Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis

Nature Reviews Rheumatology volume 13, pages 719–730 (2017)Cite this article

Subjects

Key Points

  • Although historically considered to be very rare cells, native mesenchymal stem cells (MSCs) are actually relatively abundant in vivo

  • Joint-resident MSCs occupy several bone and joint cavity niches including synovium, adipose tissue and synovial fluid

  • Advanced osteoarthritis (OA) is associated with a numerical increase, but functional decline, in MSCs in regions of MRI-determined bone oedema, suggesting direct involvement of MSCs in OA pathology in vivo

  • The expression of CD271 (also known as low-affinity nerve growth factor receptor) on native bone marrow-resident MSCs might be important in pathological bone changes following anti-nerve growth factor therapy

  • In experimental models, there is strong evidence for the involvement of synovium-derived MSCs in cartilage repair following joint injury

  • Emerging features of joint-resident MSCs suggests the potential for their use in the development of single-stage therapy to treat large cartilage defects in patients with OA

Abstract

The role of native (not culture-expanded) joint-resident mesenchymal stem cells (MSCs) in the repair of joint damage in osteoarthritis (OA) is poorly understood. MSCs differ from bone marrow-residing haematopoietic stem cells in that they are present in multiple niches in the joint, including subchondral bone, cartilage, synovial fluid, synovium and adipose tissue. Research in experimental models suggests that the migration of MSCs adjacent to the joint cavity is crucial for chonodrogenesis during embryogenesis, and also shows that synovium-derived MSCs might be the primary drivers of cartilage repair in adulthood. In this Review, the available data is synthesized to produce a proposed model in which joint-resident MSCs with access to superficial cartilage are key cells in adult cartilage repair and represent important targets for manipulation in 'chondrogenic' OA, especially in the context of biomechanical correction of joints in early disease. Growing evidence links the expression of CD271, a nerve growth factor (NGF) receptor by native bone marrow-resident MSCs to a wider role for neurotrophins in OA pathobiology, the implications of which require exploration since anti-NGF therapy might worsen OA. Recognizing that joint-resident MSCs are comparatively abundant in vivo and occupy multiple niches will enable the optimization of single-stage therapeutic interventions for OA.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Stem cells in the joint.
Figure 2: Appositional growth versus interstitial growth.
Figure 3: Progenitor cells in joint development and cartilage repair.
Figure 4: Tissue repair mechanisms differ depending on location and tissue microenvironment.
Figure 5: Endogenous factors influencing mesenchymal stem cells in adult cartilage repair.

Similar content being viewed by others

References

  1. McGonagle, D., Tan, A. L., Carey, J. & Benjamin, M. The anatomical basis for a novel classification of osteoarthritis and allied disorders. J. Anat. 216, 279–291 (2010).

    PubMed  PubMed Central  Google Scholar 

  2. Martel-Pelletier, J. et al. Osteoarthritis. Nat. Rev. Dis. Primers 2, 16072 (2016).

    PubMed  Google Scholar 

  3. Goldring, S. R. & Goldring, M. B. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat. Rev. Rheumatol. 12, 632–644 (2016).

    PubMed  Google Scholar 

  4. Wolfe, F. & Lane, N. E. The longterm outcome of osteoarthritis: rates and predictors of joint space narrowing in symptomatic patients with knee osteoarthritis. J. Rheumatol. 29, 139–146 (2002).

    PubMed  Google Scholar 

  5. Roemer, F. W. et al. Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritis. Ann. Rheum. Dis. 68, 1461–1465 (2009).

    CAS  PubMed  Google Scholar 

  6. Brittberg, M. et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N. Engl. J. Med. 331, 889–895 (1994).

    CAS  PubMed  Google Scholar 

  7. Steadman, J. R. et al. Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up. Arthroscopy 19, 477–484 (2003).

    PubMed  Google Scholar 

  8. Wakitani, S. et al. Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees. Osteoarthritis Cartilage 10, 199–206 (2002).

    CAS  PubMed  Google Scholar 

  9. Prakash, D. & Learmonth, D. Natural progression of osteo-chondral defect in the femoral condyle. Knee 9, 7–10 (2002).

    PubMed  Google Scholar 

  10. Cicuttini, F. et al. Association of cartilage defects with loss of knee cartilage in healthy, middle-age adults: a prospective study. Arthritis Rheum. 52, 2033–2039 (2005).

    PubMed  Google Scholar 

  11. Davies-Tuck, M. et al. The natural history of cartilage defects in people with knee osteoarthritis. Osteoarthritis Cartilage 16, 337–342 (2008).

    CAS  PubMed  Google Scholar 

  12. Koshino, T., Wada, S., Ara, Y. & Saito, T. Regeneration of degenerated articular cartilage after high tibial valgus osteotomy for medial compartmental osteoarthritis of the knee. Knee 10, 229–236 (2003).

    PubMed  Google Scholar 

  13. Intema, F. et al. Tissue structure modification in knee osteoarthritis by use of joint distraction: an open 1-year pilot study. Ann. Rheum. Dis. 70, 1441–1446 (2011).

    PubMed  Google Scholar 

  14. Wiegant, K. et al. Sustained clinical and structural benefit after joint distraction in the treatment of severe knee osteoarthritis. Osteoarthritis Cartilage 21, 1660–1667 (2013).

    CAS  PubMed  Google Scholar 

  15. Mastbergen, S. C., Saris, D. B. & Lafeber, F. P. Functional articular cartilage repair: here, near, or is the best approach not yet clear? Nat. Rev. Rheumatol. 9, 277–290 (2013).

    CAS  PubMed  Google Scholar 

  16. Pers, Y. M. et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl. Med. 5, 847–856 (2016).

    PubMed  PubMed Central  Google Scholar 

  17. Yubo, M. et al. Clinical efficacy and safety of mesenchymal stem cell transplantation for osteoarthritis treatment: a meta-analysis. PLoS ONE 12, e0175449 (2017).

    PubMed  PubMed Central  Google Scholar 

  18. Wagner, W. et al. Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS ONE 3, e2213 (2008).

    PubMed  PubMed Central  Google Scholar 

  19. Stolzing, A. & Scutt, A. Age-related impairment of mesenchymal progenitor cell function. Aging Cell 5, 213–224 (2006).

    CAS  PubMed  Google Scholar 

  20. Eaves, C. J. Hematopoietic stem cells: concepts, definitions, and the new reality. Blood 125, 2605–2613 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Prockop, D. J. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276, 71–74 (1997).

    CAS  PubMed  Google Scholar 

  22. Barbero, A., Ploegert, S., Heberer, M. & Martin, I. Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum. 48, 1315–1325 (2003).

    CAS  PubMed  Google Scholar 

  23. Park, S. R., Oreffo, R. O. & Triffitt, J. T. Interconversion potential of cloned human marrow adipocytes in vitro. Bone 24, 549–554 (1999).

    CAS  PubMed  Google Scholar 

  24. Shapiro, F., Koide, S. & Glimcher, M. J. Cell origin and differentiation in the repair of full-thickness defects of articular cartilage. J. Bone Joint Surg. Am. 75, 532–553 (1993).

    CAS  PubMed  Google Scholar 

  25. Onyekwelu, I., Goldring, M. B. & Hidaka, C. Chondrogenesis, joint formation, and articular cartilage regeneration. J. Cell. Biochem. 107, 383–392 (2009).

    CAS  PubMed  Google Scholar 

  26. Isern, J. & Méndez-Ferrer, S. Stem cell interactions in a bone marrow niche. Curr. Osteoporos. Rep. 9, 210–218 (2011).

    PubMed  Google Scholar 

  27. Garcia-Garcia, A., de Castillejo, C. L. F. & Mendez-Ferrer, S. BMSCs and hematopoiesis. Immunol. Lett. 168, 129–135 (2015).

    CAS  PubMed  Google Scholar 

  28. Bianco, P. & Robey, P. G. Marrow stromal stem cells. J. Clin. Invest. 105, 1663–1668 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Jones, E. & McGonagle, D. Human bone marrow mesenchymal stem cells in vivo. Rheumatology (Oxford) 47, 126–131 (2008).

    CAS  Google Scholar 

  30. Jones, E. et al. 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. 62, 1944–1954 (2010).

    CAS  PubMed  Google Scholar 

  31. Friedenstein, A., Chailakhjan, R. & Lalykina, K. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3, 393–403 (1970).

    CAS  PubMed  Google Scholar 

  32. Boxall, S. A. & Jones, E. Markers for characterization of bone marrow multipotential stromal cells. Stem Cells Int. 2012, 975871 (2012).

    PubMed  PubMed Central  Google Scholar 

  33. Komada, Y. et al. Origins and properties of dental, thymic, and bone marrow mesenchymal cells and their stem cells. PLoS ONE 7, e46436 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Isern, J. et al. The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem-cell-niche function. eLife 3, e03696 (2014).

    PubMed  PubMed Central  Google Scholar 

  35. Worthley, D. L. et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160, 269–284 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. McGonagle, D. & Jones, E. A. Musculoskeletal biology and bioengineering: a new in vivo stem cell model for regenerative rheumatology. Nat. Rev. Rheumatol. 11, 200–201 (2015).

    PubMed  Google Scholar 

  37. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

    CAS  PubMed  Google Scholar 

  38. Ghazanfari, R., Li, H. Z., Zacharaki, D., Lim, H. C. & Scheding, S. Human non-hematopoietic CD271pos/CD140alow/neg bone marrow stroma cells fulfill stringent stem cell criteria in serial transplantations. Stem Cells Dev. 25, 1652–1658 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Bianco, P., Riminucci, M., Gronthos, S. & Robey, P. G. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19, 180–192 (2001).

    CAS  PubMed  Google Scholar 

  40. Tormin, A. et al. CD146 expression on primary non-hematopoietic bone marrow stem cells correlates to in situ localization. Blood 117, 5067–5077 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Einhorn, T. A. & Gerstenfeld, L. C. Fracture healing: mechanisms and interventions. Nat. Rev. Rheumatol. 11, 45–54 (2015).

    PubMed  Google Scholar 

  42. Welner, R. S. & Kincade, P. W. 9-1-1: HSCs respond to emergency calls. Cell Stem Cell 14, 415–416 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Sethe, S., Scutt, A. & Stolzing, A. Aging of mesenchymal stem cells. Ageing Res. Rev. 5, 91–116 (2006).

    CAS  PubMed  Google Scholar 

  44. Sakaguchi, Y. et al. Suspended cells from trabecular bone by collagenase digestion become virtually identical to mesenchymal stem cells obtained from marrow aspirates. Blood 104, 2728–2735 (2004).

    CAS  PubMed  Google Scholar 

  45. Cuthbert, R. J. et al. Examining the feasibility of clinical grade CD271+ enrichment of mesenchymal stromal cells for bone regeneration. PLoS ONE 10, e0117855 (2015).

    PubMed  PubMed Central  Google Scholar 

  46. Li, H., Ghazanfari, R., Zacharaki, D., Lim, H. C. & Scheding, S. Isolation and characterization of primary bone marrow mesenchymal stromal cells. Ann. NY Acad. Sci. 1370, 109–118 (2016).

    CAS  PubMed  Google Scholar 

  47. Mapp, P. I. & Walsh, D. A. Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol. 8, 390–398 (2012).

    CAS  PubMed  Google Scholar 

  48. Freemont, A. et al. Nerve ingrowth into diseased intervertebral disc in chronic back pain. Lancet 350, 178–181 (1997).

    CAS  PubMed  Google Scholar 

  49. Campbell, T. M. et al. Mesenchymal stem cell alterations in bone marrow lesions in patients with hip osteoarthritis. Arthritis Rheumatol. 68, 1648–1659 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Tomlinson, R. E. et al. NGF-TrkA signaling in sensory nerves is required for skeletal adaptation to mechanical loads in mice. Proc. Natl Acad. Sci. USA 114, E3632–E3641 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Pritzker, K. et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis Cartilage 14, 13–29 (2006).

    CAS  PubMed  Google Scholar 

  52. Hayes, A. J., MacPherson, S., Morrison, H., Dowthwaite, G. & Archer, C. W. The development of articular cartilage: evidence for an appositional growth mechanism. Anat. Embryol. (Berl.) 203, 469–479 (2001).

    CAS  Google Scholar 

  53. Dowthwaite, G. P. et al. The surface of articular cartilage contains a progenitor cell population. J. Cell Sci. 117, 889–897 (2004).

    CAS  PubMed  Google Scholar 

  54. Hunziker, E. B., Kapfinger, E. & Geiss, J. The structural architecture of adult mammalian articular cartilage evolves by a synchronized process of tissue resorption and neoformation during postnatal development. Osteoarthritis Cartilage 15, 403–413 (2007).

    CAS  PubMed  Google Scholar 

  55. Kozhemyakina, E. et al. Identification of a Prg4-expressing articular cartilage progenitor cell population in mice. Arthritis Rheumatol. 67, 1261–1273 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Fellows, C. R. et al. Characterisation of a divergent progenitor cell sub-populations in human osteoarthritic cartilage: the role of telomere erosion and replicative senescence. Sci. Rep. 7, 41421 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Lotz, M. K. et al. Cartilage cell clusters. Arthritis Rheum. 62, 2206–2218 (2010).

    PubMed  PubMed Central  Google Scholar 

  58. Kim, A. C. & Spector, M. Distribution of chondrocytes containing α-smooth muscle actin in human articular cartilage. J. Orthop. Res. 18, 749–755 (2000).

    CAS  PubMed  Google Scholar 

  59. Kinner, B., Zaleskas, J. M. & Spector, M. Regulation of smooth muscle actin expression and contraction in adult human mesenchymal stem cells. Exp. Cell Res. 278, 72–83 (2002).

    CAS  PubMed  Google Scholar 

  60. Koelling, S. et al. Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell 4, 324–335 (2009).

    CAS  PubMed  Google Scholar 

  61. McGonagle, D., Lories, R. J. U., Tan, A. L. & Benjamin, M. The concept of a “synovio-entheseal complex” and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis Rheum. 56, 2482–2491 (2007).

    PubMed  Google Scholar 

  62. Shintani, N. & Hunziker, E. B. Chondrogenic differentiation of bovine synovium: bone morphogenetic proteins 2 and 7 and transforming growth factor β1 induce the formation of different types of cartilaginous tissue. Arthritis Rheum. 56, 1869–1879 (2007).

    CAS  PubMed  Google Scholar 

  63. Jones, E. A. et al. Enumeration and phenotypic characterization of synovial fluid multipotential mesenchymal progenitor cells in inflammatory and degenerative arthritis. Arthritis Rheum. 50, 817–827 (2004).

    PubMed  Google Scholar 

  64. Gullo, F. & De Bari, C. Prospective purification of a subpopulation of human synovial mesenchymal stem cells with enhanced chondro-osteogenic potency. Rheumatology (Oxford) 52, 1758–1768 (2013).

    CAS  Google Scholar 

  65. Koyama, E. et al. A distinct cohort of progenitor cells participates in synovial joint and articular cartilage formation during mouse limb skeletogenesis. Dev. Biol. 316, 62–73 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. De Bari, C., Dell'Accio, F., Tylzanowski, P. & Luyten, F. P. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 44, 1928–1942 (2001).

    CAS  PubMed  Google Scholar 

  67. 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. 52, 2521–2529 (2005).

    PubMed  Google Scholar 

  68. Mochizuki, T. et al. Higher chondrogenic potential of fibrous synovium- and adipose synovium-derived cells compared with. subcutaneous fat-derived cells — distinguishing properties of mesenchymal stem cells in humans. Arthritis Rheum. 54, 843–853 (2006).

    CAS  PubMed  Google Scholar 

  69. Hunziker, E. B. & Rosenberg, L. C. Repair of partial-thickness defects in articular cartilage: cell recruitment from the synovial membrane. J. Bone Joint Surg. Am. 78, 721–733 (1996).

    CAS  PubMed  Google Scholar 

  70. Kurth, T. B. et al. Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum. 63, 1289–1300 (2011).

    PubMed  Google Scholar 

  71. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    CAS  PubMed  Google Scholar 

  72. Muinos-Lopez, E. et al. Modulation of synovial fluid-derived mesenchymal stem cells by intra-articular and intraosseous platelet rich plasma administration. Stem Cells Int. 2016, 1247950 (2016).

    PubMed  PubMed Central  Google Scholar 

  73. Buckley, C. T. et al. Functional properties of cartilaginous tissues engineered from infrapatellar fat pad-derived mesenchymal stem cells. J. Biomech. 43, 920–926 (2010).

    PubMed  Google Scholar 

  74. Katagiri, K. et al. Fibrous synovium releases higher numbers of mesenchymal stem cells than adipose synovium in a suspended synovium culture model. Arthroscopy 33, 800–810 (2017).

    PubMed  Google Scholar 

  75. Jones, E. A. et al. Synovial fluid mesenchymal stem cells in health and early osteoarthritis: detection and functional evaluation at the single-cell level. Arthritis Rheum. 58, 1731–1740 (2008).

    CAS  PubMed  Google Scholar 

  76. Sekiya, I. et al. Human mesenchymal stem cells in synovial fluid increase in the knee with degenerated cartilage and osteoarthritis. J. Orthop. Res. 30, 943–949 (2012).

    PubMed  Google Scholar 

  77. Baboolal, T. G. et al. Intrinsic multipotential mesenchymal stromal cell activity in gelatinous Heberden's nodes in osteoarthritis at clinical presentation. Arthritis Res. Ther. 16, R119 (2014).

    PubMed  PubMed Central  Google Scholar 

  78. Harris, Q. et al. Monocyte chemotactic protein-1 inhibits chondrogenesis of synovial mesenchymal progenitor cells: an in vitro study. Stem Cells 31, 2253–2265 (2013).

    CAS  PubMed  Google Scholar 

  79. Morito, T. et al. Synovial fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans. Rheumatology (Oxford) 47, 1137–1143 (2008).

    CAS  Google Scholar 

  80. Matsukura, Y., Muneta, T., Tsuji, K., Koga, H. & Sekiya, I. Mesenchymal stem cells in synovial fluid increase after meniscus injury. Clin. Orthop. Relat. Res. 472, 1357–1364 (2014).

    PubMed  Google Scholar 

  81. Murphy, J. M., Fink, D. J., Hunziker, E. B. & Barry, F. P. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 48, 3464–3474 (2003).

    PubMed  Google Scholar 

  82. Wood, J. A. 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. 28, 307–317 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Baboolal, T. G. et al. Synovial fluid hyaluronan mediates MSC attachment to cartilage, a potential novel mechanism contributing to cartilage repair in osteoarthritis using knee joint distraction. Ann. Rheum. Dis. 75, 908–915 (2016).

    CAS  PubMed  Google Scholar 

  84. Kuznetsov, S. A. et al. Circulating skeletal stem cells. J. Cell Biol. 153, 1133–1139 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Tan, H. B., Giannoudis, P. V., Boxall, S. A., McGonagle, D. & Jones, E. The systemic influence of platelet-derived growth factors on bone marrow mesenchymal stem cells in fracture patients. BMC Med. 13, 6 (2015).

    PubMed  PubMed Central  Google Scholar 

  86. Sergijenko, A., Roelofs, A. J., Riemen, A. H. & De Bari, C. Bone marrow contribution to synovial hyperplasia following joint surface injury. Arthritis Res. Ther. 18, 166 (2016).

    PubMed  PubMed Central  Google Scholar 

  87. Nguyen, P. D. et al. Comparative clinical observation of arthroscopic microfracture in the presence and absence of a stromal vascular fraction injection for osteoarthritis. Stem Cells Transl Med. 6, 187–195 (2017).

    PubMed  Google Scholar 

  88. Sekiya, I., Muneta, T., Horie, M. & Koga, H. Arthroscopic transplantation of synovial stem cells improves clinical outcomes in knees with cartilage defects. Clin. Orthop. Relat. Res. 473, 2316–2326 (2015).

    PubMed  PubMed Central  Google Scholar 

  89. Featherstone, J. Dental caries: a dynamic disease process. Aust. Dent. J. 53, 286–291 (2008).

    CAS  PubMed  Google Scholar 

  90. Shwartz, Y., Viukov, S., Krief, S. & Zelzer, E. Joint development involves a continuous influx of Gdf5-positive cells. Cell Rep. 15, 2577–2587 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Roelofs, A. J. et al. Joint morphogenetic cells in the adult mammalian synovium. Nat. Commun. 8, 15040 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Decker, R. S. et al. Cell origin, volume and arrangement are drivers of articular cartilage formation, morphogenesis and response to injury in mouse limbs. Dev. Biol. 1, 56–68 (2017).

    Google Scholar 

  93. English, A. et al. A comparative assessment of cartilage and joint fat pad as a potential source of cells for autologous therapy development in knee osteoarthritis. Rheumatology (Oxford) 46, 1676–1683 (2007).

    CAS  Google Scholar 

  94. Marsano, A. et al. Differential cartilaginous tissue formation by human synovial membrane, fat pad, meniscus cells and articular chondrocytes. Osteoarthritis Cartilage 15, 48–58 (2007).

    CAS  PubMed  Google Scholar 

  95. Saxer, F. et al. Implantation of stromal vascular fraction progenitors at bone fracture sites: from a rat model to a first-in-man study. Stem Cells 34, 2956–2966 (2016).

    CAS  PubMed  Google Scholar 

  96. Scotti, C. et al. Cartilage repair in the inflamed joint: considerations for biological augmentation toward tissue regeneration. Tissue Eng. Part B Rev. 22, 149–159 (2016).

    CAS  PubMed  Google Scholar 

  97. Jones, E. et al. Mesenchymal stem cells in rheumatoid synovium: enumeration and functional assessment in relation to synovial inflammation level. Ann. Rheum. Dis. 69, 450–457 (2010).

    CAS  PubMed  Google Scholar 

  98. Del Rey, M. J. et al. CD271+ stromal cells expand in arthritic synovium and exhibit a proinflammatory phenotype. Arthritis Res. Ther. 18, 66 (2016).

    PubMed  PubMed Central  Google Scholar 

  99. Matsukura, Y. et al. Mouse synovial mesenchymal stem cells increase in yield with knee inflammation. J. Orthop. Res. 33, 246–253 (2015).

    PubMed  Google Scholar 

  100. Richter, W. Mesenchymal stem cells and cartilage in situ regeneration. J. Intern. Med. 266, 390–405 (2009).

    CAS  PubMed  Google Scholar 

  101. Gobbi, A. et al. One-step cartilage repair with bone marrow aspirate concentrated cells and collagen matrix in full-thickness knee cartilage lesions: results at 2-year follow-up. Cartilage 2, 286–299 (2011).

    PubMed  PubMed Central  Google Scholar 

  102. Min, B.-H. et al. Effect of different bone marrow stimulation techniques (BSTS) on MSCs mobilization. J. Orthop. Res. 31, 1814–1819 (2013).

    CAS  PubMed  Google Scholar 

  103. Kuttapitiya, A. et al. Microarray analysis of bone marrow lesions in osteoarthritis demonstrates upregulation of genes implicated in osteochondral turnover, neurogenesis and inflammation. Ann. Rheum. Dis. 76, 1764–1773 (2017).

    CAS  PubMed  Google Scholar 

  104. Battula, V. L. et al. Isolation of functionally distinct mesenchymal stem cell subsets using antibodies against CD56, CD271, and mesenchymal stem cell antigen-1. Haematologica 94, 173–184 (2009).

    CAS  PubMed  Google Scholar 

  105. Balanescu, A. R. et al. Efficacy and safety of tanezumab added on to diclofenac sustained release in patients with knee or hip osteoarthritis: a double-blind, placebo-controlled, parallel-group, multicentre phase III randomised clinical trial. Ann. Rheum. Dis. 73, 1665–1672 (2014).

    CAS  PubMed  Google Scholar 

  106. Schnitzer, T. J. et al. Efficacy and safety of tanezumab monotherapy or combined with non-steroidal anti-inflammatory drugs in the treatment of knee or hip osteoarthritis pain. Ann. Rheum. Dis. 74, 1202–1211 (2014).

    PubMed  Google Scholar 

  107. Hochberg, M. C. et al. When is osteonecrosis not osteonecrosis?: Adjudication of reported serious adverse joint events in the tanezumab clinical development program. Arthritis Rheumatol. 68, 382–391 (2016).

    CAS  PubMed  Google Scholar 

  108. Johnson, E. M., Taniuchi, M. & DiStefano, P. S. Expression and possible function of nerve growth factor receptors on Schwann cells. Trends Neurosci. 11, 299–304 (1988).

    CAS  PubMed  Google Scholar 

  109. Pountos, I. et al. NSAIDS inhibit in vitro MSC chondrogenesis but not osteogenesis: implications for mechanism of bone formation inhibition in man. J. Cell. Mol. Med. 15, 525–534 (2011).

    CAS  PubMed  Google Scholar 

  110. Anton, E. S., Weskamp, G., Reichardt, L. F. & Matthew, W. D. Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc. Natl Acad. Sci. USA 91, 2795–2799 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Jiang, Y. et al. Cartilage stem/progenitor cells are activated in osteoarthritis via interleukin-1β/nerve growth factor signaling. Arthritis Res. Ther. 17, 327 (2015).

    PubMed  PubMed Central  Google Scholar 

  112. Huey, D. J., Hu, J. C. & Athanasiou, K. A. Unlike bone, cartilage regeneration remains elusive. Science 338, 917–921 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The work of the authors is supported by the National Institute for Health Research (NIHR)–Leeds Musculoskeletal and Biomedical Research Centre.

Author information

Authors and Affiliations

  1. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds, LS7 4SA, UK

    Dennis McGonagle, Thomas G. Baboolal & Elena Jones

Authors
  1. Dennis McGonagle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas G. Baboolal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elena Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Dennis McGonagle.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

'Chondrogenic' OA

A type of osteoarthritis (OA) in which early lesions form in the articular cartilage; distinct from OA that starts in other structures, such as OA that begins following meniscus or bone injury.

Osteotomy

A technique whereby bone is surgically realigned to change the joint alignment and load distribution.

Total joint distraction

A surgical technique in which external fixator devices are placed across the joint to restore the joint space; associated with cartilage repair.

Epiphyseal cartilage ossification centres

Areas of the cartilagenous growth plate at the metaphyseal ends of long bones in which bone formation follows the primary ossification seen in the diaphysis of long bones.

One-stage fracture repair

A single orthopaedic intervention to correct mechanical instability that optimizes strategies for rapid repair to prevent the need for further interventions.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

McGonagle, D., Baboolal, T. & Jones, E. Native joint-resident mesenchymal stem cells for cartilage repair in osteoarthritis. Nat Rev Rheumatol 13, 719–730 (2017). https://doi.org/10.1038/nrrheum.2017.182

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrrheum.2017.182

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing