Review Article

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

  • Nature Reviews Rheumatology volume 13, pages 719730 (2017)
  • doi:10.1038/nrrheum.2017.182
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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.

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References

  1. 1.

    , , & The anatomical basis for a novel classification of osteoarthritis and allied disorders. J. Anat. 216, 279–291 (2010).

  2. 2.

    et al. Osteoarthritis. Nat. Rev. Dis. Primers 2, 16072 (2016).

  3. 3.

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

  4. 4.

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

  5. 5.

    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).

  6. 6.

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

  7. 7.

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

  8. 8.

    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).

  9. 9.

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

  10. 10.

    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).

  11. 11.

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

  12. 12.

    , , & Regeneration of degenerated articular cartilage after high tibial valgus osteotomy for medial compartmental osteoarthritis of the knee. Knee 10, 229–236 (2003).

  13. 13.

    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).

  14. 14.

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

  15. 15.

    , & Functional articular cartilage repair: here, near, or is the best approach not yet clear? Nat. Rev. Rheumatol. 9, 277–290 (2013).

  16. 16.

    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).

  17. 17.

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

  18. 18.

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

  19. 19.

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

  20. 20.

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

  21. 21.

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

  22. 22.

    , , & Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum. 48, 1315–1325 (2003).

  23. 23.

    , & Interconversion potential of cloned human marrow adipocytes in vitro. Bone 24, 549–554 (1999).

  24. 24.

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

  25. 25.

    , & Chondrogenesis, joint formation, and articular cartilage regeneration. J. Cell. Biochem. 107, 383–392 (2009).

  26. 26.

    & Stem cell interactions in a bone marrow niche. Curr. Osteoporos. Rep. 9, 210–218 (2011).

  27. 27.

    , & BMSCs and hematopoiesis. Immunol. Lett. 168, 129–135 (2015).

  28. 28.

    & Marrow stromal stem cells. J. Clin. Invest. 105, 1663–1668 (2000).

  29. 29.

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

  30. 30.

    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).

  31. 31.

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

  32. 32.

    & Markers for characterization of bone marrow multipotential stromal cells. Stem Cells Int. 2012, 975871 (2012).

  33. 33.

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

  34. 34.

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

  35. 35.

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

  36. 36.

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

  37. 37.

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

  38. 38.

    , , , & 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).

  39. 39.

    , , & Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19, 180–192 (2001).

  40. 40.

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

  41. 41.

    & Fracture healing: mechanisms and interventions. Nat. Rev. Rheumatol. 11, 45–54 (2015).

  42. 42.

    & 9-1-1: HSCs respond to emergency calls. Cell Stem Cell 14, 415–416 (2014).

  43. 43.

    , & Aging of mesenchymal stem cells. Ageing Res. Rev. 5, 91–116 (2006).

  44. 44.

    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).

  45. 45.

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

  46. 46.

    , , , & Isolation and characterization of primary bone marrow mesenchymal stromal cells. Ann. NY Acad. Sci. 1370, 109–118 (2016).

  47. 47.

    & Mechanisms and targets of angiogenesis and nerve growth in osteoarthritis. Nat. Rev. Rheumatol. 8, 390–398 (2012).

  48. 48.

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

  49. 49.

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

  50. 50.

    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).

  51. 51.

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

  52. 52.

    , , , & The development of articular cartilage: evidence for an appositional growth mechanism. Anat. Embryol. (Berl.) 203, 469–479 (2001).

  53. 53.

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

  54. 54.

    , & 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).

  55. 55.

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

  56. 56.

    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).

  57. 57.

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

  58. 58.

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

  59. 59.

    , & Regulation of smooth muscle actin expression and contraction in adult human mesenchymal stem cells. Exp. Cell Res. 278, 72–83 (2002).

  60. 60.

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

  61. 61.

    , , & 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).

  62. 62.

    & 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).

  63. 63.

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

  64. 64.

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

  65. 65.

    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).

  66. 66.

    , , & Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 44, 1928–1942 (2001).

  67. 67.

    , , & Comparison of human stem cells derived from various mesenchymal tissues — superiority of synovium as a cell source. Arthritis Rheum. 52, 2521–2529 (2005).

  68. 68.

    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).

  69. 69.

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

  70. 70.

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

  71. 71.

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

  72. 72.

    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).

  73. 73.

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

  74. 74.

    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).

  75. 75.

    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).

  76. 76.

    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).

  77. 77.

    et al. Intrinsic multipotential mesenchymal stromal cell activity in gelatinous Heberden's nodes in osteoarthritis at clinical presentation. Arthritis Res. Ther. 16, R119 (2014).

  78. 78.

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

  79. 79.

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

  80. 80.

    , , , & Mesenchymal stem cells in synovial fluid increase after meniscus injury. Clin. Orthop. Relat. Res. 472, 1357–1364 (2014).

  81. 81.

    , , & Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 48, 3464–3474 (2003).

  82. 82.

    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).

  83. 83.

    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).

  84. 84.

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

  85. 85.

    , , , & The systemic influence of platelet-derived growth factors on bone marrow mesenchymal stem cells in fracture patients. BMC Med. 13, 6 (2015).

  86. 86.

    , , & Bone marrow contribution to synovial hyperplasia following joint surface injury. Arthritis Res. Ther. 18, 166 (2016).

  87. 87.

    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).

  88. 88.

    , , & Arthroscopic transplantation of synovial stem cells improves clinical outcomes in knees with cartilage defects. Clin. Orthop. Relat. Res. 473, 2316–2326 (2015).

  89. 89.

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

  90. 90.

    , , & Joint development involves a continuous influx of Gdf5-positive cells. Cell Rep. 15, 2577–2587 (2016).

  91. 91.

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

  92. 92.

    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).

  93. 93.

    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).

  94. 94.

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

  95. 95.

    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).

  96. 96.

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

  97. 97.

    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).

  98. 98.

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

  99. 99.

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

  100. 100.

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

  101. 101.

    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).

  102. 102.

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

  103. 103.

    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).

  104. 104.

    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).

  105. 105.

    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).

  106. 106.

    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).

  107. 107.

    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).

  108. 108.

    , & Expression and possible function of nerve growth factor receptors on Schwann cells. Trends Neurosci. 11, 299–304 (1988).

  109. 109.

    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).

  110. 110.

    , , & Nerve growth factor and its low-affinity receptor promote Schwann cell migration. Proc. Natl Acad. Sci. USA 91, 2795–2799 (1994).

  111. 111.

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

  112. 112.

    , & Unlike bone, cartilage regeneration remains elusive. Science 338, 917–921 (2012).

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Acknowledgements

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

Author information

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

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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.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Dennis McGonagle.

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.