but it’s important to note that it is not possible to produce a fully formed individual in this way. With a recently awarded grant from Arthritis Research UK, Dr Susan Kimber’s team at Manchester University aims to take its fundamental laboratory work on embryonic stem cells a step further, testing the ability of chondrocytes derived from embryonic stem cells to form cartilage when implanted into animals. This work is in its early stages, but could lead to methods to produce chondrocytes on a very large scale, potentially benefiting many patients with OA.
In reality, tissue engineering solutions for the extensive damage characteristic of moderate to severe OA are some way off. But with their extensive work to understand stem cell behaviour and to use this knowledge to develop methods to engineer new cartilage, researchers have already made great progress towards developing the solutions we need for the future.
Arthritis Research UK has recognised that the tissue engineering research effort for arthritic diseases would benefit from a boost in the UK. For this reason, the charity plans to award £2.5million over five years to establish a collaborative National Centre of Excellence in Tissue Engineering, bringing together the expertise of individuals who would otherwise be working in isolation–biologists, tissue engineers, biomaterial scientists, orthopaedic surgeons and other clinical professionals. The successful applicants will be charged with developing new tissue engineering solutions for large-scale applications in humans. The centre will be awarded in June, and Arthritis Research UK is confident that its ambition and scope will lead to the new therapeutic solutions that a growing population with disabling and painful musculoskeletal disease so desperately needs.
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