Stem Cells in Bone and Articular Cartilage Tissue Regeneration

  • Christopher R. Fellows
  • Kalamegam Gauthaman
  • Peter N. Pushparaj
  • Mohammed Abbas
  • Csaba Matta
  • Rebecca Lewis
  • Constanze Buhrmann
  • Mehdi Shakibaei
  • Ali MobasheriEmail author
Part of the Stem Cells in Clinical Applications book series (SCCA)


Multiple factors including trauma, infection, ageing, obesity and tumours result in bone and cartilage defects. The regeneration and functional restoration of bone and cartilage remains a significant clinical challenge. ‘Autologous grafts’ continue to remain the ‘gold standard’ in both bone and cartilage regeneration but stem cell-based therapies offer great promise in both these areas. Despite the plethora of stem cells that exist within the human body, the challenge remains in identifying the most beneficial cell type, assessing their availability, expansion under cGMP culture conditions, differentiation potential and functional restoration capacity. Embryonic stem cells; mesenchymal stem cells from the bone marrow, synovial fluid, adipose tissue and umbilical cord; and primary articular chondrocytes are some of the candidate cell types that are extensively studied in the context of bone (and cartilage) regeneration. The limited regeneration potential of cartilage adds further complexity to cartilage tissue engineering compared to the bone. However, major bone reconstruction as in the case of large bone defects due to tumour resection, fractures, and skeletal deformities is equally challenging. Incorporation of novel biomaterials, understanding the optimal cell-scaffold interactions, the addition of growth factors and provision of molecular cues are all essential in achieving effective tissue regeneration. Intensive effects in tissue regeneration can actually predispose to tissue hypertrophy, which also limits functional capacity. The current state of-the-art in both bone and cartilage regeneration is reviewed in this chapter, which highlights the importance of combined approaches involving stem/progenitor cells, biomolecules and/or biomaterials for therapies as well as rehabilitation and improvement in quality of life.


Stem Cells Cartilage Bone Tissue Engineering Osteoarthritis 



AM is the coordinator of the D-BOARD Consortium funded by the European Commission Framework Seventh programme (EU FP7; HEALTH.2012.2.4.5-2, project number 305815, Novel Diagnostics and Biomarkers for Early Identification of Chronic Inflammatory Joint Diseases). AM is a member of the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium, a 5-year project funded by the European Commission Innovative Medicines Initiative (IMI). APPROACH is a public–private partnership directed towards osteoarthritis biomarker development through the establishment of a heavily phenotyped and comprehensively analysed longitudinal cohort. The research leading to these results has received partial support from the Innovative Medicines Initiative (IMI) Joint Undertaking under grant agreement no. 115770, resources of which are composed of financial contribution from the European Union’s Seventh Framework programme (FP7/2007–2013) and EFPIA companies’ in-kind contribution. CM is supported by the European Union through a Marie Curie Intra-European Fellowship for career development (project number 625746; acronym: CHONDRION; FP7-PEOPLE-2013-IEF). A.M. has received funding from the Deanship of Scientific Research (DSR), King Abdulaziz University (grant no. 1–141/1434 HiCi). KG acknowledges the financial support provided by the ‘Sheikh Salem Bin Mahfouz Scientific Chair for Treatment of Osteoarthritis by Stem Cells’ and the stem cell laboratory facility at CEGMR and King Abdulaziz University Hospital. The funders had no role in decision to publish or the preparation of this chapter.

Competing Interests and Disclosures

The authors wrote this chapter within the scope of their academic and affiliated research positions. The authors declare no competing interests. The authors do not have any commercial relationships that could be construed as biased or inappropriate.


  1. Agrawal CM, Ray RB. Biodegradable polymeric scaffolds for musculoskeletal tissue engineering. J Biomed Mater Res. 2001;55(2):141–50.PubMedCrossRefGoogle Scholar
  2. Ahn SE, et al. Primary bone-derived cells induce osteogenic differentiation without exogenous factors in human embryonic stem cells. Biochem Biophys Res Commun. 2006;340(2):403–8.PubMedCrossRefGoogle Scholar
  3. Akhavan O, Ghaderi E, Shahsavar M. Graphene nanogrids for selective and fast osteogenic differentiation of human mesenchymal stem cells. Carbon. 2013;59:200–11.CrossRefGoogle Scholar
  4. Alsalameh S, et al. Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis Rheum. 2004;50(5):1522–32.PubMedCrossRefGoogle Scholar
  5. Amini AR, Laurencin CT, Nukavarapu SP. Bone tissue engineering: recent advances and challenges.Crit Rev Biomed Eng. 2012;40(5):363–408Google Scholar
  6. Archer CW, Dowthwaite GP, Francis-West P. Development of synovial joints. Birth Defects Res Part C Embryo Today Rev. 2003a;69(2):144–55.CrossRefGoogle Scholar
  7. Ardeshirylajimi A, et al. A comparative study of osteogenic differentiation human induced pluripotent stem cells and adipose tissue derived mesenchymal stem cells. Cell Journal (Yakhteh). 2014;16(3):235.Google Scholar
  8. Arinzeh TL, et al. Allogeneic mesenchymal stem cells regenerate bone in a critical-sized canine segmental defect. J Bone Joint Surg. 2003;85(10):1927–35.PubMedCrossRefGoogle Scholar
  9. Armstrong CG, Mow VC. Variations in the intrinsic mechanical properties of human articular cartilage with age, degeneration, and water content. J Bone Joint Surg Am. 1982;64(1):88–94.PubMedCrossRefGoogle Scholar
  10. Arpornmaeklong P, et al. Phenotypic characterization, osteoblastic differentiation, and bone regeneration capacity of human embryonic stem cell-derived mesenchymal stem cells. Stem Cells Dev. 2009;18(7):955–68.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Asakura A, Rudnicki MA, Komaki M. Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation. 2001;68(4–5):245–53.PubMedCrossRefGoogle Scholar
  12. Bader DL, Salter DM, Chowdhury TT. Biomechanical influence of cartilage homeostasis in health and disease. Arthritis. 2011;2011:979032.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Baksh D, Yao R, Tuan RS. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells. 2007;25(6):1384–92.PubMedCrossRefGoogle Scholar
  14. Baraniak PR, McDevitt TC. Stem cell paracrine actions and tissue regeneration. Regen Med. 2010;5(1):121–43.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Barbero A, et al. Plasticity of clonal populations of dedifferentiated adult human articular chondrocytes. Arthritis Rheum. 2003;48(5):1315–25.PubMedCrossRefGoogle Scholar
  16. Barrett-Jolley R, et al. The emerging chondrocyte channelome. Front Physiol. 2010;1:135.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Bartlett W, et al. Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective randomised study. J Bone Joint Surg Br. 2005;87-B(5):640–5.CrossRefGoogle Scholar
  18. Beier F. Cell-cycle control and the cartilage growth plate. J Cell Physiol. 2005;202(1):1–8.PubMedCrossRefGoogle Scholar
  19. Benya PD, Shaffer JD. Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell. 1982;30(1):215–24.PubMedCrossRefGoogle Scholar
  20. Bhosale AM, Richardson JB. Articular cartilage: structure, injuries and review of management. Br Med Bull. 2008;87(1):77–95.PubMedCrossRefGoogle Scholar
  21. Bielby RC, et al. In vitro differentiation and in vivo mineralization of osteogenic cells derived from human embryonic stem cells. Tissue Eng. 2004;10(9–10):1518–25.PubMedCrossRefGoogle Scholar
  22. Bitton R. The economic burden of osteoarthritis. Am J Manag Care. 2009;15(8 Suppl):S230–5.PubMedGoogle Scholar
  23. Bobick BE, Kulyk WM. Regulation of cartilage formation and maturation by mitogen-activated protein kinase signaling. Birth Defects Res C Embryo Today. 2008;84(2):131–54.PubMedCrossRefGoogle Scholar
  24. Bobick BE, et al. Regulation of the chondrogenic phenotype in culture. Birth Defects Res C Embryo Today. 2009;87(4):351–71.PubMedCrossRefGoogle Scholar
  25. Brittberg M, et al. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med. 1994;331(14):889–95.PubMedCrossRefGoogle Scholar
  26. Brittberg M, et al. Articular cartilage engineering with autologous chondrocyte transplantation. A review of recent developments. J Bone Joint Surg Am. 2003;3:109–15.CrossRefGoogle Scholar
  27. Buckwalter JA, Lane NE. Aging, sports, and osteoarthritis. Sports Med Arthrosc Rev. 1996;4(3):276–87.CrossRefGoogle Scholar
  28. Buckwalter JA, Mankin HJ. Articular cartilage: tissue design and chondrocyte-matrix interactions. Instr Course Lect. 1998a;47:477–86.PubMedGoogle Scholar
  29. Buckwalter JA, Mankin HJ. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr Course Lect. 1998b;47:487–504.PubMedGoogle Scholar
  30. Buckwalter JA, Martin JA. Osteoarthritis. Adv Drug Deliv Rev. 2006;58(2):150–67.PubMedCrossRefGoogle Scholar
  31. Buckwalter JA, Hunziker EB. Articular cartilage morphology and biology. In: Archer CW, et al. editors. Biology of the synovial joint. Amsterdam: Harwood Academic; 1999.Google Scholar
  32. Buhrmann C, et al. Sirtuin-1 (SIRT1) is required for promoting chondrogenic differentiation of mesenchymal stem cells. J Biol Chem. 2014;289(32):22048–62.PubMedPubMedCentralCrossRefGoogle Scholar
  33. Calori G, et al. Risk factors contributing to fracture non-unions. Injury. 2007;38:S11–8.PubMedCrossRefGoogle Scholar
  34. Cao T, et al. Osteogenic differentiation within intact human embryoid bodies result in a marked increase in osteocalcin secretion after 12 days of in vitro culture, and formation of morphologically distinct nodule-like structures. Tissue Cell. 2005;37(4):325–34.PubMedCrossRefGoogle Scholar
  35. Caplan AI. Why are MSCs therapeutic? New data: new insight. J Pathol. 2009;217:318–24.Google Scholar
  36. Caterson EJ, et al. Three-dimensional cartilage formation by bone marrow-derived cells seeded in polylactide/alginate amalgam. J Biomed Mater Res. 2001;57(3):394–403.PubMedCrossRefGoogle Scholar
  37. Chaĭlakhan R, Lalykina K. Spontaneous and induced differentiation of osseous tissue in a population of fibroblast-like cells obtained from long-term monolayer cultures of bone marrow and spleen. Dokl Akad Nauk SSSR. 1969;187(2):473.PubMedGoogle Scholar
  38. Chapekar MS. Tissue engineering: challenges and opportunities. J Biomed Mater Res. 2000;53(6):617–20.PubMedCrossRefGoogle Scholar
  39. Chenu C, et al. Glutamate receptors are expressed by bone cells and are involved in bone resorption. Bone. 1998;22(4):295–9.PubMedCrossRefGoogle Scholar
  40. Cochran D, et al. Evaluation of an endosseous titanium implant with a sandblasted and acid‐etched surface in the canine mandible: radiographic results. Clin Oral Implants Res. 1996;7(3):240–52.PubMedCrossRefGoogle Scholar
  41. Coelho PG, et al. Argon‐based atmospheric pressure plasma enhances early bone response to rough titanium surfaces. J Biomed Mater Res A. 2012;100(7):1901–6.PubMedCrossRefGoogle Scholar
  42. Cournil-Henrionnet C, et al. Phenotypic analysis of cell surface markers and gene expression of human mesenchymal stem cells and chondrocytes during monolayer expansion. Biorheology. 2008;45(3-4):513–26.PubMedGoogle Scholar
  43. Crowder SW, et al. Three-dimensional graphene foams promote osteogenic differentiation of human mesenchymal stem cells. Nanoscale. 2013;5(10):4171–6.PubMedPubMedCentralCrossRefGoogle Scholar
  44. Csaki C, et al. Chondrogenesis, osteogenesis and adipogenesis of canine mesenchymal stem cells: a biochemical, morphological and ultrastructural study. Histochem Cell Biol. 2007;128(6):507–20.PubMedCrossRefGoogle Scholar
  45. Csaki C, et al. Co-culture of canine mesenchymal stem cells with primary bone-derived osteoblasts promotes osteogenic differentiation. Histochem Cell Biol. 2009;131(2):251–66.PubMedCrossRefGoogle Scholar
  46. Dawson JI, Oreffo RO. Bridging the regeneration gap: stem cells, biomaterials and clinical translation in bone tissue engineering. Arch Biochem Biophys. 2008;473(2):124–31.PubMedCrossRefGoogle Scholar
  47. de Sousa EB, et al. Synovial fluid and synovial membrane mesenchymal stem cells: latest discoveries and therapeutic perspectives. Stem cell Res Ther. 2014;5(5):112.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Del Fattore A, Teti A, Rucci N. Osteoclast receptors and signaling. Arch Biochem Biophys. 2008;473(2):147–60.PubMedCrossRefGoogle Scholar
  49. DeLise AM, Fischer L, Tuan RS. Cellular interactions and signaling in cartilage development. Osteoarthritis Cartilage. 2000;8(5):309–34.PubMedCrossRefGoogle Scholar
  50. Derubeis AR, Cancedda R. Bone marrow stromal cells (BMSCs) in bone engineering: limitations and recent advances. Ann Biomed Eng. 2004;32(1):160–5.PubMedCrossRefGoogle Scholar
  51. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425(6958):577–84.PubMedCrossRefGoogle Scholar
  52. Doherty MJ, et al. Vascular pericytes express osteogenic potential in vitro and in vivo. J Bone Miner Res. 1998;13(5):828–38.PubMedCrossRefGoogle Scholar
  53. Dowthwaite GP, et al. The surface of articular cartilage contains a progenitor cell population. J Cell Sci. 2004;117(6):889–97.PubMedCrossRefGoogle Scholar
  54. Dubey N, et al. Graphene: a versatile carbon-based material for bone tissue engineering. Stem Cells Int. 2015;2015:804213.PubMedPubMedCentralCrossRefGoogle Scholar
  55. Edwards CM, Mundy GR. Eph receptors and ephrin signaling pathways: a role in bone homeostasis. Int J Med Sci. 2008;5(5):263.PubMedPubMedCentralCrossRefGoogle Scholar
  56. Ehnes D, et al. Embryonic stem cell-derived osteocytes are capable of responding to mechanical oscillatory hydrostatic pressure. J Biomech. 2015;48:1915–21.PubMedCrossRefGoogle Scholar
  57. Eom T-G, et al. Experimental study of bone response to hydroxyapatite coating implants: bone-implant contact and removal torque test. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;114(4):411–8.PubMedCrossRefGoogle Scholar
  58. Eyre D. Collagen of articular cartilage. Arthritis Res. 2002;4(1):30–5.PubMedCrossRefGoogle Scholar
  59. Eyre DR, Dickson IR, Van Ness K. Collagen cross-linking in human bone and articular cartilage. Age-related changes in the content of mature hydroxypyridinium residues. Biochem J. 1988;252(2):495–500.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Fernandez-Moure JS, et al. Enhanced osteogenic potential of mesenchymal stem cells from cortical bone: a comparative analysis. Stem Cell Res Ther. 2015;6(1):1–13.CrossRefGoogle Scholar
  61. Fickert S, Fiedler J, Brenner RE. Identification of subpopulations with characteristics of mesenchymal progenitor cells from human osteoarthritic cartilage using triple staining for cell surface markers. Arthritis Res Ther. 2004;6(5):R422–32.PubMedPubMedCentralCrossRefGoogle Scholar
  62. Fodor J, et al. Store-operated calcium entry and calcium influx via voltage-operated calcium channels regulate intracellular calcium oscillations in chondrogenic cells. Cell Calcium. 2013;54(1):1–16.PubMedCrossRefGoogle Scholar
  63. Fong C-Y, et al. Derivation efficiency, cell proliferation, freeze–thaw survival, stem-cell properties and differentiation of human Wharton’s jelly stem cells. Reprod Biomed Online. 2010;21(3):391–401.PubMedCrossRefGoogle Scholar
  64. Friedenstein, A.J., Determined and Inducible Osteogenic Precursor Cells, in Ciba Foundation Symposium 11 - Hard Tissue Growth, Repair and Remineralization. 1973. p. 169–185.Google Scholar
  65. Friedenstein A, Chailakhjan R, Lalykina K. The development of fibroblast colonies in monolayer cultures of guinea‐pig bone marrow and spleen cells. Cell Prolif. 1970;3(4):393–403.CrossRefGoogle Scholar
  66. Gao X, et al. A comparison of bone regeneration with human mesenchymal stem cells and muscle-derived stem cells and the critical role of BMP. Biomaterials. 2014;35(25):6859–70.PubMedPubMedCentralCrossRefGoogle Scholar
  67. Gauthaman K, et al. Nanofibrous substrates support colony formation and maintain stemness of human embryonic stem cells. J Cell Mol Med. 2009;13(9b):3475–84.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Gauthaman K, et al. Extra-embryonic human Wharton’s jelly stem cells do not induce tumorigenesis, unlike human embryonic stem cells. Reprod Biomed Online. 2012;24(2):235–46.PubMedCrossRefGoogle Scholar
  69. Goldring MB, Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther. 2009;11(3):224.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Goldring MB, Tsuchimochi K, Ijiri K. The control of chondrogenesis. J Cell Biochem. 2006;97(1):33–44.PubMedCrossRefGoogle Scholar
  71. Gomoll AH, et al. Surgical treatment for early osteoarthritis. Part II: allografts and concurrent procedures. Knee Surg Sports Traumatol Arthrosc. 2012;20(3):468–86.PubMedCrossRefGoogle Scholar
  72. Grogan SP, et al. Mesenchymal progenitor cell markers in human articular cartilage: normal distribution and changes in osteoarthritis. Arthritis Res Ther. 2009;11(3):R85.PubMedPubMedCentralCrossRefGoogle Scholar
  73. Hangody L, et al. Mosaicplasty for the treatment of articular cartilage defects: application in clinical practice. Orthopedics. 1998;21(7):751–6.PubMedGoogle Scholar
  74. Hangody L, et al. Autologous osteochondral mosaicplasty. Surgical technique. J Bone Joint Surg Am. 2004;1:65–72.CrossRefGoogle Scholar
  75. Hardingham TE, Oldershaw RA, Tew SR. Cartilage, SOX9 and Notch signals in chondrogenesis. J Anat. 2006;209(4):469–80.PubMedPubMedCentralCrossRefGoogle Scholar
  76. Hendren L, Beeson P. A review of the differences between normal and osteoarthritis articular cartilage in human knee and ankle joints. The Foot. 2009;19(3):171–6.PubMedCrossRefGoogle Scholar
  77. Heng BC, et al. An autologous cell lysate extract from human embryonic stem cell (hESC) derived osteoblasts can enhance osteogenesis of hESC. Tissue Cell. 2008;40(3):219–28.PubMedCrossRefGoogle Scholar
  78. Horton WE, Jr., Bennion P, Yang L. Cellular, molecular, and matrix changes in cartilage during aging and osteoarthritis. J Musculoskelet Neuronal Interact. 2006;6(4):379–81.Google Scholar
  79. Hou S, et al. Coating of hydrophobins on three-dimensional electrospun poly (lactic-co-glycolic acid) scaffolds for cell adhesion. Biofabrication. 2009;1(3):035004.PubMedCrossRefGoogle Scholar
  80. Hunziker EB, 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. 2007;15(4):403–13.PubMedCrossRefGoogle Scholar
  81. Hutmacher DW. Scaffolds in tissue engineering bone and cartilage. Biomaterials. 2000;21(24):2529–43.PubMedCrossRefGoogle Scholar
  82. Jakob RP, et al. Autologous osteochondral grafting in the knee: indication, results, and reflections. Clin Orthop Relat Res. 2002;401:170–84.CrossRefGoogle Scholar
  83. Javed F, et al. Implant surface morphology and primary stability: is there a connection? Implant Dent. 2011;20(1):40–6.PubMedCrossRefGoogle Scholar
  84. Jeffery AK, et al. 3-dimensional collagen architecture in bovine articular-cartilage. J Bone Joint Surg Br. 1991;73(5):795–801.PubMedGoogle Scholar
  85. Jin HJ, et al. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci. 2013;14(9):17986–8001.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Jones EA, et al. Synovial fluid mesenchymal stem cells in health and early osteoarthritis: detection and functional evaluation at the single-cell level. Arthritis Rheum. 2008;58(6):1731–40.PubMedCrossRefGoogle Scholar
  87. Jukes JM, et al. Endochondral bone tissue engineering using embryonic stem cells. Proc Natl Acad Sci. 2008;105(19):6840–5.PubMedPubMedCentralCrossRefGoogle Scholar
  88. Kalbacova M, et al. Graphene substrates promote adherence of human osteoblasts and mesenchymal stromal cells. Carbon. 2010;48(15):4323–9.CrossRefGoogle Scholar
  89. Kang R, et al. Mesenchymal stem cells derived from human induced pluripotent stem cells retain adequate osteogenicity and chondrogenicity but less adipogenicity. Stem cell Res Ther. 2015;6(1):1–14.CrossRefGoogle Scholar
  90. Karlsson C, et al. Identification of a stem cell niche in the zone of Ranvier within the knee joint. J Anat. 2009;215(3):355–63.PubMedPubMedCentralCrossRefGoogle Scholar
  91. Kawaguchi J, Mee PJ, Smith AG. Osteogenic and chondrogenic differentiation of embryonic stem cells in response to specific growth factors. Bone. 2005;36(5):758–69.PubMedCrossRefGoogle Scholar
  92. Khan WS, et al. Human infrapatellar fat pad-derived stem cells express the pericyte marker 3G5 and show enhanced chondrogenesis after expansion in fibroblast growth factor-2. Arthritis Res Ther. 2008;10(4):3.CrossRefGoogle Scholar
  93. Kim S, et al. In vivo bone formation from human embryonic stem cell-derived osteogenic cells in poly (d, l-lactic-co-glycolic acid)/hydroxyapatite composite scaffolds. Biomaterials. 2008a;29(8):1043–53.PubMedCrossRefGoogle Scholar
  94. Kim YJ, Kim HJ, Im GI. PTHrP promotes chondrogenesis and suppresses hypertrophy from both bone marrow-derived and adipose tissue-derived MSCs. Biochem Biophys Res Commun. 2008b;373(1):104–8.PubMedCrossRefGoogle Scholar
  95. Knudson CB, Knudson W. Cartilage proteoglycans. Semin Cell Dev Biol. 2001;12(2):69–78.PubMedCrossRefGoogle Scholar
  96. Knutsen G, et al. A randomized trial comparing autologous chondrocyte implantation with microfracture. Findings at five years. J Bone Joint Surg Am. 2007;89(10):2105–12.PubMedGoogle Scholar
  97. Kramer J, et al. Embryonic stem cell-derived chondrogenic differentiation in vitro: activation by BMP-2 and BMP-4. Mech Dev. 2000;92(2):193–205.PubMedCrossRefGoogle Scholar
  98. Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423(6937):332–6.PubMedCrossRefGoogle Scholar
  99. Kurth TB, et al. Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum. 2011;63(5):1289–300.PubMedCrossRefGoogle Scholar
  100. Lafont JE, Talma S, Murphy CL. Hypoxia-inducible factor 2alpha is essential for hypoxic induction of the human articular chondrocyte phenotype. Arthritis Rheum. 2007;56(10):3297–306.PubMedCrossRefGoogle Scholar
  101. Lajeunesse D, Reboul P. Subchondral bone in osteoarthritis: a biologic link with articular cartilage leading to abnormal remodeling. Curr Opin Rheumatol. 2003;15(5):628–33.PubMedCrossRefGoogle Scholar
  102. Lajeunesse D, et al. Subchondral bone sclerosis in osteoarthritis: not just an innocent bystander. Mod Rheumatol. 2003;13(1):0007–14.CrossRefGoogle Scholar
  103. Le Graverand MP, et al. Change in regional cartilage morphology and joint space width in osteoarthritis participants versus healthy controls: a multicentre study using 3.0 Tesla MRI and Lyon-Schuss radiography. Ann Rheum Dis. 2010;69(1):155–62.PubMedCrossRefGoogle Scholar
  104. LeBaron RG, Athanasiou KA. Ex vivo synthesis of articular cartilage. Biomaterials. 2000;21(24):2575–87.PubMedCrossRefGoogle Scholar
  105. Lee RB, Urban JP. Evidence for a negative Pasteur effect in articular cartilage. Biochem J. 1997;321(Pt 1):95–102.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Lee C, et al. Measurement of the elastic properties and intrinsic strength of monolayer graphene. Science. 2008;321(5887):385–8.Google Scholar
  107. Lee WC, et al. Origin of enhanced stem cell growth and differentiation on graphene and graphene oxide. ACS Nano. 2011;5(9):7334–41.PubMedCrossRefGoogle Scholar
  108. Lefebvre V, Behringer RR, de Crombrugghe B. L-Sox5, Sox6 and Sox9 control essential steps of the chondrocyte differentiation pathway. Osteoarthr Cartil. 2001;(9 Suppl A):S69–75.Google Scholar
  109. Li W, et al. Formation of controllable hydrophilic/hydrophobic drug-delivery systems by electrospinning of vesicles. Langmuir. 2015;31:5141–6.PubMedCrossRefGoogle Scholar
  110. Liu X, Ma PX. Polymeric scaffolds for bone tissue engineering. Ann Biomed Eng. 2004;32(3):477–86.PubMedCrossRefGoogle Scholar
  111. Lovati AB, et al. Tenogenic differentiation of equine mesenchymal progenitor cells under indirect co-culture. Int J Artif Organs. 2012;35(11):996–1005.PubMedCrossRefGoogle Scholar
  112. Martel-Pelletier J, Pelletier JP. Is osteoarthritis a disease involving only cartilage or other articular tissues? Eklem Hastalik Cerrahisi. 2010;21(1):2–14.PubMedGoogle Scholar
  113. Martin R. Toward a unifying theory of bone remodeling. Bone. 2000;26(1):1–6.PubMedCrossRefGoogle Scholar
  114. Martin JA, Buckwalter JA. Aging, articular cartilage chondrocyte senescence and osteoarthritis. Biogerontology. 2002;3(5):257–64.PubMedCrossRefGoogle Scholar
  115. Mason DJ. The role of glutamate transporters in bone cell signalling. J Musculoskelet Neuronal Interact. 2004;4(2):128.PubMedGoogle Scholar
  116. Mason D, et al. Mechanically regulated expression of a neural glutamate transporter in bone: a role for excitatory amino acids as osteotropic agents? Bone. 1997;20(3):199–205.PubMedCrossRefGoogle Scholar
  117. Matta C, Mobasheri A. Regulation of chondrogenesis by protein kinase C: emerging new roles in calcium signalling. Cell Signal. 2014;26(5):979–1000.PubMedCrossRefGoogle Scholar
  118. Matta C, et al. Cytosolic free Ca2+ concentration exhibits a characteristic temporal pattern during in vitro cartilage differentiation: a possible regulatory role of calcineurin in Ca-signalling of chondrogenic cells. Cell Calcium. 2008;44(3):310–23.PubMedCrossRefGoogle Scholar
  119. Matta C, Zakany R. Calcium signalling in chondrogenesis: implications for cartilage repair. Front Biosci (Schol Ed). 2013;5:305–24.Google Scholar
  120. Matta C, et al. Ser/Thr-phosphoprotein phosphatases in chondrogenesis: neglected components of a two-player game. Cell Signal. 2014;26(10):2175–85.PubMedCrossRefGoogle Scholar
  121. Matta C, Zakany R, Mobasheri A. Voltage-dependent calcium channels in chondrocytes: roles in health and disease. Curr Rheumatol Rep. 2015;17(7):43.PubMedCrossRefGoogle Scholar
  122. Mihaila SM, et al. The osteogenic differentiation of SSEA-4 sub-population of human adipose derived stem cells using silicate nanoplatelets. Biomaterials. 2014;35(33):9087–99.PubMedCrossRefGoogle Scholar
  123. Mobasheri A, et al. Potassium channels in articular chondrocytes. Channels (Austin). 2012;6(6):416–25.CrossRefGoogle Scholar
  124. Moore M, et al. Characterization of human bone marrow fibroblast colony-forming cells. Blood. 1980;56(2):289.PubMedGoogle Scholar
  125. Nakano N, et al. Characterization of conditioned medium of cultured bone marrow stromal cells. Neurosci Lett. 2010;483(1):57–61.PubMedCrossRefGoogle Scholar
  126. Nelson L, et al. Evidence of a viable pool of stem cells within human osteoarthritic cartilage. Cartilage. 2014;5:203–14.PubMedPubMedCentralCrossRefGoogle Scholar
  127. Otto F, et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. 1997;89(5):765–71.PubMedCrossRefGoogle Scholar
  128. Pearle AD, Warren RF, Rodeo SA. Basic science of articular cartilage and osteoarthritis. Clin Sports Med. 2005;24(1):1–12.PubMedCrossRefGoogle Scholar
  129. Peng L, et al. Comparative analysis of mesenchymal stem cells from bone marrow, cartilage, and adipose tissue. Stem Cells Dev. 2008;17(4):761–74.PubMedCrossRefGoogle Scholar
  130. Peterson L, et al. Autologous chondrocyte implantation: a long-term follow-up. Am J Sports Med. 2010;38(6):1117–24.PubMedCrossRefGoogle Scholar
  131. Pittenger MF, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999;284(5411):143–7.PubMedCrossRefGoogle Scholar
  132. Poole AR, et al. Association of an extracellular protein (chondrocalcin) with the calcification of cartilage in endochondral bone formation. J Cell Biol. 1984;98(1):54–65.PubMedCrossRefGoogle Scholar
  133. Poole CA, Flint MH, Beaumont BW. Chondrons in cartilage: ultrastructural analysis of the pericellular microenvironment in adult human articular cartilages. J Orthop Res. 1987;5(4):509–22.PubMedCrossRefGoogle Scholar
  134. Poole CA, Matsuoka A, Schofield JR. Chondrons from articular cartilage. III. Morphologic changes in the cellular microenvironment of chondrons isolated from osteoarthritic cartilage. Arthritis Rheum. 1991;34(1):22–35.PubMedCrossRefGoogle Scholar
  135. Poole AR, et al. Composition and structure of articular cartilage: a template for tissue repair. Clin Orthop Relat Res. 2001;391(Suppl):S26–33.CrossRefGoogle Scholar
  136. Pretzel D, et al. Relative percentage and zonal distribution of mesenchymal progenitor cells in human osteoarthritic and normal cartilage. Arthritis Res Ther. 2011;13(2):R64.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Ramamoorthi M, et al. Osteogenic potential of dental mesenchymal stem cells in preclinical studies: a systematic review using modified ARRIVE and CONSORT guidelines. Stem Cells Int. 2015;2015:378368.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Redman SN, Oldfield SF, Archer CW. Current strategies for articular cartilage repair. Eur Cell Mater. 2005;9:23–32.PubMedCrossRefGoogle Scholar
  139. Revell PA, et al. Metabolic activity in the calcified zone of cartilage: observations on tetracycline labelled articular cartilage in human osteoarthritic hips. Rheumatol Int. 1990;10(4):143–7.PubMedCrossRefGoogle Scholar
  140. Riekstina U, et al. Characterization of human skin-derived mesenchymal stem cell proliferation rate in different growth conditions. Cytotechnology. 2008;58(3):153–62.PubMedCrossRefGoogle Scholar
  141. Roberts S, et al. Autologous chondrocyte implantation for cartilage repair: monitoring its success by magnetic resonance imaging and histology. Arthritis Res Ther. 2002;5(1):1–14.Google Scholar
  142. Ronn K, et al. Current surgical treatment of knee osteoarthritis. Arthritis. 2011. doi: 10.1155/2011/454873.PubMedPubMedCentralGoogle Scholar
  143. Rothwell AG, Bentley G. Chondrocyte multiplication in osteoarthritic articular cartilage. J Bone Joint Surg Br. 1973;55(3):588–94.PubMedGoogle Scholar
  144. Sahota O, Morgan N, Moran C. The direct cost of acute hip fracture care in care home residents in the UK. Osteoporos Int. 2012;23(3):917–20.PubMedCrossRefGoogle Scholar
  145. Schulze-Tanzil G, et al. Loss of chondrogenic potential in dedifferentiated chondrocytes correlates with deficient Shc-Erk interaction and apoptosis. Osteoarthritis Cartilage. 2004;12(6):448–58.PubMedCrossRefGoogle Scholar
  146. Serre C, et al. Evidence for a dense and intimate innervation of the bone tissue, including glutamate-containing fibers. Bone. 1999;25(6):623–9.PubMedCrossRefGoogle Scholar
  147. Shakibaei M, et al. Signal transduction by beta1 integrin receptors in human chondrocytes in vitro: collaboration with the insulin-like growth factor-I receptor. Biochem J. 1999;342(Pt 3):615–23.PubMedPubMedCentralCrossRefGoogle Scholar
  148. Shakibaei M, et al. Inhibition of mitogen-activated protein kinase kinase induces apoptosis of human chondrocytes. J Biol Chem. 2001;276(16):13289–94.PubMedCrossRefGoogle Scholar
  149. Shakibaei M, et al. Igf-I extends the chondrogenic potential of human articular chondrocytes in vitro: molecular association between Sox9 and Erk1/2. Biochem Pharmacol. 2006;72(11):1382–95.PubMedCrossRefGoogle Scholar
  150. Shakibaei M, Buhrmann C, Mobasheri A. Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB signaling and inhibit osteoclastogenesis in bone-derived cells. J Biol Chem. 2011;286(13):11492–505.PubMedPubMedCentralCrossRefGoogle Scholar
  151. Shakibaei M, et al. Resveratrol mediated modulation of Sirt-1/Runx2 promotes osteogenic differentiation of mesenchymal stem cells: potential role of Runx2 deacetylation. PLoS One. 2012;7(4), e35712.PubMedPubMedCentralCrossRefGoogle Scholar
  152. Sharif M, George E, Dieppe PA. Correlation between synovial fluid markers of cartilage and bone turnover and scintigraphic scan abnormalities in osteoarthritis of the knee. Arthritis Rheum. 1995;38(1):78–81.PubMedCrossRefGoogle Scholar
  153. Song B, Estrada KD, Lyons KM. Smad signaling in skeletal development and regeneration. Cytokine Growth Factor Rev. 2009;20(5-6):379–88.PubMedPubMedCentralCrossRefGoogle Scholar
  154. Sottile V, Thomson A, McWhir J. In vitro osteogenic differentiation of human ES cells. Cloning Stem Cells. 2003;5(2):149–55.PubMedCrossRefGoogle Scholar
  155. Steadman JR, et al. Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up. Arthroscopy. 2003;19(5):477–84.PubMedCrossRefGoogle Scholar
  156. Stoddart MJ, et al. Cells and biomaterials in cartilage tissue engineering. Regen Med. 2009;4(1):81–98.PubMedCrossRefGoogle Scholar
  157. Thonar EJ, Buckwalter JA, Kuettner KE. Maturation-related differences in the structure and composition of proteoglycans synthesized by chondrocytes from bovine articular cartilage. J Biol Chem. 1986;261(5):2467–74.PubMedGoogle Scholar
  158. Tremoleda J, et al. Bone tissue formation from human embryonic stem cells in vivo. Cloning Stem Cells. 2008;10(1):119–32.PubMedCrossRefGoogle Scholar
  159. Tuan RS, Chen AF, Klatt BA. Cartilage regeneration. J Am Acad Orthop Surg. 2013;21(5):303–11.PubMedPubMedCentralGoogle Scholar
  160. Urban JP. The chondrocyte: a cell under pressure. Br J Rheumatol. 1994;33(10):901–8.PubMedCrossRefGoogle Scholar
  161. Van Assche D, et al. Autologous chondrocyte implantation versus microfracture for knee cartilage injury: a prospective randomized trial, with 2-year follow-up. Knee Surg Sports Traumatol Arthrosc. 2010;18(4):486–95.PubMedCrossRefGoogle Scholar
  162. van de Putte KA, Urist MR. 23 Osteogenesis in the interior of intramuscular implants of decalcified bone matrix. Clin Orthop Relat Res. 1965;43:257–70.PubMedCrossRefGoogle Scholar
  163. Visna P, et al. Treatment of deep cartilage defects of the knee using autologous chondrograft transplantation and by abrasive techniques–a randomized controlled study. Acta Chir Belg. 2004;104(6):709–14.PubMedCrossRefGoogle Scholar
  164. Wang R, et al. Light-induced amphiphilic surfaces. Nature. 1997;388:431–2.CrossRefGoogle Scholar
  165. Wang Y, Zhao L, Hantash BM. Support of human adipose-derived mesenchymal stem cell multipotency by a poloxamer-octapeptide hybrid hydrogel. Biomaterials. 2010;31(19):5122–30.PubMedCrossRefGoogle Scholar
  166. Wary KK, et al. The adaptor protein Shc couples a class of integrins to the control of cell cycle progression. Cell. 1996;87(4):733–43.PubMedCrossRefGoogle Scholar
  167. Williams R, et al. Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PLoS One. 2010;5(10), e13246.PubMedPubMedCentralCrossRefGoogle Scholar
  168. Witkowska-Zimny M, Wrobel E, Mrowka P. α2β1 integrin-mediated mechanical signals during osteodifferentiation of stem cells from the Wharton’s jelly of the umbilical cord. Folia Histochem Cytobiol. 2014;52(4):297–307.PubMedCrossRefGoogle Scholar
  169. Yamada K, et al. Subchondral bone of the human knee joint in aging and osteoarthritis. Osteoarthritis Cartilage. 2002;10(5):360–9.PubMedCrossRefGoogle Scholar
  170. Yen YM, et al. Treatment of osteoarthritis of the knee with microfracture and rehabilitation. Med Sci Sports Exerc. 2008;40(2):200–5.PubMedCrossRefGoogle Scholar
  171. Yoon BS, Lyons KM. Multiple functions of BMPs in chondrogenesis. J Cell Biochem. 2004;93(1):93–103.PubMedCrossRefGoogle Scholar
  172. Yoon YM, et al. Protein kinase A regulates chondrogenesis of mesenchymal cells at the post-precartilage condensation stage via protein kinase C-alpha signaling. J Bone Miner Res. 2000;15(11):2197–205.PubMedCrossRefGoogle Scholar
  173. Zhang Y, et al. Electrospun biomimetic nanocomposite nanofibers of hydroxyapatite/chitosan for bone tissue engineering. Biomaterials. 2008;29(32):4314–22.PubMedCrossRefGoogle Scholar
  174. Zur Nieden NI, Kempka G, Ahr HJ. In vitro differentiation of embryonic stem cells into mineralized osteoblasts. Differentiation. 2003;71(1):18–27.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Christopher R. Fellows
    • 1
  • Kalamegam Gauthaman
    • 2
    • 3
  • Peter N. Pushparaj
    • 2
  • Mohammed Abbas
    • 3
  • Csaba Matta
    • 1
    • 4
  • Rebecca Lewis
    • 1
  • Constanze Buhrmann
    • 5
  • Mehdi Shakibaei
    • 5
  • Ali Mobasheri
    • 1
    • 2
    • 6
    Email author
  1. 1.Department of Veterinary Preclinical Sciences, School of Veterinary Medicine, Faculty of Health and Medical SciencesUniversity of SurreyGuildfordUK
  2. 2.Center of Excellence in Genomic Medicine Research (CEGMR)King Abdulaziz UniversityJeddahSaudi Arabia
  3. 3.Sheikh Salem Bin Mahfouz Scientific Chair for Treatment of Osteoarthritis by Stem CellsKing Abdulaziz UniversityJeddahSaudi Arabia
  4. 4.Department of Anatomy, Histology and Embryology, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  5. 5.Institute of AnatomyLudwig-Maximilians-University MunichMunichGermany
  6. 6.Arthritis Research UK Centre for Sport, Exercise and Osteoarthritis, Arthritis Research UK Pain Centre, Medical Research Council and Arthritis Research UK Centre for Musculoskeletal Ageing ResearchQueen’s Medical CentreNottinghamUK

Personalised recommendations