Science China Life Sciences

, Volume 57, Issue 6, pp 586–595

Treatment of osteoarthritis with mesenchymal stem cells

Open Access
Review Special Topic: Stem Cells and Regenerative Medicine


Osteoarthritis (OA) is one of the most prevalent joint diseases with prominent symptoms affecting the daily life of millions of middle aged and elderly people. Despite this, there are no successful medical interventions that can prevent the progressive destruction of OA joints. The onset of pathological changes in OA is associated with deviant activity of mesenchymal stem cells (MSCs), the multipotent precursors of connective tissue cells that reside in joints. Current therapies for OA have resulted in poor clinical outcomes without repairing the damaged cartilage. Intra-articular delivery of culture-expanded MSCs has opened new avenues of OA treatment. Pre-clinical and clinical trials demonstrated the feasibility, safety, and efficacy of MSC therapy. The Wnt/β-catenin, bone morphogenetic protein 2, Indian hedgehog, and Mitogen-activated protein kinase signaling pathways have been demonstrated to be involved in OA and the mechanism of action of MSC therapies.


osteoarthritis mesenchymal stem cells intra-articular delivery 


  1. 1.
    Centers for Disease Control and Prevention. Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation-United States, 2010–2012. MMWR Morb Mortal Wkly Rep, 2013, 62: 869–873Google Scholar
  2. 2.
    Deng LF, Yang QM. Osteoarthritis. J Chin Med, 2007, 42: 76–78Google Scholar
  3. 3.
    Ethgen O, Kahler KH, Kong SX, Reginster JY, Wolfe F. The effect of health related quality of life on reported use of health care resources in patients with osteoarthritis and rheumatoid arthritis: a longitudinal analysis. J Rheumatol, 2002, 29: 1147–1155PubMedGoogle Scholar
  4. 4.
    Blagojevic M, Jinks C, Jeffery A, Jordan KP. Risk factors for onset of osteoarthritis of the knee in older adults: a systematic review and meta-analysis. Osteoarthr Cartilage, 2010, 18: 24–33Google Scholar
  5. 5.
    Loeser RF, Goldring SR, Scanzello CR, Goldring MB. Osteoarthritis: a disease of the joint as an organ. Arthritis Rheum, 2012, 64: 1697–1707PubMedPubMedCentralGoogle Scholar
  6. 6.
    Hawker G, Mendel A, Lam MA, Akhavan PS, Cancino-Romero J, Waugh E, Jamal S, Mian S, Jaglal S. A clinical decision rule to enhance targeted bone mineral density testing in healthy mid-life women. Osteoporos Int, 2012, 23: 1931–1938PubMedGoogle Scholar
  7. 7.
    Brown GA. AAOS clinical practice guideline: treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. J Am Acad Orthop Surg, 2013, 21: 577–579PubMedGoogle Scholar
  8. 8.
    Katz JN, Losina E. Surgery versus physical therapy for meniscal tear and osteoarthritis. N Engl J Med, 2013, 369: 677–678PubMedGoogle Scholar
  9. 9.
    Kirkley A, Birmingham TB, Litchfield RB, Giffin JR, Willits KR, Wong CJ, Feagan BG, Donner A, Griffin SH, D’Ascanio LM, Pope JE, Fowler PJ. A randomized trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med, 2008, 359: 1097–1107PubMedGoogle Scholar
  10. 10.
    Sihvonen R, Paavola M, Malmivaara A, Itälä A, Joukainen A, Nurmi H, Kalske J, Järvinen T L, Finnish Degenerative Meniscal Lesion Study (FIDELITY) Group. Arthroscopic partial meniscectomy versus sham surgery for a degenerative meniscal tear. N Engl J Med, 2013, 369: 2515–2524PubMedGoogle Scholar
  11. 11.
    Moseley JB, O’Malley K, Petersen NJ, Menke TJ, Brody BA, Kuykendall DH, Hollingsworth JC, Ashton CM, Wray NP. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med, 2002, 347: 81–88PubMedGoogle Scholar
  12. 12.
    Rutjes AW, Juni P, da Costa BR, Trelle S, Nüesch E, Reichenbach S. Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med, 2012, 157: 180–191PubMedGoogle Scholar
  13. 13.
    Sawitzke AD, Shi H, Finco MF, Harris CL, Singer NG, Bradley JD, Silver D, Jackson CG, Lane NE, Oddis CV, Wolfe F, Lisse J, Furst DE, Bingham CO, Reda DJ, Moskowitz RW, Williams HJ, Clegg DO. Clinical efficacy and safety of glucosamine, chondroitin sulphate, their combination, celecoxib or placebo taken to treat osteoarthritis of the knee: 2-year results from gait. Ann Rheum Dis, 2010, 69: 1459–1464PubMedPubMedCentralGoogle Scholar
  14. 14.
    Witt C, Brinkhaus B, Jena S, Linde K, Streng A, Wagenpfeil S, Hummelsberger J, Walther HU, Melchart D, Willich SN. Acupuncture in patients with osteoarthritis of the knee: a randomised trial. Lancet, 2005, 366: 136–143PubMedGoogle Scholar
  15. 15.
    Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med, 1994, 331: 889–895PubMedGoogle Scholar
  16. 16.
    Brittberg M, Faxen E, Peterson L. Carbon fiber scaffolds in the treatment of early knee osteoarthritis. A prospective 4-year followup of 37 patients. Clin Orthop Relat Res, 1994, 155–164Google Scholar
  17. 17.
    Knutsen G, Engebretsen L, Ludvigsen TC, Drogset JO, Grøntvedt T, Solheim E, Strand T, Roberts S, Isaksen V, Johansen O. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial. J Bone Joint Surg Am, 2004, 86-A: 455–464PubMedGoogle Scholar
  18. 18.
    Saris DB, Vanlauwe J, Victor J, Haspl M, Bohnsack M, Fortems Y, Vandekerckhove B, Almqvist KF, Claes T, Handelberg F, Lagae K, van der Bauwhede J, Vandenneucker H, Yang KG, Jelic M, Verdonk R, Veulemans N, Bellemans J, Luyten FP. Characterized chondrocyte implantation results in better structural repair when treating symptomatic cartilage defects of the knee in a randomized controlled trial versus microfracture. Am J Sports Med, 2008, 36: 235–246PubMedGoogle Scholar
  19. 19.
    Saris DB, Vanlauwe J, Victor J, Almqvist KF, Verdonk R, Bellemans J, Luyten FP, TIG/ACT/01/2000&EXT Study Group. Treatment of symptomatic cartilage defects of the knee: characterized chondrocyte implantation results in better clinical outcome at 36 months in a randomized trial compared to microfracture. Am J Sports Med, 2009, 37(Suppl 1): 10S–19SPubMedGoogle Scholar
  20. 20.
    Vanlauwe J, Saris DB, Victor J, Almqvist KF, Bellemans J, Luyten FP, TIG/ACT/01/2000&EXT Study Group. Five-year outcome of characterized chondrocyte implantation versus microfracture for symptomatic cartilage defects of the knee: early treatment matters. Am J Sports Med, 2011, 39: 2566–2574PubMedGoogle Scholar
  21. 21.
    von der Mark K, Gauss V, von der Mark H, Müller P. Relationship between cell shape and type of collagen synthesised as chondrocytes lose their cartilage phenotype in culture. Nature, 1977, 267: 531–532PubMedGoogle Scholar
  22. 22.
    Knutsen G, Drogset JO, Engebretsen L, Grøntvedt T, Isaksen V, Ludvigsen TC, Roberts S, Solheim E, Strand T, Johansen O. A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am, 2007, 89: 2105–2112PubMedGoogle Scholar
  23. 23.
    Barbero A, Grogan S, Schäfer D, Heberer M, Mainil-Varlet P, Martin I. Age related changes in human articular chondrocyte yield, proliferation and post-expansion chondrogenic capacity. Osteoarthr Cartilage, 2004, 12: 476–484Google Scholar
  24. 24.
    Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum, 2003, 48: 3464–3474PubMedGoogle Scholar
  25. 25.
    Vangsness CT Jr., Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am, 2014, 96: 90–98PubMedGoogle Scholar
  26. 26.
    Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, Kim JE, Shim H, Shin JS, Shin IS, Ra JC, Oh S, Yoon KS. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells, 2014, 32: 1254–1266PubMedGoogle Scholar
  27. 27.
    Friedenstein AJ, Piatetzky S II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol, 1966, 16: 381–390PubMedGoogle Scholar
  28. 28.
    Friedenstein AJ, Chailakhjan RK, Lalykina KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet, 1970, 3: 393–403PubMedGoogle Scholar
  29. 29.
    Caplan AI. Mesenchymal stem cells. J Orthop Res, 1991, 9: 641–650PubMedGoogle Scholar
  30. 30.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop Dj, Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement. Cytotherapy, 2006, 8: 315–317PubMedGoogle Scholar
  31. 31.
    Jones EA, Kinsey SE, English A, Jones RA, Straszynski L, Meredith DM, Markham AF, Jack A, Emery P, McGonagle D. Isolation and characterization of bone marrow multipotential mesenchymal progenitor cells. Arthritis Rheum, 2002, 46: 3349–3360PubMedGoogle Scholar
  32. 32.
    Tormin A, Li O, Brune JC, Walsh S, Schütz B, Ehinger M, Ditzel N, Kassem M, Scheding S. Cd146 expression on primary nonhematopoietic bone marrow stem cells is correlated with in situ localization. Blood, 2011, 117: 5067–5077PubMedPubMedCentralGoogle Scholar
  33. 33.
    Maijenburg MW, Kleijer M, Vermeul K, Mul EP, van Alphen FP, van der Schoot CE, Voermans C. The composition of the mesenchymal stromal cell compartment in human bone marrow changes during development and aging. Haematologica, 2012, 97: 179–183PubMedPubMedCentralGoogle Scholar
  34. 34.
    Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (dpscs) in vitro and in vivo. Proc Natl Acad Sci USA, 2000, 97: 13625–13630PubMedPubMedCentralGoogle Scholar
  35. 35.
    Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol, 2000, 109: 235–242PubMedGoogle Scholar
  36. 36.
    De Bari C, Dell’Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum, 2001, 44: 1928–1942PubMedGoogle Scholar
  37. 37.
    Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH. Multilineage cells from human adipose tissue: Implications for cell-based therapies. Tissue Eng, 2001, 7: 211–228PubMedGoogle Scholar
  38. 38.
    In’t Anker PS, Scherjon SA, Kleijburg-van der Keur C, de Groot-Swings GM, Claas FH, Fibbe WE, Kanhai HH. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells, 2004, 22: 1338–1345Google Scholar
  39. 39.
    Shih DT, Lee DC, Chen SC, Tsai RY, Huang CT, Tsai CC, Shen EY, Chiu WT. Isolation and characterization of neurogenic mesenchymal stem cells in human scalp tissue. Stem Cells, 2005, 23: 1012–1020PubMedGoogle Scholar
  40. 40.
    Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE. Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem cells, 2005, 23: 220–229PubMedGoogle Scholar
  41. 41.
    Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Péault B. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Tell, 2008, 3: 301–313Google Scholar
  42. 42.
    Troyer DL, Weiss ML. Concise review: Wharton’s jelly-derived cells are a primitive stromal cell population. Stem Cells, 2008, 26: 591–599PubMedPubMedCentralGoogle Scholar
  43. 43.
    Segawa Y, Muneta T, Makino H, Nimura A, Mochizuki T, Ju YJ, Ezura Y, Umezawa A, Sekiya I. Mesenchymal stem cells derived from synovium, meniscus, anterior cruciate ligament, and articular chondrocytes share similar gene expression profiles. J Orthop Res, 2009, 27: 435–441PubMedGoogle Scholar
  44. 44.
    Patki S, Kadam S, Chandra V, Bhonde R. Human breast milk is a rich source of multipotent mesenchymal stem cells. Human cell, 2010, 23: 35–40PubMedGoogle Scholar
  45. 45.
    Williams R, Khan IM, Richardson K, Nelson L, McCarthy HE, Analbelsi T, Singhrao SK, Dowthwaite GP, Jones RE, Baird DM, Lewis H, Roberts S, Shaw HM, Dudhia J, Fairclough J, Briggs T, Archer CW. Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PLoS ONE, 2010, 5: e13246PubMedPubMedCentralGoogle Scholar
  46. 46.
    Steinert AF, Kunz M, Prager P, Barthel T, Jakob F, Nöth U, Murray MM, Evans CH, Porter RM. Mesenchymal stem cell characteristics of human anterior cruciate ligament outgrowth cells. Tissue Eng Part A, 2011, 17: 1375–1388PubMedPubMedCentralGoogle Scholar
  47. 47.
    Khan WS, Adesida AB, Tew SR, Longo UG, Hardingham TE. Fat pad-derived mesenchymal stem cells as a potential source for cell-based adipose tissue repair strategies. Cell Prolif, 2012, 45: 111–120PubMedGoogle Scholar
  48. 48.
    Frohlich J, Vost A, Hollenberg CH. Organ culture of rat white adipose tissue. Biochim Biophys Acta, 1972, 280: 579–587PubMedGoogle Scholar
  49. 49.
    Zuk PA. Stem cell research has only just begun. Science, 2001, 293: 211–212PubMedGoogle Scholar
  50. 50.
    Lindroos B, Suuronen R, Miettinen S. The potential of adipose stem cells in regenerative medicine. Stem Cell Rev, 2011, 7: 269–291PubMedGoogle Scholar
  51. 51.
    Mirsaidi A, Kleinhans KN, Rimann M, Tiaden AN, Stauber M, Rudolph KL, Richards PJ. Telomere length, telomerase activity and osteogenic differentiation are maintained in adipose-derived stromal cells from senile osteoporotic samp6 mice. J Tissue Eng Regen Med, 2012, 6: 378–390PubMedGoogle Scholar
  52. 52.
    Takemitsu H, Zhao D, Yamamoto I, Harada Y, Michishita M, Arai T. Comparison of bone marrow and adipose tissue-derived canine mesenchymal stem cells. BMC Vet Res, 2012, 8: 150PubMedPubMedCentralGoogle Scholar
  53. 53.
    Zannettino AC, Paton S, Arthur A, Khor F, Itescu S, Gimble JM, Gronthos S. Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. J Cell Physiol, 2008, 214: 413–421PubMedGoogle Scholar
  54. 54.
    Strem BM, Hicok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE, Fraser JK, Hedrick MH. Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med, 2005, 54: 132–141PubMedGoogle Scholar
  55. 55.
    Walsh S, Jefferiss C, Stewart K, Jordan GR, Screen J, Beresford JN. Expression of the developmental markers STRO-1 and alkaline phosphatase in cultures of human marrow stromal cells: regulation by fibroblast growth factor (FGF)-2 and relationship to the expression of FGF receptors 1–4. Bone, 2000, 27: 185–195PubMedGoogle Scholar
  56. 56.
    Kim HJ, Im GI. Chondrogenic differentiation of adipose tissue-derived mesenchymal stem cells: greater doses of growth factor are necessary. J Orthop Res, 2009, 27: 612–619PubMedGoogle Scholar
  57. 57.
    Lindroos B, Boucher S, Chase L, Kuokkanen H, Huhtala H, Haataja R, Vemuri M, Suuronen R, Miettinen S. Serum-free, xeno-free culture media maintain the proliferation rate and multipotentiality of adipose stem cells in vitro. Cytotherapy, 2009, 11: 958–972PubMedGoogle Scholar
  58. 58.
    Chevallier N, Anagnostou F, Zilber S, Bodivit G, Maurin S, Barrault A, Bierling P, Hernigou P, Layrolle P, Rouard H. Osteoblastic differentiation of human mesenchymal stem cells with platelet lysate. Biomaterials, 2010, 31: 270–278PubMedGoogle Scholar
  59. 59.
    Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood, 2005, 105: 1815–1822PubMedGoogle Scholar
  60. 60.
    Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol, 2008, 8: 726–736PubMedGoogle Scholar
  61. 61.
    Aust L, Devlin B, Foster SJ, Halvorsen YD, Hicok K, du Laney T, Sen A, Willingmyre GD, Gimble JM. Yield of human adipose-derived adult stem cells from liposuction aspirates. Cytotherapy, 2004, 6: 7–14PubMedGoogle Scholar
  62. 62.
    Yanez R, Lamana ML, Garcia-Castro J, Colmenero I, Ramírez M, Bueren JA. Adipose tissue-derived mesenchymal stem cells have in vivo immunosuppressive properties applicable for the control of the graft-versus-host disease. Stem Cells, 2006, 24: 2582–2591PubMedGoogle Scholar
  63. 63.
    Gonzalez-Rey E, Anderson P, Gonzalez MA, Rico L, Büscher D, Delgado M. Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut, 2009, 58: 929–939PubMedGoogle Scholar
  64. 64.
    Saka Y, Furuhashi K, Katsuno T, Kim H, Ozaki T, Iwasaki K, Haneda M, Sato W, Tsuboi N, Ito Y, Matsuo S, Kobayashi T, Maruyama S. Adipose-derived stromal cells cultured in a low-serum medium, but not bone marrow-derived stromal cells, impede xenoantibody production. Xenotransplantation, 2011, 18: 196–208PubMedGoogle Scholar
  65. 65.
    Murphy JM, Dixon K, Beck S, Fabian D, Feldman A, Barry F. Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum, 2002, 46: 704–713PubMedGoogle Scholar
  66. 66.
    Im GI, Jung NH, Tae SK. Chondrogenic differentiation of mesenchymal stem cells isolated from patients in late adulthood: the optimal conditions of growth factors. Tissue Eng, 2006, 12: 527–536PubMedGoogle Scholar
  67. 67.
    Scharstuhl A, Schewe B, Benz K, Gaissmaier C, Bühring HJ, Stoop R. Chondrogenic potential of human adult mesenchymal stem cells is independent of age or osteoarthritis etiology. Stem Cells, 2007, 25: 3244–3251PubMedGoogle Scholar
  68. 68.
    De Bari C, Dell’Accio F, Luyten FP. Human periosteum-derived cells maintain phenotypic stability and chondrogenic potential throughout expansion regardless of donor age. Arthritis Rheum, 2001, 44: 85–95PubMedGoogle Scholar
  69. 69.
    Jones E, English A, Churchman SM, Kouroupis D, Boxall SA, Kinsey S, Giannoudis PG, Emery P, McGonagle D. Large-scale extraction and characterization of CD271+ multipotential stromal cells from trabecular bone in health and osteoarthritis: implications for bone regeneration strategies based on uncultured or minimally cultured multipotential stromal cells. Arthritis Rheum, 2010, 62: 1944–1954PubMedGoogle Scholar
  70. 70.
    Sekiya I, Ojima M, Suzuki S, Yamaga M, Horie M, Koga H, Tsuji K, Miyaguchi K, Ogishima S, Tanaka H, Muneta T. Human mesenchymal stem cells in synovial fluid increase in the knee with degenerated cartilage and osteoarthritis. J Orthop Res, 2012, 30: 943–949PubMedGoogle Scholar
  71. 71.
    Sakaguchi Y, Sekiya I, Yagishita K, Muneta T. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum, 2005, 52: 2521–2529PubMedGoogle Scholar
  72. 72.
    Lee KB, Hui JH, Song IC, Ardany L, Lee EH. Injectable mesenchymal stem cell therapy for large cartilage defects-a porcine model. Stem Cells, 2007, 25: 2964–2971PubMedGoogle Scholar
  73. 73.
    Grigolo B, Lisignoli G, Desando G, Cavallo C, Marconi E, Tschon M, Giavaresi G, Fini M, Giardino R, Facchini A. Osteoarthritis treated with mesenchymal stem cells on hyaluronan-based scaffold in rabbit. Tissue Eng Part C Methods, 2009, 15: 647–658PubMedGoogle Scholar
  74. 74.
    Horie M, Sekiya I, Muneta T, Ichinose S, Matsumoto K, Saito H, Murakami T, Kobayashi E. Intra-articular injected synovial stem cells differentiate into meniscal cells directly and promote meniscal regeneration without mobilization to distant organs in rat massive meniscal defect. Stem Cells, 2009, 27: 878–887PubMedGoogle Scholar
  75. 75.
    Sato M, Uchida K, Nakajima H, Miyazaki T, Guerrero AR, Watanabe S, Roberts S, Baba H. Direct transplantation of mesenchymal stem cells into the knee joints of hartley strain guinea pigs with spontaneous osteoarthritis. Arthritis Res Ther, 2012, 14: R31PubMedPubMedCentralGoogle Scholar
  76. 76.
    Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH. Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy, 2013, 29: 2020–2028PubMedGoogle Scholar
  77. 77.
    Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentís J, Sánchez A, García-Sancho J. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation, 2013, 95: 1535–1541PubMedGoogle Scholar
  78. 78.
    Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M. Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis-results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthr Cartilage, 2005, 13: 361–367Google Scholar
  79. 79.
    ter Huurne M, Schelbergen R, Blattes R, Blom A, de Munter W, Grevers LC, Jeanson J, Noël D, Casteilla L, Jorgensen C, van den Berg W, van Lent PL. Antiinflammatory and chondroprotective effects of intraarticular injection of adipose-derived stem cells in experimental osteoarthritis. Arthritis Rheum, 2012, 64: 3604–3613PubMedGoogle Scholar
  80. 80.
    Benito MJ, Veale DJ, FitzGerald O, van den Berg WB, Bresnihan B. Synovial tissue inflammation in early and late osteoarthritis. Ann Rheum Dis, 2005, 64: 1263–1267PubMedPubMedCentralGoogle Scholar
  81. 81.
    Loeser RF. The effects of aging on the development of osteoarthritis. HSS J, 2012, 8: 18–19PubMedPubMedCentralGoogle Scholar
  82. 82.
    Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther, 2009, 11: 224PubMedPubMedCentralGoogle Scholar
  83. 83.
    Troeberg L, Nagase H. Proteases involved in cartilage matrix degradation in osteoarthritis. Biochim Biophys Acta, 2012, 1824: 133–145PubMedPubMedCentralGoogle Scholar
  84. 84.
    Glasson SS, Askew R, Sheppard B, Carito B, Blanchet T, Ma HL, Flannery CR, Peluso D, Kanki K, Yang Z, Majumdar MK, Morris EA. Deletion of active ADAMTS5 prevents cartilage degradation in a murine model of osteoarthritis. Nature, 2005, 434: 644–648PubMedGoogle Scholar
  85. 85.
    Little CB, Barai A, Burkhardt D, Smith SM, Fosang AJ, Werb Z, Shah M, Thompson EW. Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum, 2009, 60: 3723–3733PubMedPubMedCentralGoogle Scholar
  86. 86.
    Lories RJ, Peeters J, Bakker A, Tylzanowski P, Derese I, Schrooten J, Thomas JT, Luyten FP. Articular cartilage and biomechanical properties of the long bones in frzb-knockout mice. Arthritis Rheum, 2007, 56: 4095–4103PubMedGoogle Scholar
  87. 87.
    Oh H, Chun CH, Chun JS. Dkk-1 expression in chondrocytes inhibits experimental osteoarthritic cartilage destruction in mice. Arthritis Rheum, 2012, 64: 2568–2578PubMedGoogle Scholar
  88. 88.
    Ma B, van Blitterswijk CA, Karperien M. A Wnt/beta-catenin negative feedback loop inhibits interleukin-1-induced matrix metalloproteinase expression in human articular chondrocytes. Arthritis Rheum, 2012, 64: 2589–2600PubMedGoogle Scholar
  89. 89.
    Chan BY, Fuller ES, Russell AK, Smith SM, Smith MM, Jackson MT, Cake MA, Read RA, Bateman JF, Sambrook PN, Little CB. Increased chondrocyte sclerostin may protect against cartilage degradation in osteoarthritis. Osteoarthr Cartilage, 2011, 19: 874–885Google Scholar
  90. 90.
    Papathanasiou I, Malizos KN, Tsezou A. Bone morphogenetic protein-2-induced Wnt/beta-catenin signaling pathway activation through enhanced low-density-lipoprotein receptor-related protein 5 catabolic activity contributes to hypertrophy in osteoarthritic chondrocytes. Arthritis Res Ther, 2012, 14: R82PubMedPubMedCentralGoogle Scholar
  91. 91.
    Prasadam I, Friis T, Shi W, van Gennip S, Crawford R, Xiao Y. Osteoarthritic cartilage chondrocytes alter subchondral bone osteoblast differentiation via MAPK signalling pathway involving ERK1/2. Bone, 2010, 46: 226–235PubMedGoogle Scholar
  92. 92.
    Prasadam I, van Gennip S, Friis T, Shi W, Crawford R, Xiao Y. ERK-1/2 and p38 in the regulation of hypertrophic changes of normal articular cartilage chondrocytes induced by osteoarthritic subchondral osteoblasts. Arthritis Rheum, 2010, 62: 1349–1360PubMedGoogle Scholar
  93. 93.
    Horie M, Choi H, Lee RH, Reger RL, Ylostalo J, Muneta T, Sekiya I, Prockop DJ. Intra-articular injection of human mesenchymal stem cells (MSCs) promote rat meniscal regeneration by being activated to express indian hedgehog that enhances expression of type II collagen. Osteoarthr Cartilage, 2012, 20: 1197–1207Google Scholar
  94. 94.
    Hiraoka K, Grogan S, Olee T, Lotz M. Mesenchymal progenitor cells in adult human articular cartilage. Biorheology, 2006, 43: 447–454PubMedGoogle Scholar
  95. 95.
    Clark AL, Votta BJ, Kumar S, Liedtke W, Guilak F. Chondroprotective role of the osmotically sensitive ion channel transient receptor potential vanilloid 4: age- and sex-dependent progression of osteoarthritis in Trpv4-deficient mice. Arthritis Rheum, 2010, 62: 2973–2983PubMedPubMedCentralGoogle Scholar
  96. 96.
    O’Conor CJ, Griffin TM, Liedtke W, Guilak F. Increased susceptibility of Trpv4-deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet. Ann Rheum Dis, 2013, 72: 300–304PubMedPubMedCentralGoogle Scholar
  97. 97.
    Desando G, Cavallo C, Sartoni F, Martini L, Parrilli A, Veronesi F, Fini M, Giardino R, Facchini A, Grigolo B. Intra-articular delivery of adipose derived stromal cells attenuates osteoarthritis progression in an experimental rabbit model. Arthritis Res Ther, 2013, 15: R22PubMedPubMedCentralGoogle Scholar
  98. 98.
    Lee KB, Hui JH, Song IC, Ardany L, Lee EH. Injectable mesenchymal stem cell therapy for large cartilage defects-a porcine model. Stem Cells, 2007, 25: 2964–2971PubMedGoogle Scholar
  99. 99.
    Koga H, Shimaya M, Muneta T, Nimura A, Morito T, Hayashi M, Suzuki S, Ju YJ, Mochizuki T, Sekiya I. Local adherent technique for transplanting mesenchymal stem cells as a potential treatment of cartilage defect. Arthritis Res Ther, 2008, 10: R84PubMedPubMedCentralGoogle Scholar
  100. 100.
    Guo X, Park H, Young S, Kretlow JD, van den Beucken JJ, Baggett LS, Tabata Y, Kasper FK, Mikos AG, Jansen JA. Repair of osteochondral defects with biodegradable hydrogel composites encapsulating marrow mesenchymal stem cells in a rabbit model. Acta Biomater, 2010, 6: 39–47PubMedPubMedCentralGoogle Scholar
  101. 101.
    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: 900–908PubMedGoogle Scholar
  102. 102.
    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: 583–585PubMedGoogle Scholar
  103. 103.
    Davatchi F, Abdollahi B S, Mohyeddin M, Shahram F, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis, 2011, 14: 211–215PubMedGoogle Scholar
  104. 104.
    Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. The Knee, 2012, 19: 902–907PubMedGoogle Scholar

Copyright information

© The Author(s) 2014

Authors and Affiliations

  1. 1.Cellular Biomedicine GroupPalo AltoUSA

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