, Volume 27, Issue 3, pp 175–180 | Cite as

Stem Cell Therapy in Osteoarthritis: A Step Too Far?

Current Opinion


Osteoarthritis (OA) is the most common joint disease and, until now, no effective medical treatment has been developed, apart from total joint replacement in end-stage disease. Since mesenchymal stem cells (MSC) can on one hand be the source of newly formed cartilage, and on the other hand inhibit inflammation with their immunomodulatory capacities, these cells are, on a theoretical basis, ideal for the treatment of OA. As a result, MSC-based treatments for OA patients are currently offered worldwide. However, the effectiveness of this treatment and the potential associated risks are not well known. To develop MSC-based treatment of OA into a generally accepted, clinically effective and safe cure, extensive studies have to be performed in controlled experimental and clinical settings. Stem cell therapy is a remedy with the potential for a great future; however, this outlook could be jeopardized if this treatment is introduced too early into clinical practice.



No sources of funding were used to prepare this manuscript. The author has no conflicts of interest that are directly relevant to the content of this article.


  1. 1.
    Buckwalter JA, Saltzman C, Brown T. The impact of osteoarthritis: implications for research. Clin Orthop Relat Res 2004;(427 Suppl.):S6–15.Google Scholar
  2. 2.
    Suri P, Morgenroth DC, Hunter DJ. Epidemiology of osteoarthritis and associated comorbidities. PM R. 2012;4(5 Suppl.):S10–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum. 2012;64(6):1697–707.PubMedCrossRefGoogle Scholar
  4. 4.
    Haugen IK, Boyesen P, Slatkowsky-Christensen B, Sesseng S, van der Heijde D, Kvien TK. Associations between MRI-defined synovitis, bone marrow lesions and structural features and measures of pain and physical function in hand osteoarthritis. Ann Rheum Dis. 2012;71(6):899–904.PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang Y, Nevitt M, Niu J, Lewis C, Torner J, Guermazi A, et al. Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging. Arthritis Rheum. 2011;63(3):691–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Hunter W. Of the structure and disease of articulating cartilages, 1743. Clin Orthop Relat Res. 1995;317:3–6.PubMedGoogle Scholar
  7. 7.
    Dell’Accio F, Vincent TL. Joint surface defects: clinical course and cellular response in spontaneous and experimental lesions. Eur Cell Mater. 2010;20:210–7.PubMedGoogle Scholar
  8. 8.
    Bedi A, Feeley BT, Williams RJ III. Management of articular cartilage defects of the knee. J Bone Joint Surg Am. 2010;92(4):994–1009.PubMedCrossRefGoogle Scholar
  9. 9.
    Meissner A, Wernig M, Jaenisch R. Direct reprogramming of genetically unmodified fibroblasts into pluripotent stem cells. Nat Biotechnol. 2007;25(10):1177–81.PubMedCrossRefGoogle Scholar
  10. 10.
    Qi H, Pei D. The magic of four: induction of pluripotent stem cells from somatic cells by Oct4, Sox2, Myc and Klf4. Cell Res. 2007;17(7):578–80.PubMedCrossRefGoogle Scholar
  11. 11.
    Ladenstein R, Peters C, Gadner H. The present role of bone marrow and stem cell transplantation in the therapy of children with acute leukemia. Ann N Y Acad Sci. 1997;824:38–64.PubMedCrossRefGoogle Scholar
  12. 12.
    Spencer ND, Gimble JM, Lopez MJ. Mesenchymal stromal cells: past, present, and future. Vet Surg. 2011;40(2):129–39.PubMedCrossRefGoogle Scholar
  13. 13.
    Friedenstein AJ. Precursor cells of mechanocytes. Int Rev Cytol. 1976;47:327–59.PubMedCrossRefGoogle Scholar
  14. 14.
    Roobrouck VD, Clavel C, Jacobs SA, Ulloa-Montoya F, Crippa S, Sohni A, et al. Differentiation potential of human postnatal mesenchymal stem cells, mesoangioblasts, and multipotent adult progenitor cells reflected in their transcriptome and partially influenced by the culture conditions. Stem Cells. 2011;29(5):871–82.PubMedCrossRefGoogle Scholar
  15. 15.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.PubMedCrossRefGoogle Scholar
  16. 16.
    Mohal JS, Tailor HD, Khan WS. Sources of adult mesenchymal stem cells and their applicability for musculoskeletal applications. Curr Stem Cell Res Ther. 2012;7(2):103–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Giordano A, Galderisi U, Marino IR. From the laboratory bench to the patient’s bedside: an update on clinical trials with mesenchymal stem cells. J Cell Physiol. 2007;211(1):27–35.PubMedCrossRefGoogle Scholar
  18. 18.
    Tadokoro M, Kanai R, Taketani T, Uchio Y, Yamaguchi S, Ohgushi H. New bone formation by allogeneic mesenchymal stem cell transplantation in a patient with perinatal hypophosphatasia. J Pediatr. 2009;154(6):924–30.PubMedCrossRefGoogle Scholar
  19. 19.
    Jones E, Yang X. Mesenchymal stem cells and bone regeneration: current status. Injury. 2011;42(6):562–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Koga H, Engebretsen L, Brinchmann JE, Muneta T, Sekiya I. Mesenchymal stem cell-based therapy for cartilage repair: a review. Knee Surg Sports Traumatol Arthrosc. 2009;17(11):1289–97.PubMedCrossRefGoogle Scholar
  21. 21.
    Noth U, Steinert AF, Tuan RS. Technology insight: adult mesenchymal stem cells for osteoarthritis therapy. Nat Clin Pract Rheumatol. 2008;4(7):371–80.PubMedGoogle Scholar
  22. 22.
    Wakitani S, Kimura T, Hirooka A, Ochi T, Yoneda M, Yasui N, et al. Repair of rabbit articular surfaces with allograft chondrocytes embedded in collagen gel. J Bone Joint Surg Br. 1989;71(1):74–80.PubMedGoogle Scholar
  23. 23.
    Freed LE, Vunjak-Novakovic G, Langer R. Cultivation of cell-polymer cartilage implants in bioreactors. J Cell Biochem. 1993;51(3):257–64.PubMedCrossRefGoogle Scholar
  24. 24.
    Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 2003;48(12):3464–74.PubMedCrossRefGoogle Scholar
  25. 25.
    Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis: preliminary report of four patients. Int J Rheum Dis. 2011;14(2):211–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Varma HS, Dadarya B, Vidyarthi A. The new avenues in the management of osteo-arthritis of knee: stem cells. J Indian Med Assoc. 2010;108(9):583–5.PubMedGoogle Scholar
  27. 27.
    Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Med Hypotheses. 2008;71(6):900–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008;11(3):343–53.PubMedGoogle Scholar
  29. 29.
    Haynesworth SE, Baber MA, Caplan AI. Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol. 1996;166(3):585–92.PubMedCrossRefGoogle Scholar
  30. 30.
    Wu L, Leijten JC, Georgi N, Post JN, van Blitterswijk CA, Karperien M. Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. Tissue Eng Part A. 2011;17(9–10):1425–36.PubMedCrossRefGoogle Scholar
  31. 31.
    Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105(4):1815–22.PubMedCrossRefGoogle Scholar
  32. 32.
    El-Badri NS, Maheshwari A, Sanberg PR. Mesenchymal stem cells in autoimmune disease. Stem Cells Dev. 2004;13(5):463–72.PubMedCrossRefGoogle Scholar
  33. 33.
    Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum. 2007;56(4):1175–86.PubMedCrossRefGoogle Scholar
  34. 34.
    Djouad F, Fritz V, Apparailly F, Louis-Plence P, Bony C, Sany J, et al. Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis. Arthritis Rheum. 2005;52(5):1595–603.PubMedCrossRefGoogle Scholar
  35. 35.
    Haniffa MA, Wang XN, Holtick U, Rae M, Isaacs JD, Dickinson AM, et al. Adult human fibroblasts are potent immunoregulatory cells and functionally equivalent to mesenchymal stem cells. J Immunol. 2007;179(3):1595–604.PubMedGoogle Scholar
  36. 36.
    Black LL, Gaynor J, Adams C, Dhupa S, Sams AE, Taylor R, et al. Effect of intraarticular injection of autologous adipose-derived mesenchymal stem and regenerative cells on clinical signs of chronic osteoarthritis of the elbow joint in dogs. Vet Ther. 2008;9(3):192–200.PubMedGoogle Scholar
  37. 37.
    Black LL, Gaynor J, Gahring D, Adams C, Aron D, Harman S, et al. Effect of adipose-derived mesenchymal stem and regenerative cells on lameness in dogs with chronic osteoarthritis of the coxofemoral joints: a randomized, double-blinded, multicenter, controlled trial. Vet Ther. 2007;8(4):272–84.PubMedGoogle Scholar
  38. 38.
    Glynn SA, Busch MP, Dodd RY, Katz LM, Stramer SL, Klein HG, et al. Emerging infectious agents and the nation’s blood supply: responding to potential threats in the 21st century. Transfusion. 2013;53(2):438–54.PubMedCrossRefGoogle Scholar
  39. 39.
    Li XY, Ding J, Zheng ZH, Li XY, Wu ZB, Zhu P. Long-term culture in vitro impairs the immunosuppressive activity of mesenchymal stem cells on T cells. Mol Med Report. 2012;6(5):1183–9.Google Scholar
  40. 40.
    Stolzing A, Coleman N, Scutt A. Glucose-induced replicative senescence in mesenchymal stem cells. Rejuvenation Res. 2006;9(1):31–5.PubMedCrossRefGoogle Scholar
  41. 41.
    Blaha M, Mericka P, Stepanova V, Splino M, Maly J, Jebavy L, et al. Prevention of infection transmission during stem cell transplantation. Folia Microbiol (Praha). 2006;51(6):609–13.CrossRefGoogle Scholar
  42. 42.
    Ho AD, Wagner W, Franke W. Heterogeneity of mesenchymal stromal cell preparations. Cytotherapy. 2008;10(4):320–30.PubMedCrossRefGoogle Scholar
  43. 43.
    Sensebe L, Bourin P, Tarte K. Good manufacturing practices production of mesenchymal stem/stromal cells. Hum Gene Ther. 2011;22(1):19–26.PubMedCrossRefGoogle Scholar
  44. 44.
    Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. J Inflamm (Lond). 2005;26(2):8.CrossRefGoogle Scholar
  45. 45.
    Rossignol J, Boyer C, Thinard R, Remy S, Dugast AS, Dubayle D, et al. Mesenchymal stem cells induce a weak immune response in the rat striatum after allo or xenotransplantation. J Cell Mol Med 2009;13(8B):2547–58.Google Scholar
  46. 46.
    Mishima Y, Lotz M. Chemotaxis of human articular chondrocytes and mesenchymal stem cells. J Orthop Res. 2008;26(10):1407–12.PubMedCrossRefGoogle Scholar
  47. 47.
    Baragi VM, Renkiewicz RR, Qiu L, Brammer D, Riley JM, Sigler RE, et al. Transplantation of adenovirally transduced allogeneic chondrocytes into articular cartilage defects in vivo. Osteoarthr Cartil. 1997;5(4):275–82.PubMedCrossRefGoogle Scholar
  48. 48.
    Kang R, Marui T, Ghivizzani SC, Nita IM, Georgescu HI, Suh JK, et al. Ex vivo gene transfer to chondrocytes in full-thickness articular cartilage defects: a feasibility study. Osteoarthr Cartil. 1997;5(2):139–43.PubMedCrossRefGoogle Scholar
  49. 49.
    Wood JA, Chung DJ, Park SA, Zwingenberger AL, Reilly CM, Ly I, et al. Periocular and intra-articular injection of canine adipose-derived mesenchymal stem cells: an in vivo imaging and migration study. J Ocul Pharmacol Ther. 2012;28(3):307–17.PubMedCrossRefGoogle Scholar
  50. 50.
    Perrot P, Heymann D, Charrier C, Couillaud S, Redini F, Duteille F. Extraosseous bone formation obtained by association of mesenchymal stem cells with a periosteal flap in the rat. Ann Plast Surg. 2007;59(2):201–6.PubMedCrossRefGoogle Scholar
  51. 51.
    Pelttari K, Winter A, Steck E, Goetzke K, Hennig T, Ochs BG, et al. Premature induction of hypertrophy during in vitro chondrogenesis of human mesenchymal stem cells correlates with calcification and vascular invasion after ectopic transplantation in SCID mice. Arthritis Rheum. 2006;54(10):3254–66.PubMedCrossRefGoogle Scholar
  52. 52.
    Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, Nygren JM, et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood. 2007;110(4):1362–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Hellingman CA, Davidson EN, Koevoet W, Vitters EL, van den Berg WB, van Osch GJ, et al. Smad signaling determines chondrogenic differentiation of bone-marrow-derived mesenchymal stem cells: inhibition of Smad1/5/8P prevents terminal differentiation and calcification. Tissue Eng Part A. 2011;17(7–8):1157–67.PubMedCrossRefGoogle Scholar
  54. 54.
    Kafienah W, Jakob M, Demarteau O, Frazer A, Barker MD, Martin I, et al. Three-dimensional tissue engineering of hyaline cartilage: comparison of adult nasal and articular chondrocytes. Tissue Eng. 2002;8(5):817–26.PubMedCrossRefGoogle Scholar
  55. 55.
    Wang D, Wang S, Shi C. Update on cancer related issues of mesenchymal stem cell-based therapies. Curr Stem Cell Res Ther. 2012;7(5):370–80.PubMedCrossRefGoogle Scholar
  56. 56.
    Tasso R, Augello A, Carida’ M, Postiglione F, Tibiletti MG, Bernasconi B, et al. Development of sarcomas in mice implanted with mesenchymal stem cells seeded onto bioscaffolds. Carcinogenesis. 2009;30(1):150–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Akay I, Oxmann D, Helfenstein A, Mentlein R, Schunke M, Hassenpflug J, et al. Tumor risk by tissue engineering: cartilaginous differentiation of mesenchymal stem cells reduces tumor growth. Osteoarthr Cartil. 2010;18(3):389–96.PubMedCrossRefGoogle Scholar
  58. 58.
    Donnenberg VS, Zimmerlin L, Rubin JP, Donnenberg AD. Regenerative therapy after cancer: what are the risks? Tissue Eng Part B Rev. 2010;16(6):567–75.Google Scholar
  59. 59.
    Pinilla S, Alt E, Abdul Khalek FJ, Jotzu C, Muehlberg F, Beckmann C, et al. Tissue resident stem cells produce CCL5 under the influence of cancer cells and thereby promote breast cancer cell invasion. Cancer Lett. 2009;284(1):80–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Kucerova L, Matuskova M, Hlubinova K, Altanerova V, Altaner C. Tumor cell behaviour modulation by mesenchymal stromal cells. Mol Cancer. 2010;9:129.PubMedCrossRefGoogle Scholar
  61. 61.
    Jeong JO, Han JW, Kim JM, Cho HJ, Park C, Lee N, et al. Malignant tumor formation after transplantation of short-term cultured bone marrow mesenchymal stem cells in experimental myocardial infarction and diabetic neuropathy. Circ Res. 2011;108(11):1340–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Rubio D, Garcia-Castro J, Martin MC, de la Fuente R, Cigudosa JC, Lloyd AC, et al. Spontaneous human adult stem cell transformation. Cancer Res. 2005;65(8):3035–9.PubMedGoogle Scholar
  63. 63.
    Prockop DJ, Brenner M, Fibbe WE, Horwitz E, Le Blanc K, Phinney DG, et al. Defining the risks of mesenchymal stromal cell therapy. Cytotherapy. 2010;12(5):576–8.PubMedCrossRefGoogle Scholar
  64. 64.
    Ben-David U, Mayshar Y, Benvenisty N. Large-scale analysis reveals acquisition of lineage-specific chromosomal aberrations in human adult stem cells. Cell Stem Cell. 2011;9(2):97–102.PubMedCrossRefGoogle Scholar
  65. 65.
    Wong RS. Mesenchymal stem cells: angels or demons? J Biomed Biotechnol 2011;2011:459510. doi: 10.1155/2011/459510.

Copyright information

© Springer International Publishing Switzerland 2013

Authors and Affiliations

  1. 1.Department of RheumatologyRadboud University, Medical CentreNijmegenThe Netherlands

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