Are stem cells the answer to treating osteoarthritis (OA)?
by Nathan Wei, MD, FACP, FACR
Nathan Wei is a nationally known board-certified rheumatologist and author of the Second Opinion Arthritis Treatment Kit. It's available exclusively at this website... not available in stores.
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This editorial was written for the 2007 National Knowledge Week on Osteoarthritis. The following member of the Expert Panel contributed to this section: Dr Wael Kefienah
In recent years, a range of methods has been developed for the repair of articular cartilage lesions (1).
These include osteochondral transplantation, microfracture and autologous chondrocyte implantation (ACI) with or without the assistance of a scaffold matrix to deliver the cells. A feature of all of these techniques is that their use is limited to the repair of focal lesions and patients with OA are mostly excluded from treatment. OA cartilage lesions are generally large and unconfined and so do not provide an appropriate environment for chondrocytes to be retained long enough to elaborate an extracellular matrix. Therefore successful repair of OA cartilage lesions is only likely to be achieved when three-dimensional cartilage implants can be generated that have enough extracellular matrix for fixation within the joint.
Effective cartilage engineering protocols have already been developed in which chondrocytes, usually from young animals, are seeded onto biodegradable scaffolds and cultured in a bioreactor (2). Generating three-dimensional cartilage using adult human chondrocytes is far more challenging and in the case of older OA patients is probably impossible in the clinical setting, because of the lack of autologous donor tissue and the senescence of OA chondrocytes.
This has led a number of groups to explore the use of mesenchymal stem cells for the generation of autologous chondrocytes (3). These are mulitpotent cells with self-renewing capacity. Many studies have utilised adherent bone marrow mesenchymal stem cells (BMSCs) cultured as small micromass pellets and stimulated with Transforming Growth Factor Beta (TGF-ß) to drive chondrogenesis (4). However micromass pellets were designed for use as an experimental model and the amount of extracellular matrix they produce is too small to be of practical value for implantation. Furthermore, there is clear evidence that BMSCs stimulated with TGF-ß express type X collagen, an early marker of hypertrophy that is normally absent from hyaline cartilage (5).
We have demonstrated recently the feasibility of tissue engineering 3D hyaline cartilage from OA BMSCs (6). Biochemically, the cartilage quality was comparable to that achieved using the best available cell source, namely bovine nasal chondrocytes (7). Furthermore, we have shown that the tendency of BMSCs to become hypertrophic can be down regulated using Parathyroid Hormone receptor Protein (PTHrP), a cytokine responsible for controlling the terminal differentiation of chondrocytes in the growth plate. This raises the possibility that BMSCs from these patients will also respond to pharmacological signals (8).
Autologous stem cells provide an attractive option for osteoarthritis patients and their clinicians. However it must also be recognized that autologous therapies are expensive, requiring growth of cells and tissue over several weeks in specialized ultraclean-rooms. Currently, the government regulations allow cartilage cells to be grown in vitro but do not allow the addition of growth factors, cytokines or chemokines without first being approved through clinical trials. Indeed, established strategies for regulating the differentiation of stem cells include all the aforementioned conditions. With each of these conditions there are limited opportunities for improving the efficacy of stem cell therapy. It will be important therefore, to develop tissue engineering protocols so that they can be undertaken in the shortest possible time in order to reduce costs. We also need to develop methods of attaching the cartilage implants to the subchondral bone and of promoting integration of the implant with surrounding tissue.
Key questions to address:
• What are the clinical options for osteoarthritic cartilage repair?
• What are the limitations of current cartilage repair techniques?
• What is the best cell source for resurfacing eroded osteoarthritic cartilage?
• Are 3D cartilage implants the way forward for treating osteoarthritic lesions?
• What are the technical and clinical challenges facing the use of stem cells to create cartilage implants for OA patients?
1. Hunziker EB. Articular cartilage repair: basic science and clinical progress. A review of the current status and prospects. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2002;10:432-463.
2. Freed LE, Hollander AP, Martin I, et al. Chondrogenesis in a cell-polymer-bioreactor system. Experimental cell research. 1998;240:58-65.
3. Raghunath J, Salacinski HJ, Sales KM, et al. Advancing cartilage tissue engineering: the application of stem cell technology. Current opinion in biotechnology. 2005;16:503-509.
4. Johnstone B, Hering TM, Caplan AI, et al. In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Experimental cell research. 1998;238:265-272.
5. Majumdar MK, Banks V, Peluso DP, et al. Isolation, characterization, and chondrogenic potential of human bone marrow-derived multipotential stromal cells. Journal of cellular physiology. 2000;185:98-106.
6. Kafienah W, Mistry S, Dickinson SC, et al. Three-dimensional cartilage tissue engineering using adult stem cells from osteoarthritis patients. Arthritis Rheum. 2007;56:177-187
7. Kafienah W, Jakob M, Demarteau O, et al. Three-dimensional tissue engineering of hyaline cartilage: comparison of adult nasal and articular chondrocytes. Tissue Eng. 2002;8:817-826.
8. Kafienah W, Mistry S, Perry MJ, et al. Pharmacological Regulation of Adult Stem Cells: Chondrogenesis can be Induced Using A Synthetic Inhibitor of the Retinoic Acid Receptor. Stem Cells. 2007: first published online July 5, 2007
For more information on stem cells and how they can help you if you have osteoarthritis, go to:
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