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Health See other Health Articles Title: Repairing joint cartilage with stem cells Anti-Aging Firewalls A weblog on the science and practices of living healthily very long - perhaps hundreds of years. * Home Calendar January 2010 M T W T F S S « Dec Feb » 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Categories * Admin (1) * Blogroll (1) * Uncategorized (339) * Weekly Posts (2) Latest Postings * 29. January 2011: US falling behind in longevity increases – why? * 23. January 2011: Public health longevity developments – focus on foods * 18. January 2011: SIRT3 research – tying together knowledge of aging * 13. January 2011: The Nuclear DNA Damage/Mutation Theory of Aging * 10. January 2011: Nitrates and nitrites –Part 2: good for you * 9. January 2011: Nitrates and nitrites – Part 1: bad for you * 6. January 2011: The reputation of aging in ancient and current mythology * 31. December 2010: Human growth hormone treatment – a fountain of accelerated aging? * 22. December 2010: Epigenetics of cancer and aging * 11. December 2010: Additional 2010 research progress with induced pluripotent stem cells Links Archives * January 2011 * December 2010 * November 2010 * October 2010 * September 2010 * August 2010 * July 2010 * June 2010 * May 2010 * April 2010 * March 2010 * February 2010 * January 2010 * December 2009 * November 2009 * October 2009 * September 2009 * August 2009 * July 2009 * June 2009 * May 2009 * April 2009 * March 2009 * February 2009 * January 2009 Meta * * Register * Login * Entries (RSS) * Comments (RSS) « Surprise! Just when we thought we knew everything about vitamin C | Exercise, telomerase and telomeres » Stem cell cartilage regeneration In the January 5 post Important new mesenchymal stem cell therapies, I promised this post specifically devoted to research on use of stem cells for cartilage regeneration. It is a long and fairly thorough post with focus on regeneration of cartilage damage due to osteoarthritis, the toughest kind to deal with. About cartilage and osteoarthritis From Wikipedia, “Cartilage is a stiff yet flexible connective tissue found in many areas in the bodies of humans and other animals, including the joints between bones, the rib cage, the ear, the nose, the elbow, the knee, the ankle, the bronchial tubes and the intervertebral discs. It is not as hard and rigid as bone but is stiffer and less flexible than muscle. — Cartilage is composed of specialized cells called chondrocytes that produce a large amount of extracellular matrix composed of collagen fibers, abundant ground substance rich in proteoglycan, and elastin fibers. Cartilage is classified in three types, elastic cartilage, hyaline cartilage and fibrocartilage, which differ in the relative amounts of these three main components. — Unlike other connective tissues, cartilage does not contain blood vessels. The chondrocytes are supplied by diffusion, helped by the pumping action generated by compression of the articular cartilage or flexion of the elastic cartilage. Thus, compared to other connective tissues, cartilage grows and repairs more slowly.” Hyaline Cartilage lines the ends of bones in joints in the body where there is movement, such as in the elbow or knee. A synovial fluid bathes the joint continuously so as to provide a frictionless interface. Osteoarthritis (OA) is classically thought to be a “wear and tear” disease where the cartilage gradually wears out, like brake shoes do in a car, leaving bones rubbing directly on bones. It can occur in the knees, hands, hips and the spinal areas of the lower back and neck. “In osteoarthritis of the spine, the spaces between the vertebrae narrow. Bone spurs often form. When bone surfaces rub together, the vertebral joints (facets) and areas around the cartilage become inflamed and painful. Gradually, your spine stiffens and loses flexibility. Once these changes appear on X-rays, osteoarthritis has already started(ref).” Osteoarthritis can create stiffness, be very painful, and be seriously debilitating. The classical view is that osteoarthritis is an incurable disease of progressing age: “Osteoarthritis gradually worsens with time, and no cure exists. But osteoarthritis treatments can relieve pain and help you remain active. Taking steps to actively manage your osteoarthritis may help you gain control over your symptoms(ref).” According to this view, if the osteoarthritis situation gets bad enough your best recourse might be surgery such as total knee replacement. The classical view of osteoarthritis is evolving in that it is increasingly being seen as a disease that can arise from multiple causes in younger as well as older people and in that there is an increasingly brighter prospect for cartilage regeneration, even of seriously damaged joints, without need for drastic surgery. Osteoarthritis can arise from mutated genes, traumatic injury or an operation as well as from wear and tear. It is not uncommon for people in their 40s and 50s to have a serious osteoarthritis problem. Osteoarthritis can frequently arise in young people and even in children, such as when associated with a mutation in the type II procollagen gene (COL2A1)(ref)(ref). Osteoarthritis can create collateral damage besides loss of cartilage. In the case of the spine, for example, “Sometimes, the wear-and-tear of osteoarthritis puts pressure on the nerves leaving the spinal column. This can cause weakness and pain in the arms or legs. Osteoarthritis might also cause bone spurs to form in the spinal area. Osteoarthritis of the spine sometimes is called spinal spondylosis if the damage affects the facet joint and the disks in the spine(ref).” Osteoarthritis involves a number of degenerative processes and any effective regenerative treatment must be able to deal with these. From the 2008 review article Technology Insight: Adult Mesenchymal Stem Cells for Osteoarthritis Therapy: “Much research into the pathophysiology of OA has focused on the loss of articular cartilage, caused by mechanical and oxidative stresses, aging or apoptotic chondrocytes. Articular chondrocytes within diseased cartilage synthesize and secrete proteolytic enzymes, such as matrix metalloproteinases and aggrecanases, which degrade the cartilaginous matrix. The proinflammatory cytokine interleukin 1 (IL-1) is the most powerful inducer of these enzymes and of other mediators of OA in articular chondrocytes. The induction of these factors leads to matrix depletion through a combination of accelerated breakdown and reduced synthesis. Other proinflammatory cytokines, such as tumor necrosis factor, are also involved in cartilage breakdown and, together with biomechanical factors implicated in OA etiopathophysiology, contribute to induction of the disease.” First-generation cartilage regeneration using implanted chondrocytes The objective of cartilage regeneration in the case of a joint where the cartilage is seriously compromised by OA is to induce new cartilage to grow in the joint, modeling and organizing itself correctly in the process so as to restore the original functionality of the joint. The area of therapy is sometimes called cartilage tissue engineering. Hyaline cartilage is formed by chondrocytes, specialized cells that reside in and “produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans.” So, first-generation attempts at joint cartilage regeneration have been focused on introduction of new chondrocytes into osteoarthritis-compromised joints. The method has become known as ACT (or ACI), standing for Autologous Chondrocyte Transplantation (or implantation) and its use goes back to 1987. “In ACT, a cartilage biopsy is taken from the patient and articular chondrocytes are isolated. The cells are then expanded after several passages in vitro and used to fill the cartilage defect. Since its introduction, ACT has become a widely applied surgical method with good to excellent clinical outcomes. More recently, classical ACT has been combined with tissue engineering and implantable scaffolds for improved results. However, there are still major problems associated with the ACT technique which relate mainly to chondrocyte de-differentiation during the expansion phase in monolayer culture and the poor integration of the implants into the surrounding cartilage tissue(ref).” Results of ACT, when it could be applied, were often not bad. According to a 2000 publication reported on a number of ACT papers, regarding one study “The Swedish clinical experience with ACT now extends to more than 800 patients, including 200 patients with a minimum follow-up of 2 years. — Treatment of chondral and osteochondral lesions with ACT appears to produce new tissue similar in histologic and mechanical characteristics to hyaline cartilage, resulting in good clinical outcomes in more than 75% of patients. Results are best in lesions of the distal femur, including multiple defects. Patellar lesions require strict attention to alignment, and trochlear results are size-dependent.” Regarding another paper “The multicenter results presented in this paper appear to parallel the Swedish experience and demonstrate a durable repair out to 36 months. ACT appears to be an efficacious and safe treatment for full-thickness chondral lesions of the femoral condyles and trochlea.” However regarding a third paper “Osteochondral grafts improve symptoms, but may increase risk of osteoarthritis.” “Currently, more than 12,000 ACIs are documented. Different studies showed a permanence of clinical results that were gained in a period of about 10 years [14-16]. Despite good clinical results, some disadvantages hamper the prevalence of ACI: (a) the nonuniform spatial distribution of chondrocytes and the lack of initial mechanical stability, (b) the suture of the periosteal flap into the surrounding healthy cartilage and the necessity of a perifocal solid cartilage shoulder that limits ACI to the treatment of small defects and excludes the treatment of OA diseased cartilage, and (c) the arthrotomic surgery(ref).” The last decade showed the emergence of Arthroscopic treatment regimens for osteoarthritis of the knee, with some degree of success. “Arthroscopic treatment included joint insufflation, lysis of adhesions, anterior interval release, contouring of cartilage defects to a stable rim, shaping of meniscus tears to a stable rim, synovectomy, removal of loose bodies, and removal of osteophytes that affected terminal extension. — CONCLUSIONS: This arthroscopic treatment regimen can improve function and activity levels in patients with moderate to severe osteoarthritis. Of 69 patients, 60 (87%) patients had a satisfactory result. However, in this group of 60, 11 patients needed a second procedure, resulting in a 71% satisfactory result after 1 surgery.” There was also some degree of success reported in implanting scaffolds in osteoarthritis-damaged knees and using a modified form of ACT to regenerate knee cartilage(ref). “Tissue regeneration was found even when implants were placed in joints that had already progressed to osteoarthrosis. Cartilage injuries can be effectively repaired using tissue engineering, and osteoarthritis does not inhibit the regeneration process.” However, ACT has several limitations and often can’t be used when severe cartilage loss is due to degenerative arthritis or osteoarthritis. An excellent summary of the limits of ACT can be found in the write-up of a clinical trial of a second-generation stem cell therapy. “this treatment requires the extraction of chondrocytes directly from the patient and thus causes trauma in healthy articular cartilage. Also, this type of treatment cannot be applied to large lesions, nor is the efficacy satisfactory in patients over the age of 40 whose cellular activation levels are low. Thus, autologous chondrocyte transplant is rather limited in the number of cells harvested and their activation level and is therefore restricted in terms of treatment site, severity of the condition, and the size of lesion. The current technology allows the application of treatments in local cartilage defects but not in degenerative arthritis or rheumatoid arthritis. The technology needs to be taken up to another level in order to benefit such prevalent arthritic disorders. Treatments using stem cells do not cause damage to healthy articular cartilage as they don’t require the harvesting of healthy cartilage tissues from the patients. Moreover, the number of successfully cultured cells is larger due to the excellent proliferation capability of stem cells and thus, mass supply is possible(ref).” Second -generation cartilage regeneration using mesenchymal stem cells Problems and limitations of ACT (chondrocyte implantation) have led to interest in a better alternative as outlined in the March 2009 publication Mesenchymal stem cells in connective tissue engineering and regenerative medicine: applications in cartilage repair and osteoarthritis therapy. Animal experiments have demonstrated that under appropriate signaling conditions, mesenchymal stem cells (MSCs) differentiate into chondrocytes and can produce hyaline cartilage replacing that lost in injured sites. I have discussed a number of attractive properties of mesenchymal stem cells in the post Important new mesenchymal stem cell therapies. These properties are highly relevant to cartilage regeneration, including freedom from an immune or inflammatory response, donor independence, easy duplication in-vitro, homing capability and, particularly, that MSCs seem to be the body’s own natural means for cartilage renewal(ref). Post Comment Private Reply Ignore Thread
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