Skip to main content

Advertisement

SpringerLink
Log in

Articular cartilage tissue engineering: the role of signaling molecules

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Effective early disease modifying options for osteoarthritis remain lacking. Tissue engineering approach to generate cartilage in vitro has emerged as a promising option for articular cartilage repair and regeneration. Signaling molecules and matrix modifying agents, derived from knowledge of cartilage development and homeostasis, have been used as biochemical stimuli toward cartilage tissue engineering and have led to improvements in the functionality of engineered cartilage. Clinical translation of neocartilage faces challenges, such as phenotypic instability of the engineered cartilage, poor integration, inflammation, and catabolic factors in the arthritic environment; these can all contribute to failure of implanted neocartilage. A comprehensive understanding of signaling molecules involved in osteoarthritis pathogenesis and their actions on engineered cartilage will be crucial. Thus, while it is important to continue deriving inspiration from cartilage development and homeostasis, it has become increasingly necessary to incorporate knowledge from osteoarthritis pathogenesis into cartilage tissue engineering.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Hootman JM, Helmick CG (2006) Projections of US prevalence of arthritis and associated activity limitations. Arthritis Rheum 54(1):226–229

    Article  PubMed  Google Scholar 

  2. Centers for Disease Control and Prevention (2013) Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation—United States, 2010–2012. MMWR Morb Mortal Wkly Rep 62(44):869–873

    Google Scholar 

  3. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, Gabriel S, Hirsch R, Hochberg MC, Hunder GG, Jordan JM, Katz JN, Kremers HM, Wolfe F, National Arthritis Data W (2008) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 58(1):26–35. doi:10.1002/art.23176

    Article  PubMed Central  PubMed  Google Scholar 

  4. Shah MR, Kaplan KM, Meislin RJ, Bosco JA 3rd (2007) Articular cartilage restoration of the knee. Bull NYU Hosp Jt Dis 65(1):51–60

    PubMed  Google Scholar 

  5. Smith GD, Knutsen G, Richardson JB (2005) A clinical review of cartilage repair techniques. J Bone Joint Surg 87(4):445–449

    Article  CAS  Google Scholar 

  6. Wieland HA, Michaelis M, Kirschbaum BJ, Rudolphi KA (2005) Osteoarthritis—an untreatable disease? Nat Rev 4(4):331–344

    CAS  Google Scholar 

  7. Elder SH, Cooley AJ Jr, Borazjani A, Sowell BL, To H, Tran SC (2009) Production of hyaline-like cartilage by bone marrow mesenchymal stem cells in a self-assembly model. Tissue Eng Part A 15(10):3025–3036. doi:10.1089/ten.TEA.2008.0617

    Article  CAS  PubMed  Google Scholar 

  8. Hu JC, Athanasiou KA (2006) A self-assembling process in articular cartilage tissue engineering. Tissue Eng 12(4):969–979. doi:10.1089/ten.2006.12.969

    Article  CAS  PubMed  Google Scholar 

  9. Grande DA, Halberstadt C, Naughton G, Schwartz R, Manji R (1997) Evaluation of matrix scaffolds for tissue engineering of articular cartilage grafts. J Biomed Mater Res 34(2):211–220

    Article  CAS  PubMed  Google Scholar 

  10. DeLise AM, Fischer L, Tuan RS (2000) Cellular interactions and signaling in cartilage development. Osteoarthritis Cartilage 8(5):309–334. doi:10.1053/joca.1999.0306

    Article  CAS  PubMed  Google Scholar 

  11. Hall BK, Miyake T (1995) Divide, accumulate, differentiate: cell condensation in skeletal development revisited. Int J Dev Biol 39(6):881–893

    CAS  PubMed  Google Scholar 

  12. Demoor M, Ollitrault D, Gomez-Leduc T, Bouyoucef M, Hervieu M, Fabre H, Lafont J, Denoix JM, Audigie F, Mallein-Gerin F, Legendre F (1840) Galera P (2014) Cartilage tissue engineering: molecular control of chondrocyte differentiation for proper cartilage matrix reconstruction. Biochim Biophys Acta 8:2414–2440. doi:10.1016/j.bbagen.2014.02.030

    Google Scholar 

  13. Athanasiou KA, Darling Eric M, DuRaine Grayson D, Hu Jerry C, Hari Reddi A (2013) Articular cartilage. CRC Press, Boca Raton

    Google Scholar 

  14. Umlauf D, Frank S, Pap T, Bertrand J (2010) Cartilage biology, pathology, and repair. Cell Mol Life Sci 67(24):4197–4211. doi:10.1007/s00018-010-0498-0

    Article  CAS  PubMed  Google Scholar 

  15. de Caestecker M (2004) The transforming growth factor-beta superfamily of receptors. Cytokine Growth Factor Rev 15(1):1–11

    Article  PubMed  CAS  Google Scholar 

  16. Ferguson CM, Schwarz EM, Reynolds PR, Puzas JE, Rosier RN, O’Keefe RJ (2000) Smad2 and 3 mediate transforming growth factor-beta1-induced inhibition of chondrocyte maturation. Endocrinology 141(12):4728–4735. doi:10.1210/endo.141.12.7848

    CAS  PubMed  Google Scholar 

  17. Furumatsu T, Tsuda M, Taniguchi N, Tajima Y, Asahara H (2005) Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment. J Biol Chem 280(9):8343–8350. doi:10.1074/jbc.M413913200

    Article  CAS  PubMed  Google Scholar 

  18. Li J, Zhao Z, Liu J, Huang N, Long D, Wang J, Li X, Liu Y (2010) MEK/ERK and p38 MAPK regulate chondrogenesis of rat bone marrow mesenchymal stem cells through delicate interaction with TGF-beta1/Smads pathway. Cell Prolif 43(4):333–343. doi:10.1111/j.1365-2184.2010.00682.x

    Article  CAS  PubMed  Google Scholar 

  19. Pogue R, Lyons K (2006) BMP signaling in the cartilage growth plate. Curr Top Dev Biol 76:1–48. doi:10.1016/S0070-2153(06)76001-X

    Article  CAS  PubMed  Google Scholar 

  20. Chimal-Monroy J, Diaz de Leon L (1999) Expression of N-cadherin, N-CAM, fibronectin and tenascin is stimulated by TGF-beta1, beta2, beta3 and beta5 during the formation of precartilage condensations. Int J Dev Biol 43(1):59–67

    CAS  PubMed  Google Scholar 

  21. Tuli R, Tuli S, Nandi S, Huang X, Manner PA, Hozack WJ, Danielson KG, Hall DJ, Tuan RS (2003) Transforming growth factor-beta-mediated chondrogenesis of human mesenchymal progenitor cells involves N-cadherin and mitogen-activated protein kinase and Wnt signaling cross-talk. J Biol Chem 278(42):41227–41236. doi:10.1074/jbc.M305312200

    Article  CAS  PubMed  Google Scholar 

  22. Oberlender SA, Tuan RS (1994) Expression and functional involvement of N-cadherin in embryonic limb chondrogenesis. Development 120(1):177–187

    CAS  PubMed  Google Scholar 

  23. Widelitz RB, Jiang TX, Murray BA, Chuong CM (1993) Adhesion molecules in skeletogenesis: II. Neural cell adhesion molecules mediate precartilaginous mesenchymal condensations and enhance chondrogenesis. J Cell Physiol 156(2):399–411. doi:10.1002/jcp.1041560224

    Article  CAS  PubMed  Google Scholar 

  24. Frenz DA, Jaikaria NS, Newman SA (1989) The mechanism of precartilage mesenchymal condensation: a major role for interaction of the cell surface with the amino-terminal heparin-binding domain of fibronectin. Dev Biol 136(1):97–103

    Article  CAS  PubMed  Google Scholar 

  25. Darling EM, Athanasiou KA (2005) Growth factor impact on articular cartilage subpopulations. Cell Tissue Res 322(3):463–473. doi:10.1007/s00441-005-0020-4

    Article  CAS  PubMed  Google Scholar 

  26. Kulyk WM, Rodgers BJ, Greer K, Kosher RA (1989) Promotion of embryonic chick limb cartilage differentiation by transforming growth factor-beta. Dev Biol 135(2):424–430

    Article  CAS  PubMed  Google Scholar 

  27. Furumatsu T, Ozaki T, Asahara H (2009) Smad3 activates the Sox9-dependent transcription on chromatin. Int J Biochem Cell Biol 41(5):1198–1204. doi:10.1016/j.biocel.2008.10.032

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Zhang X, Ziran N, Goater JJ, Schwarz EM, Puzas JE, Rosier RN, Zuscik M, Drissi H, O’Keefe RJ (2004) Primary murine limb bud mesenchymal cells in long-term culture complete chondrocyte differentiation: TGF-beta delays hypertrophy and PGE2 inhibits terminal differentiation. Bone 34(5):809–817. doi:10.1016/j.bone.2003.12.026

    Article  CAS  PubMed  Google Scholar 

  29. Yang X, Chen L, Xu X, Li C, Huang C, Deng CX (2001) TGF-beta/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol 153(1):35–46

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Jonason JH, Xiao G, Zhang M, Xing L, Chen D (2009) Post-translational regulation of Runx2 in bone and cartilage. J Dent Res 88(8):693–703. doi:10.1177/0022034509341629

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Alliston T, Choy L, Ducy P, Karsenty G, Derynck R (2001) TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation. EMBO J 20(9):2254–2272. doi:10.1093/emboj/20.9.2254

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Nakamura K, Shirai T, Morishita S, Uchida S, Saeki-Miura K, Makishima F (1999) p38 mitogen-activated protein kinase functionally contributes to chondrogenesis induced by growth/differentiation factor-5 in ATDC5 cells. Exp Cell Res 250(2):351–363. doi:10.1006/excr.1999.4535

    Article  CAS  PubMed  Google Scholar 

  33. Zehentner BK, Dony C, Burtscher H (1999) The transcription factor Sox9 is involved in BMP-2 signaling. J Bone Miner Res 14(10):1734–1741. doi:10.1359/jbmr.1999.14.10.1734

    Article  CAS  PubMed  Google Scholar 

  34. Fernandez-Lloris R, Vinals F, Lopez-Rovira T, Harley V, Bartrons R, Rosa JL, Ventura F (2003) Induction of the Sry-related factor SOX6 contributes to bone morphogenetic protein-2-induced chondroblastic differentiation of C3H10T1/2 cells. Mol Endocrinol 17(7):1332–1343. doi:10.1210/me.2002-0254

    Article  CAS  PubMed  Google Scholar 

  35. Yoon BS, Ovchinnikov DA, Yoshii I, Mishina Y, Behringer RR, Lyons KM (2005) Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo. Proc Natl Acad Sci USA 102(14):5062–5067. doi:10.1073/pnas.0500031102

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Liao J, Hu N, Zhou N, Lin L, Zhao C, Yi S, Fan T, Bao W, Liang X, Chen H, Xu W, Chen C, Cheng Q, Zeng Y, Si W, Yang Z, Huang W (2014) Sox9 potentiates BMP2-induced chondrogenic differentiation and inhibits BMP2-induced osteogenic differentiation. PLoS One 9(2):e89025. doi:10.1371/journal.pone.0089025

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  37. De Luca F, Barnes KM, Uyeda JA, De-Levi S, Abad V, Palese T, Mericq V, Baron J (2001) Regulation of growth plate chondrogenesis by bone morphogenetic protein-2. Endocrinology 142(1):430–436. doi:10.1210/endo.142.1.7901

    PubMed  Google Scholar 

  38. Tsumaki N, Nakase T, Miyaji T, Kakiuchi M, Kimura T, Ochi T, Yoshikawa H (2002) Bone morphogenetic protein signals are required for cartilage formation and differently regulate joint development during skeletogenesis. J Bone Miner Res 17(5):898–906. doi:10.1359/jbmr.2002.17.5.898

    Article  CAS  PubMed  Google Scholar 

  39. Leboy P, Grasso-Knight G, D’Angelo M, Volk SW, Lian JV, Drissi H, Stein GS, Adams SL (2001) Smad–Runx interactions during chondrocyte maturation. J Bone Joint Surg Am 83-A Suppl 1(Pt 1):S15–S22

    CAS  PubMed  Google Scholar 

  40. Miljkovic ND, Cooper GM, Marra KG (2008) Chondrogenesis, bone morphogenetic protein-4 and mesenchymal stem cells. Osteoarthritis Cartilage 16(10):1121–1130. doi:10.1016/j.joca.2008.03.003

    Article  CAS  PubMed  Google Scholar 

  41. Danisovic L, Varga I, Polak S (2012) Growth factors and chondrogenic differentiation of mesenchymal stem cells. Tissue Cell 44(2):69–73. doi:10.1016/j.tice.2011.11.005

    Article  CAS  PubMed  Google Scholar 

  42. Chubinskaya S, Hurtig M, Rueger DC (2007) OP-1/BMP-7 in cartilage repair. Int Orthop 31(6):773–781. doi:10.1007/s00264-007-0423-9

    Article  PubMed Central  PubMed  Google Scholar 

  43. Erlacher L, McCartney J, Piek E, ten Dijke P, Yanagishita M, Oppermann H, Luyten FP (1998) Cartilage-derived morphogenetic proteins and osteogenic protein-1 differentially regulate osteogenesis. J Bone Miner Res 13(3):383–392. doi:10.1359/jbmr.1998.13.3.383

    Article  CAS  PubMed  Google Scholar 

  44. Takahara M, Harada M, Guan D, Otsuji M, Naruse T, Takagi M, Ogino T (2004) Developmental failure of phalanges in the absence of growth/differentiation factor 5. Bone 35(5):1069–1076. doi:10.1016/j.bone.2004.06.020

    Article  CAS  PubMed  Google Scholar 

  45. Tsumaki N, Tanaka K, Arikawa-Hirasawa E, Nakase T, Kimura T, Thomas JT, Ochi T, Luyten FP, Yamada Y (1999) Role of CDMP-1 in skeletal morphogenesis: promotion of mesenchymal cell recruitment and chondrocyte differentiation. J Cell Biol 144(1):161–173

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Furumatsu T, Asahara H (2010) Histone acetylation influences the activity of Sox9-related transcriptional complex. Acta Med Okayama 64(6):351–357

    CAS  PubMed  Google Scholar 

  47. Akiyama H, Chaboissier MC, Martin JF, Schedl A, de Crombrugghe B (2002) The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 16(21):2813–2828. doi:10.1101/gad.1017802

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Lefebvre V, Li P, de Crombrugghe B (1998) A new long form of Sox5 (L-Sox5), Sox6 and Sox9 are coexpressed in chondrogenesis and cooperatively activate the type II collagen gene. EMBO J 17(19):5718–5733. doi:10.1093/emboj/17.19.5718

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Smits P, Li P, Mandel J, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B, Lefebvre V (2001) The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev Cell 1(2):277–290

    Article  CAS  PubMed  Google Scholar 

  50. Brent AE, Braun T, Tabin CJ (2005) Genetic analysis of interactions between the somitic muscle, cartilage and tendon cell lineages during mouse development. Development 132(3):515–528. doi:10.1242/dev.01605

    Article  CAS  PubMed  Google Scholar 

  51. Bi W, Huang W, Whitworth DJ, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B (2001) Haploinsufficiency of Sox9 results in defective cartilage primordia and premature skeletal mineralization. Proc Natl Acad Sci USA 98(12):6698–6703. doi:10.1073/pnas.111092198

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, Deng JM, Taketo MM, Nakamura T, Behringer RR, McCrea PD, de Crombrugghe B (2004) Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev 18(9):1072–1087. doi:10.1101/gad.1171104

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Leung VY, Gao B, Leung KK, Melhado IG, Wynn SL, Au TY, Dung NW, Lau JY, Mak AC, Chan D, Cheah KS (2011) SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet 7(11):e1002356. doi:10.1371/journal.pgen.1002356

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Zhou G, Zheng Q, Engin F, Munivez E, Chen Y, Sebald E, Krakow D, Lee B (2006) Dominance of SOX9 function over RUNX2 during skeletogenesis. Proc Natl Acad Sci USA 103(50):19004–19009. doi:10.1073/pnas.0605170103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Hattori T, Muller C, Gebhard S, Bauer E, Pausch F, Schlund B, Bosl MR, Hess A, Surmann-Schmitt C, von der Mark H, de Crombrugghe B, von der Mark K (2010) SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification. Development 137(6):901–911. doi:10.1242/dev.045203

    Article  CAS  PubMed  Google Scholar 

  56. Oh CD, Chun JS (2003) Signaling mechanisms leading to the regulation of differentiation and apoptosis of articular chondrocytes by insulin-like growth factor-1. J Biol Chem 278(38):36563–36571. doi:10.1074/jbc.M304857200

    Article  CAS  PubMed  Google Scholar 

  57. Schoenle E, Zapf J, Humbel RE, Froesch ER (1982) Insulin-like growth factor I stimulates growth in hypophysectomized rats. Nature 296(5854):252–253

    Article  CAS  PubMed  Google Scholar 

  58. Vetter U, Zapf J, Heit W, Helbing G, Heinze E, Froesch ER, Teller WM (1986) Human fetal and adult chondrocytes. Effect of insulinlike growth factors I and II, insulin, and growth hormone on clonal growth. J Clin Investig 77(6):1903–1908. doi:10.1172/JCI112518

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Longobardi L, O’Rear L, Aakula S, Johnstone B, Shimer K, Chytil A, Horton WA, Moses HL, Spagnoli A (2006) Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling. J Bone Miner Res 21(4):626–636. doi:10.1359/jbmr.051213

    Article  CAS  PubMed  Google Scholar 

  60. Renard E, Poree B, Chadjichristos C, Kypriotou M, Maneix L, Bigot N, Legendre F, Ollitrault D, De Crombrugghe B, Mallein-Gerin F, Moslemi S, Demoor M, Boumediene K, Galera P (2012) Sox9/Sox6 and Sp1 are involved in the insulin-like growth factor-I-mediated upregulation of human type II collagen gene expression in articular chondrocytes. J Mol Med 90(6):649–666. doi:10.1007/s00109-011-0842-3

    Article  CAS  PubMed  Google Scholar 

  61. Karsenty G, Kronenberg HM, Settembre C (2009) Genetic control of bone formation. Annu Rev Cell Dev Biol 25:629–648. doi:10.1146/annurev.cellbio.042308.113308

    Article  CAS  PubMed  Google Scholar 

  62. Yang L, Tsang KY, Tang HC, Chan D, Cheah KS (2014) Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci USA 111(33):12097–12102. doi:10.1073/pnas.1302703111

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  63. Wang E, Wang J, Chin E, Zhou J, Bondy CA (1995) Cellular patterns of insulin-like growth factor system gene expression in murine chondrogenesis and osteogenesis. Endocrinology 136(6):2741–2751. doi:10.1210/endo.136.6.7750499

    CAS  PubMed  Google Scholar 

  64. Wang Y, Cheng Z, Elalieh HZ, Nakamura E, Nguyen MT, Mackem S, Clemens TL, Bikle DD, Chang W (2011) IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway. J Bone Miner Res 26(7):1437–1446. doi:10.1002/jbmr.359

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Ornitz DM, Itoh N (2001) Fibroblast growth factors. Genome Biol 2(3):REVIEWS3005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Bellus GA, Gaudenz K, Zackai EH, Clarke LA, Szabo J, Francomano CA, Muenke M (1996) Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes. Nat Genet 14(2):174–176. doi:10.1038/ng1096-174

    Article  CAS  PubMed  Google Scholar 

  67. Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet JM, Maroteaux P, Le Merrer M, Munnich A (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371(6494):252–254. doi:10.1038/371252a0

    Article  CAS  PubMed  Google Scholar 

  68. Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, Winokur ST, Wasmuth JJ (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78(2):335–342

    Article  CAS  PubMed  Google Scholar 

  69. Wilkie AO, Slaney SF, Oldridge M, Poole MD, Ashworth GJ, Hockley AD, Hayward RD, David DJ, Pulleyn LJ, Rutland P et al (1995) Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome. Nat Genet 9(2):165–172. doi:10.1038/ng0295-165

    Article  CAS  PubMed  Google Scholar 

  70. Jabs EW, Li X, Scott AF, Meyers G, Chen W, Eccles M, Mao JI, Charnas LR, Jackson CE, Jaye M (1994) Jackson–Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2. Nat Genet 8(3):275–279. doi:10.1038/ng1194-275

    Article  CAS  PubMed  Google Scholar 

  71. Reardon W, Winter RM, Rutland P, Pulleyn LJ, Jones BM, Malcolm S (1994) Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome. Nat Genet 8(1):98–103. doi:10.1038/ng0994-98

    Article  CAS  PubMed  Google Scholar 

  72. Schell U, Hehr A, Feldman GJ, Robin NH, Zackai EH, de Die-Smulders C, Viskochil DH, Stewart JM, Wolff G, Ohashi H et al (1995) Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Hum Mol Genet 4(3):323–328

    Article  CAS  PubMed  Google Scholar 

  73. Muenke M, Schell U, Hehr A, Robin NH, Losken HW, Schinzel A, Pulleyn LJ, Rutland P, Reardon W, Malcolm S et al (1994) A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome. Nat Genet 8(3):269–274. doi:10.1038/ng1194-269

    Article  CAS  PubMed  Google Scholar 

  74. Ornitz DM, Marie PJ (2002) FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 16(12):1446–1465. doi:10.1101/gad.990702

    Article  CAS  PubMed  Google Scholar 

  75. Ito T, Sawada R, Fujiwara Y, Tsuchiya T (2008) FGF-2 increases osteogenic and chondrogenic differentiation potentials of human mesenchymal stem cells by inactivation of TGF-beta signaling. Cytotechnology 56(1):1–7. doi:10.1007/s10616-007-9092-1

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  76. Peters KG, Werner S, Chen G, Williams LT (1992) Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. Development 114(1):233–243

    CAS  PubMed  Google Scholar 

  77. Deng CX, Wynshaw-Boris A, Shen MM, Daugherty C, Ornitz DM, Leder P (1994) Murine FGFR-1 is required for early postimplantation growth and axial organization. Genes Dev 8(24):3045–3057

    Article  CAS  PubMed  Google Scholar 

  78. Murakami S, Kan M, McKeehan WL, de Crombrugghe B (2000) Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proc Natl Acad Sci USA 97(3):1113–1118

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  79. Ellman MB, Yan D, Ahmadinia K, Chen D, An HS, Im HJ (2013) Fibroblast growth factor control of cartilage homeostasis. J Cell Biochem 114(4):735–742. doi:10.1002/jcb.24418

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Valta MP, Hentunen T, Qu Q, Valve EM, Harjula A, Seppanen JA, Vaananen HK, Harkonen PL (2006) Regulation of osteoblast differentiation: a novel function for fibroblast growth factor 8. Endocrinology 147(5):2171–2182. doi:10.1210/en.2005-1502

    Article  CAS  PubMed  Google Scholar 

  81. Raucci A, Laplantine E, Mansukhani A, Basilico C (2004) Activation of the ERK1/2 and p38 mitogen-activated protein kinase pathways mediates fibroblast growth factor-induced growth arrest of chondrocytes. J Biol Chem 279(3):1747–1756. doi:10.1074/jbc.M310384200

    Article  CAS  PubMed  Google Scholar 

  82. Su N, Jin M, Chen L (2014) Role of FGF/FGFR signaling in skeletal development and homeostasis: learning from mouse models. Bone Res 2:14003. doi:10.1038/boneres.2014.3

    Article  PubMed Central  PubMed  Google Scholar 

  83. Delezoide AL, Benoist-Lasselin C, Legeai-Mallet L, Le Merrer M, Munnich A, Vekemans M, Bonaventure J (1998) Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification. Mech Dev 77(1):19–30

    Article  CAS  PubMed  Google Scholar 

  84. Liu Z, Lavine KJ, Hung IH, Ornitz DM (2007) FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev Biol 302(1):80–91. doi:10.1016/j.ydbio.2006.08.071

    Article  CAS  PubMed  Google Scholar 

  85. Hung IH, Yu K, Lavine KJ, Ornitz DM (2007) FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. Dev Biol 307(2):300–313. doi:10.1016/j.ydbio.2007.04.048

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Cleary MA, van Osch GJ, Brama PA, Hellingman CA, Narcisi R (2015) FGF, TGFbeta and Wnt crosstalk: embryonic to in vitro cartilage development from mesenchymal stem cells. J Tissue Eng Regen Med 9(4):332–342. doi:10.1002/term.1744

    Article  CAS  PubMed  Google Scholar 

  87. Schmal H, Zwingmann J, Fehrenbach M, Finkenzeller G, Stark GB, Sudkamp NP, Hartl D, Mehlhorn AT (2007) bFGF influences human articular chondrocyte differentiation. Cytotherapy 9(2):184–193. doi:10.1080/14653240601182846

    Article  CAS  PubMed  Google Scholar 

  88. Loeser RF, Pacione CA, Chubinskaya S (2003) The combination of insulin-like growth factor 1 and osteogenic protein 1 promotes increased survival of and matrix synthesis by normal and osteoarthritic human articular chondrocytes. Arthritis Rheum 48(8):2188–2196. doi:10.1002/art.11209

    Article  CAS  PubMed  Google Scholar 

  89. Loeser RF, Chubinskaya S, Pacione C, Im HJ (2005) Basic fibroblast growth factor inhibits the anabolic activity of insulin-like growth factor 1 and osteogenic protein 1 in adult human articular chondrocytes. Arthritis Rheum 52(12):3910–3917. doi:10.1002/art.21472

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  90. Yaeger PC, Masi TL, de Ortiz JL, Binette F, Tubo R, McPherson JM (1997) Synergistic action of transforming growth factor-beta and insulin-like growth factor-I induces expression of type II collagen and aggrecan genes in adult human articular chondrocytes. Exp Cell Res 237(2):318–325. doi:10.1006/excr.1997.3781

    Article  CAS  PubMed  Google Scholar 

  91. Claus S, Aubert-Foucher E, Demoor M, Camuzeaux B, Paumier A, Piperno M, Damour O, Duterque-Coquillaud M, Galera P, Mallein-Gerin F (2010) Chronic exposure of bone morphogenetic protein-2 favors chondrogenic expression in human articular chondrocytes amplified in monolayer cultures. J Cell Biochem 111(6):1642–1651. doi:10.1002/jcb.22897

    Article  CAS  PubMed  Google Scholar 

  92. Sailor LZ, Hewick RM, Morris EA (1996) Recombinant human bone morphogenetic protein-2 maintains the articular chondrocyte phenotype in long-term culture. J Orthop Res 14(6):937–945. doi:10.1002/jor.1100140614

    Article  CAS  PubMed  Google Scholar 

  93. Stewart MC, Saunders KM, Burton-Wurster N, Macleod JN (2000) Phenotypic stability of articular chondrocytes in vitro: the effects of culture models, bone morphogenetic protein 2, and serum supplementation. J Bone Miner Res 15(1):166–174. doi:10.1359/jbmr.2000.15.1.166

    Article  CAS  PubMed  Google Scholar 

  94. Lin L, Zhou C, Wei X, Hou Y, Zhao L, Fu X, Zhang J, Yu C (2008) Articular cartilage repair using dedifferentiated articular chondrocytes and bone morphogenetic protein 4 in a rabbit model of articular cartilage defects. Arthritis Rheum 58(4):1067–1075. doi:10.1002/art.23380

    Article  CAS  PubMed  Google Scholar 

  95. Jakob M, Demarteau O, Schafer D, Hintermann B, Dick W, Heberer M, Martin I (2001) Specific growth factors during the expansion and redifferentiation of adult human articular chondrocytes enhance chondrogenesis and cartilaginous tissue formation in vitro. J Cell Biochem 81(2):368–377

    Article  CAS  PubMed  Google Scholar 

  96. Murphy MK, Huey DJ, Hu JC, Athanasiou KA (2015) TGF-beta1, GDF-5, and BMP-2 stimulation induces chondrogenesis in expanded human articular chondrocytes and marrow-derived stromal cells. Stem Cells 33(3):762–773. doi:10.1002/stem.1890

    Article  CAS  PubMed  Google Scholar 

  97. Das R, Timur UT, Edip S, Haak E, Wruck C, Weinans H, Jahr H (2015) TGF-beta2 is involved in the preservation of the chondrocyte phenotype under hypoxic conditions. Ann Anat 198:1–10. doi:10.1016/j.aanat.2014.11.003

    Article  CAS  PubMed  Google Scholar 

  98. Foldager CB, Nielsen AB, Munir S, Ulrich-Vinther M, Soballe K, Bunger C, Lind M (2011) Combined 3D and hypoxic culture improves cartilage-specific gene expression in human chondrocytes. Acta Orthop 82(2):234–240. doi:10.3109/17453674.2011.566135

    Article  PubMed Central  PubMed  Google Scholar 

  99. Solchaga LA, Penick K, Porter JD, Goldberg VM, Caplan AI, Welter JF (2005) FGF-2 enhances the mitotic and chondrogenic potentials of human adult bone marrow-derived mesenchymal stem cells. J Cell Physiol 203(2):398–409. doi:10.1002/jcp.20238

    Article  CAS  PubMed  Google Scholar 

  100. Kim JH, Lee MC, Seong SC, Park KH, Lee S (2011) Enhanced proliferation and chondrogenic differentiation of human synovium-derived stem cells expanded with basic fibroblast growth factor. Tissue Eng Part A 17(7–8):991–1002. doi:10.1089/ten.TEA.2010.0277

    Article  CAS  PubMed  Google Scholar 

  101. Kabiri A, Esfandiari E, Hashemibeni B, Kazemi M, Mardani M, Esmaeili A (2012) Effects of FGF-2 on human adipose tissue derived adult stem cells morphology and chondrogenesis enhancement in Transwell culture. Biochem Biophys Res Commun 424(2):234–238. doi:10.1016/j.bbrc.2012.06.082

    Article  CAS  PubMed  Google Scholar 

  102. Indrawattana N, Chen G, Tadokoro M, Shann LH, Ohgushi H, Tateishi T, Tanaka J, Bunyaratvej A (2004) Growth factor combination for chondrogenic induction from human mesenchymal stem cell. Biochem Biophys Res Commun 320(3):914–919. doi:10.1016/j.bbrc.2004.06.029

    Article  CAS  PubMed  Google Scholar 

  103. Sekiya I, Larson BL, Vuoristo JT, Reger RL, Prockop DJ (2005) Comparison of effect of BMP-2, -4, and -6 on in vitro cartilage formation of human adult stem cells from bone marrow stroma. Cell Tissue Res 320(2):269–276. doi:10.1007/s00441-004-1075-3

    Article  CAS  PubMed  Google Scholar 

  104. Kim HJ, Im GI (2009) Combination of transforming growth factor-beta2 and bone morphogenetic protein 7 enhances chondrogenesis from adipose tissue-derived mesenchymal stem cells. Tissue Eng Part A 15(7):1543–1551. doi:10.1089/ten.tea.2008.0368

    Article  CAS  PubMed  Google Scholar 

  105. Shirasawa S, Sekiya I, Sakaguchi Y, Yagishita K, Ichinose S, Muneta T (2006) In vitro chondrogenesis of human synovium-derived mesenchymal stem cells: optimal condition and comparison with bone marrow-derived cells. J Cell Biochem 97(1):84–97. doi:10.1002/jcb.20546

    Article  CAS  PubMed  Google Scholar 

  106. Pei M, He F, Vunjak-Novakovic G (2008) Synovium-derived stem cell-based chondrogenesis. Differentiation 76(10):1044–1056. doi:10.1111/j.1432-0436.2008.00299.x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Duval E, Bauge C, Andriamanalijaona R, Benateau H, Leclercq S, Dutoit S, Poulain L, Galera P, Boumediene K (2012) Molecular mechanism of hypoxia-induced chondrogenesis and its application in in vivo cartilage tissue engineering. Biomaterials 33(26):6042–6051. doi:10.1016/j.biomaterials.2012.04.061

    Article  CAS  PubMed  Google Scholar 

  108. Tian HT, Zhang B, Tian Q, Liu Y, Yang SH, Shao ZW (2013) Construction of self-assembled cartilage tissue from bone marrow mesenchymal stem cells induced by hypoxia combined with GDF-5. J Huazhong Univ Sci Technol Med Sci 33(5):700–706. doi:10.1007/s11596-013-1183-y

    Article  CAS  PubMed  Google Scholar 

  109. Kim YJ, Kim HJ, Im GI (2008) PTHrP promotes chondrogenesis and suppresses hypertrophy from both bone marrow-derived and adipose tissue-derived MSCs. Biochem Biophys Res Commun 373(1):104–108. doi:10.1016/j.bbrc.2008.05.183

    Article  CAS  PubMed  Google Scholar 

  110. Mwale F, Yao G, Ouellet JA, Petit A, Antoniou J (2010) Effect of parathyroid hormone on type X and type II collagen expression in mesenchymal stem cells from osteoarthritic patients. Tissue Eng Part A 16(11):3449–3455. doi:10.1089/ten.TEA.2010.0091

    Article  CAS  PubMed  Google Scholar 

  111. Park S, Im GI (2014) Embryonic stem cells and induced pluripotent stem cells for skeletal regeneration. Tissue Eng Part B Rev 20(5):381–391. doi:10.1089/ten.TEB.2013.0530

    Article  PubMed  Google Scholar 

  112. Koay EJ, Hoben GM, Athanasiou KA (2007) Tissue engineering with chondrogenically differentiated human embryonic stem cells. Stem Cells 25(9):2183–2190. doi:10.1634/stemcells.2007-0105

    Article  CAS  PubMed  Google Scholar 

  113. Bai HY, Chen GA, Mao GH, Song TR, Wang YX (2010) Three step derivation of cartilage like tissue from human embryonic stem cells by 2D-3D sequential culture in vitro and further implantation in vivo on alginate/PLGA scaffolds. J Biomed Mater Res Part A 94(2):539–546. doi:10.1002/jbm.a.32732

    Google Scholar 

  114. Nakagawa T, Lee SY, Reddi AH (2009) Induction of chondrogenesis from human embryonic stem cells without embryoid body formation by bone morphogenetic protein 7 and transforming growth factor beta1. Arthritis Rheum 60(12):3686–3692. doi:10.1002/art.27229

    Article  CAS  PubMed  Google Scholar 

  115. Koay EJ, Athanasiou KA (2008) Hypoxic chondrogenic differentiation of human embryonic stem cells enhances cartilage protein synthesis and biomechanical functionality. Osteoarthritis Cartilage 16(12):1450–1456. doi:10.1016/j.joca.2008.04.007

    Article  CAS  PubMed  Google Scholar 

  116. Yodmuang S, Marolt D, Marcos-Campos I, Gadjanski I, Vunjak-Novakovic G (2015) Synergistic effects of hypoxia and morphogenetic factors on early chondrogenic commitment of human embryonic stem cells in embryoid body culture. Stem Cell Rev 11(2):228–241. doi:10.1007/s12015-015-9584-x

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  117. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4):663–676. doi:10.1016/j.cell.2006.07.024

    Article  CAS  PubMed  Google Scholar 

  118. Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, Hong H, Nakagawa M, Tanabe K, Tezuka K, Shibata T, Kunisada T, Takahashi M, Takahashi J, Saji H, Yamanaka S (2011) A more efficient method to generate integration-free human iPS cells. Nat Methods 8(5):409–412. doi:10.1038/nmeth.1591

    Article  CAS  PubMed  Google Scholar 

  119. Zhou W, Freed CR (2009) Adenoviral gene delivery can reprogram human fibroblasts to induced pluripotent stem cells. Stem Cells 27(11):2667–2674. doi:10.1002/stem.201

    Article  CAS  PubMed  Google Scholar 

  120. Yu J, Hu K, Smuga-Otto K, Tian S, Stewart R, Slukvin II, Thomson JA (2009) Human induced pluripotent stem cells free of vector and transgene sequences. Science 324(5928):797–801. doi:10.1126/science.1172482

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  121. Kim D, Kim CH, Moon JI, Chung YG, Chang MY, Han BS, Ko S, Yang E, Cha KY, Lanza R, Kim KS (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4(6):472–476. doi:10.1016/j.stem.2009.05.005

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Nejadnik H, Diecke S, Lenkov OD, Chapelin F, Donig J, Tong X, Derugin N, Chan RC, Gaur A, Yang F, Wu JC, Daldrup-Link HE (2015) Improved approach for chondrogenic differentiation of human induced pluripotent stem cells. Stem Cell Rev 11(2):242–253. doi:10.1007/s12015-014-9581-5

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  123. Koyama N, Miura M, Nakao K, Kondo E, Fujii T, Taura D, Kanamoto N, Sone M, Yasoda A, Arai H, Bessho K, Nakao K (2013) Human induced pluripotent stem cells differentiated into chondrogenic lineage via generation of mesenchymal progenitor cells. Stem Cells Dev 22(1):102–113. doi:10.1089/scd.2012.0127

    Article  CAS  PubMed  Google Scholar 

  124. Guzzo RM, Gibson J, Xu RH, Lee FY, Drissi H (2013) Efficient differentiation of human iPSC-derived mesenchymal stem cells to chondroprogenitor cells. J Cell Biochem 114(2):480–490. doi:10.1002/jcb.24388

    Article  CAS  PubMed  Google Scholar 

  125. Medvedev SP, Grigor’eva EV, Shevchenko AI, Malakhova AA, Dementyeva EV, Shilov AA, Pokushalov EA, Zaidman AM, Aleksandrova MA, Plotnikov EY, Sukhikh GT, Zakian SM (2011) Human induced pluripotent stem cells derived from fetal neural stem cells successfully undergo directed differentiation into cartilage. Stem Cells Dev 20(6):1099–1112. doi:10.1089/scd.2010.0249

    Article  CAS  PubMed  Google Scholar 

  126. Yamashita A, Morioka M, Yahara Y, Okada M, Kobayashi T, Kuriyama S, Matsuda S, Tsumaki N (2015) Generation of scaffoldless hyaline cartilaginous tissue from human iPSCs. Stem Cell Rep 4(3):404–418. doi:10.1016/j.stemcr.2015.01.016

    Article  CAS  Google Scholar 

  127. Hiramatsu K, Sasagawa S, Outani H, Nakagawa K, Yoshikawa H, Tsumaki N (2011) Generation of hyaline cartilaginous tissue from mouse adult dermal fibroblast culture by defined factors. J Clin Investig 121(2):640–657. doi:10.1172/JCI44605

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  128. Outani H, Okada M, Yamashita A, Nakagawa K, Yoshikawa H, Tsumaki N (2013) Direct induction of chondrogenic cells from human dermal fibroblast culture by defined factors. PLoS One 8(10):e77365. doi:10.1371/journal.pone.0077365

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  129. French MM, Rose S, Canseco J, Athanasiou KA (2004) Chondrogenic differentiation of adult dermal fibroblasts. Ann Biomed Eng 32(1):50–56

    Article  CAS  PubMed  Google Scholar 

  130. Yin S, Cen L, Wang C, Zhao G, Sun J, Liu W, Cao Y, Cui L (2010) Chondrogenic transdifferentiation of human dermal fibroblasts stimulated with cartilage-derived morphogenetic protein 1. Tissue Eng Part A 16(5):1633–1643. doi:10.1089/ten.TEA.2009.0570

    Article  CAS  PubMed  Google Scholar 

  131. Vapniarsky N, Arzi B, Hu JC, Nolta JA, Athanasiou KA (2015) Concise review: human dermis as an autologous source of stem cells for tissue engineering and regenerative medicine. Stem Cells Transl Med. doi:10.5966/sctm.2015-0084

    Google Scholar 

  132. Toma JG, McKenzie IA, Bagli D, Miller FD (2005) Isolation and characterization of multipotent skin-derived precursors from human skin. Stem Cells 23(6):727–737. doi:10.1634/stemcells.2004-0134

    Article  CAS  PubMed  Google Scholar 

  133. Lavoie JF, Biernaskie JA, Chen Y, Bagli D, Alman B, Kaplan DR, Miller FD (2009) Skin-derived precursors differentiate into skeletogenic cell types and contribute to bone repair. Stem Cells Dev 18(6):893–906. doi:10.1089/scd.2008.0260

    Article  CAS  PubMed  Google Scholar 

  134. Junker JP, Sommar P, Skog M, Johnson H, Kratz G (2010) Adipogenic, chondrogenic and osteogenic differentiation of clonally derived human dermal fibroblasts. Cells Tissues Organs 191(2):105–118. doi:10.1159/000232157

    Article  PubMed  Google Scholar 

  135. Chen FG, Zhang WJ, Bi D, Liu W, Wei X, Chen FF, Zhu L, Cui L, Cao Y (2007) Clonal analysis of nestin(−) vimentin(+) multipotent fibroblasts isolated from human dermis. J Cell Sci 120(Pt 16):2875–2883. doi:10.1242/jcs.03478

    Article  CAS  PubMed  Google Scholar 

  136. Sanchez-Adams J, Athanasiou KA (2012) Dermis isolated adult stem cells for cartilage tissue engineering. Biomaterials 33(1):109–119. doi:10.1016/j.biomaterials.2011.09.038

    Article  CAS  PubMed  Google Scholar 

  137. Kalpakci KN, Brown WE, Hu JC, Athanasiou KA (2014) Cartilage tissue engineering using dermis isolated adult stem cells: the use of hypoxia during expansion versus chondrogenic differentiation. PLoS One 9(5):e98570. doi:10.1371/journal.pone.0098570

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  138. Baker DE, Harrison NJ, Maltby E, Smith K, Moore HD, Shaw PJ, Heath PR, Holden H, Andrews PW (2007) Adaptation to culture of human embryonic stem cells and oncogenesis in vivo. Nat Biotechnol 25(2):207–215. doi:10.1038/nbt1285

    Article  CAS  PubMed  Google Scholar 

  139. Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS (2005) Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans 33(Pt 6):1526–1530. doi:10.1042/BST20051526

    Article  CAS  PubMed  Google Scholar 

  140. Rosland GV, Svendsen A, Torsvik A, Sobala E, McCormack E, Immervoll H, Mysliwietz J, Tonn JC, Goldbrunner R, Lonning PE, Bjerkvig R, Schichor C (2009) Long-term cultures of bone marrow-derived human mesenchymal stem cells frequently undergo spontaneous malignant transformation. Cancer Res 69(13):5331–5339. doi:10.1158/0008-5472.CAN-08-4630

    Article  CAS  PubMed  Google Scholar 

  141. Heslop JA, Hammond TG, Santeramo I, Tort Piella A, Hopp I, Zhou J, Baty R, Graziano EI, Proto Marco B, Caron A, Skold P, Andrews PW, Baxter MA, Hay DC, Hamdam J, Sharpe ME, Patel S, Jones DR, Reinhardt J, Danen EH, Ben-David U, Stacey G, Bjorquist P, Piner J, Mills J, Rowe C, Pellegrini G, Sethu S, Antoine DJ, Cross MJ, Murray P, Williams DP, Kitteringham NR, Goldring CE, Park BK (2015) Concise review: workshop review: understanding and assessing the risks of stem cell-based therapies. Stem Cells Transl Med 4(4):389–400. doi:10.5966/sctm.2014-0110

    Article  CAS  PubMed  Google Scholar 

  142. Murphy MK, Huey DJ, Reimer AJ, Hu JC, Athanasiou KA (2013) Enhancing post-expansion chondrogenic potential of costochondral cells in self-assembled neocartilage. PLoS One 8(2):e56983. doi:10.1371/journal.pone.0056983

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  143. DuRaine G, Neu CP, Chan SM, Komvopoulos K, June RK, Reddi AH (2009) Regulation of the friction coefficient of articular cartilage by TGF-beta1 and IL-1beta. J Orthop Res 27(2):249–256. doi:10.1002/jor.20713

    Article  PubMed  Google Scholar 

  144. Blunk T, Sieminski AL, Gooch KJ, Courter DL, Hollander AP, Nahir AM, Langer R, Vunjak-Novakovic G, Freed LE (2002) Differential effects of growth factors on tissue-engineered cartilage. Tissue Eng 8(1):73–84. doi:10.1089/107632702753503072

    Article  CAS  PubMed  Google Scholar 

  145. Gooch KJ, Blunk T, Courter DL, Sieminski AL, Vunjak-Novakovic G, Freed LE (2002) Bone morphogenetic proteins-2, -12, and -13 modulate in vitro development of engineered cartilage. Tissue Eng 8(4):591–601. doi:10.1089/107632702760240517

    Article  CAS  PubMed  Google Scholar 

  146. Elder BD, Athanasiou KA (2009) Systematic assessment of growth factor treatment on biochemical and biomechanical properties of engineered articular cartilage constructs. Osteoarthritis Cartilage 17(1):114–123. doi:10.1016/j.joca.2008.05.006

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  147. Sah RL, Kim YJ, Doong JY, Grodzinsky AJ, Plaas AH, Sandy JD (1989) Biosynthetic response of cartilage explants to dynamic compression. J Orthop Res 7(5):619–636. doi:10.1002/jor.1100070502

    Article  CAS  PubMed  Google Scholar 

  148. Bonassar LJ, Grodzinsky AJ, Frank EH, Davila SG, Bhaktav NR, Trippel SB (2001) The effect of dynamic compression on the response of articular cartilage to insulin-like growth factor-I. J Orthop Res 19(1):11–17. doi:10.1016/S0736-0266(00)00004-8

    Article  CAS  PubMed  Google Scholar 

  149. Mauck RL, Nicoll SB, Seyhan SL, Ateshian GA, Hung CT (2003) Synergistic action of growth factors and dynamic loading for articular cartilage tissue engineering. Tissue Eng 9(4):597–611. doi:10.1089/107632703768247304

    Article  CAS  PubMed  Google Scholar 

  150. Elder BD, Athanasiou KA (2009) Effects of temporal hydrostatic pressure on tissue-engineered bovine articular cartilage constructs. Tissue Eng Part A 15(5):1151–1158. doi:10.1089/ten.tea.2008.0200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  151. Miyanishi K, Trindade MC, Lindsey DP, Beaupre GS, Carter DR, Goodman SB, Schurman DJ, Smith RL (2006) Effects of hydrostatic pressure and transforming growth factor-beta 3 on adult human mesenchymal stem cell chondrogenesis in vitro. Tissue Eng 12(6):1419–1428. doi:10.1089/ten.2006.12.1419

    Article  CAS  PubMed  Google Scholar 

  152. Elder BD, Athanasiou KA (2008) Synergistic and additive effects of hydrostatic pressure and growth factors on tissue formation. PLoS One 3(6):e2341. doi:10.1371/journal.pone.0002341

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  153. Kim SH, Kim SH, Jung Y (2015) TGF-beta3 encapsulated PLCL scaffold by a supercritical CO2-HFIP co-solvent system for cartilage tissue engineering. J Control Release 206:101–107. doi:10.1016/j.jconrel.2015.03.026

    Article  CAS  PubMed  Google Scholar 

  154. Makris EA, Responte DJ, Paschos NK, Hu JC, Athanasiou KA (2014) Developing functional musculoskeletal tissues through hypoxia and lysyl oxidase-induced collagen cross-linking. Proc Natl Acad Sci USA 111(45):E4832–E4841. doi:10.1073/pnas.1414271111

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  155. Natoli RM, Revell CM, Athanasiou KA (2009) Chondroitinase ABC treatment results in greater tensile properties of self-assembled tissue-engineered articular cartilage. Tissue Eng Part A 15(10):3119–3128. doi:10.1089/ten.TEA.2008.0478

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  156. Asanbaeva A, Masuda K, Thonar EJ, Klisch SM, Sah RL (2007) Mechanisms of cartilage growth: modulation of balance between proteoglycan and collagen in vitro using chondroitinase ABC. Arthritis Rheum 56(1):188–198. doi:10.1002/art.22298

    Article  CAS  PubMed  Google Scholar 

  157. Natoli RM, Responte DJ, Lu BY, Athanasiou KA (2009) Effects of multiple chondroitinase ABC applications on tissue engineered articular cartilage. J Orthop Res 27(7):949–956. doi:10.1002/jor.20821

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  158. O’Connell GD, Nims RJ, Green J, Cigan AD, Ateshian GA, Hung CT (2014) Time and dose-dependent effects of chondroitinase ABC on growth of engineered cartilage. Eur Cells Mater 27:312–320

    Google Scholar 

  159. O’Connell GD, Fong JV, Dunleavy N, Joffe A, Ateshian GA, Hung CT (2012) Trimethylamine N-oxide as a media supplement for cartilage tissue engineering. J Orthop Res 30(12):1898–1905. doi:10.1002/jor.22171

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  160. Nandini CD, Sugahara K (2006) Role of the sulfation pattern of chondroitin sulfate in its biological activities and in the binding of growth factors. Adv Pharmacol 53:253–279. doi:10.1016/S1054-3589(05)53012-6

    Article  CAS  PubMed  Google Scholar 

  161. Responte DJ, Arzi B, Natoli RM, Hu JC, Athanasiou KA (2012) Mechanisms underlying the synergistic enhancement of self-assembled neocartilage treated with chondroitinase-ABC and TGF-beta1. Biomaterials 33(11):3187–3194. doi:10.1016/j.biomaterials.2012.01.028

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  162. Bastiaansen-Jenniskens YM, Koevoet W, de Bart AC, van der Linden JC, Zuurmond AM, Weinans H, Verhaar JA, van Osch GJ, Degroot J (2008) Contribution of collagen network features to functional properties of engineered cartilage. Osteoarthritis Cartilage 16(3):359–366. doi:10.1016/j.joca.2007.07.003

    Article  CAS  PubMed  Google Scholar 

  163. Ahsan T, Harwood F, McGowan KB, Amiel D, Sah RL (2005) Kinetics of collagen crosslinking in adult bovine articular cartilage. Osteoarthritis Cartilage 13(8):709–715. doi:10.1016/j.joca.2005.03.005

    Article  CAS  PubMed  Google Scholar 

  164. Makris EA, Hu JC, Athanasiou KA (2013) Hypoxia-induced collagen crosslinking as a mechanism for enhancing mechanical properties of engineered articular cartilage. Osteoarthritis Cartilage 21(4):634–641. doi:10.1016/j.joca.2013.01.007

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  165. Schumacher BL, Hughes CE, Kuettner KE, Caterson B, Aydelotte MB (1999) Immunodetection and partial cDNA sequence of the proteoglycan, superficial zone protein, synthesized by cells lining synovial joints. J Orthop Res 17(1):110–120. doi:10.1002/jor.1100170117

    Article  CAS  PubMed  Google Scholar 

  166. Peng G, McNary SM, Athanasiou KA, Reddi AH (2014) Surface zone articular chondrocytes modulate the bulk and surface mechanical properties of the tissue-engineered cartilage. Tissue Eng Part A 20(23–24):3332–3341. doi:10.1089/ten.TEA.2014.0099

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  167. Peng G, McNary SM, Athanasiou KA, Reddi AH (2015) The distribution of superficial zone protein (SZP)/lubricin/PRG4 and boundary mode frictional properties of the bovine diarthrodial joint. J Biomech. doi:10.1016/j.jbiomech.2015.05.032

    Google Scholar 

  168. Wang N, Tytell JD, Ingber DE (2009) Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nat Rev Mol Cell Biol 10(1):75–82. doi:10.1038/nrm2594

    Article  CAS  PubMed  Google Scholar 

  169. Ryan JA, Eisner EA, DuRaine G, You Z, Reddi AH (2009) Mechanical compression of articular cartilage induces chondrocyte proliferation and inhibits proteoglycan synthesis by activation of the ERK pathway: implications for tissue engineering and regenerative medicine. J Tissue Eng Regen Med 3(2):107–116. doi:10.1002/term.146

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  170. DuRaine GD, Athanasiou KA (2015) ERK activation is required for hydrostatic pressure-induced tensile changes in engineered articular cartilage. J Tissue Eng Regen Med 9(4):368–374. doi:10.1002/term.1678

    Article  CAS  PubMed  Google Scholar 

  171. Hall AC (1999) Differential effects of hydrostatic pressure on cation transport pathways of isolated articular chondrocytes. J Cell Physiol 178(2):197–204. doi:10.1002/(SICI)1097-4652(199902)178:2<197:AID-JCP9>3.0.CO;2-3

    Article  CAS  PubMed  Google Scholar 

  172. Browning JA, Walker RE, Hall AC, Wilkins RJ (1999) Modulation of Na+ × H+ exchange by hydrostatic pressure in isolated bovine articular chondrocytes. Acta Physiol Scand 166(1):39–45. doi:10.1046/j.1365-201x.1999.00534.x

    Article  CAS  PubMed  Google Scholar 

  173. Natoli RM, Skaalure S, Bijlani S, Chen KX, Hu J, Athanasiou KA (2010) Intracellular Na(+) and Ca(2+) modulation increases the tensile properties of developing engineered articular cartilage. Arthritis Rheum 62(4):1097–1107. doi:10.1002/art.27313

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  174. Wu Q, Zhang Y, Chen Q (2001) Indian hedgehog is an essential component of mechanotransduction complex to stimulate chondrocyte proliferation. J Biol Chem 276(38):35290–35296. doi:10.1074/jbc.M101055200

    Article  CAS  PubMed  Google Scholar 

  175. Jortikka MO, Parkkinen JJ, Inkinen RI, Karner J, Jarvelainen HT, Nelimarkka LO, Tammi MI, Lammi MJ (2000) The role of microtubules in the regulation of proteoglycan synthesis in chondrocytes under hydrostatic pressure. Arch Biochem Biophys 374(2):172–180. doi:10.1006/abbi.1999.1543

    Article  CAS  PubMed  Google Scholar 

  176. Vinardell T, Sheehy EJ, Buckley CT, Kelly DJ (2012) A comparison of the functionality and in vivo phenotypic stability of cartilaginous tissues engineered from different stem cell sources. Tissue Eng Part A 18(11–12):1161–1170. doi:10.1089/ten.TEA.2011.0544

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  177. Caron MM, Emans PJ, Cremers A, Surtel DA, Coolsen MM, van Rhijn LW, Welting TJ (2013) Hypertrophic differentiation during chondrogenic differentiation of progenitor cells is stimulated by BMP-2 but suppressed by BMP-7. Osteoarthritis Cartilage 21(4):604–613. doi:10.1016/j.joca.2013.01.009

    Article  CAS  PubMed  Google Scholar 

  178. Ikeda T, Kamekura S, Mabuchi A, Kou I, Seki S, Takato T, Nakamura K, Kawaguchi H, Ikegawa S, Chung UI (2004) The combination of SOX5, SOX6, and SOX9 (the SOX trio) provides signals sufficient for induction of permanent cartilage. Arthritis Rheum 50(11):3561–3573. doi:10.1002/art.20611

    Article  CAS  PubMed  Google Scholar 

  179. Lengner CJ, Hassan MQ, Serra RW, Lepper C, van Wijnen AJ, Stein JL, Lian JB, Stein GS (2005) Nkx3.2-mediated repression of Runx2 promotes chondrogenic differentiation. J Biol Chem 280(16):15872–15879. doi:10.1074/jbc.M411144200

    Article  CAS  PubMed  Google Scholar 

  180. von der Mark K, Kirsch T, Nerlich A, Kuss A, Weseloh G, Gluckert K, Stoss H (1992) Type X collagen synthesis in human osteoarthritic cartilage. Indication of chondrocyte hypertrophy. Arthritis Rheum 35(7):806–811

    Article  PubMed  Google Scholar 

  181. Pitsillides AA, Beier F (2011) Cartilage biology in osteoarthritis—lessons from developmental biology. Nat Rev Rheumatol 7(11):654–663. doi:10.1038/nrrheum.2011.129

    Article  CAS  PubMed  Google Scholar 

  182. Khan IM, Gilbert SJ, Singhrao SK, Duance VC, Archer CW (2008) Cartilage integration: evaluation of the reasons for failure of integration during cartilage repair. A review. Eur Cells Mater 16:26–39

    CAS  Google Scholar 

  183. Obradovic B, Martin I, Padera RF, Treppo S, Freed LE, Vunjak-Novakovic G (2001) Integration of engineered cartilage. J Orthop Res 19(6):1089–1097. doi:10.1016/S0736-0266(01)00030-4

    Article  CAS  PubMed  Google Scholar 

  184. Hunziker EB, Kapfinger E (1998) Removal of proteoglycans from the surface of defects in articular cartilage transiently enhances coverage by repair cells. J Bone Joint Surg 80(1):144–150

    Article  CAS  Google Scholar 

  185. Rice MA, Homier PM, Waters KR, Anseth KS (2008) Effects of directed gel degradation and collagenase digestion on the integration of neocartilage produced by chondrocytes encapsulated in hydrogel carriers. J Tissue Eng Regen Med 2(7):418–429. doi:10.1002/term.113

    Article  CAS  PubMed  Google Scholar 

  186. van de Breevaart Bravenboer J, In der Maur CD, Bos PK, Feenstra L, Verhaar JA, Weinans H, van Osch GJ (2004) Improved cartilage integration and interfacial strength after enzymatic treatment in a cartilage transplantation model. Arthritis Res Ther 6(5):R469–R476. doi:10.1186/ar1216

    Article  CAS  Google Scholar 

  187. McGowan KB, Sah RL (2005) Treatment of cartilage with beta-aminopropionitrile accelerates subsequent collagen maturation and modulates integrative repair. J Orthop Res 23(3):594–601. doi:10.1016/j.orthres.2004.02.015

    Article  CAS  PubMed  Google Scholar 

  188. Makris EA, MacBarb RF, Paschos NK, Hu JC, Athanasiou KA (2014) Combined use of chondroitinase-ABC, TGF-beta1, and collagen crosslinking agent lysyl oxidase to engineer functional neotissues for fibrocartilage repair. Biomaterials 35(25):6787–6796. doi:10.1016/j.biomaterials.2014.04.083

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  189. Bastiaansen-Jenniskens YM, Koevoet W, Feijt C, Bos PK, Verhaar JA, Van Osch GJ, DeGroot J (2009) Proteoglycan production is required in initial stages of new cartilage matrix formation but inhibits integrative cartilage repair. J Tissue Eng Regen Med 3(2):117–123. doi:10.1002/term.147

    Article  CAS  PubMed  Google Scholar 

  190. Rainbow R, Ren W, Zeng L (2012) Inflammation and joint tissue interactions in OA: implications for potential therapeutic approaches. Arthritis 2012:741582. doi:10.1155/2012/741582

    Article  PubMed Central  PubMed  Google Scholar 

  191. Goldring SR, Goldring MB (2004) The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin Orthop Relat Res 427 Suppl:S27–S36

    Article  PubMed  Google Scholar 

  192. Wehling N, Palmer GD, Pilapil C, Liu F, Wells JW, Muller PE, Evans CH, Porter RM (2009) Interleukin-1beta and tumor necrosis factor alpha inhibit chondrogenesis by human mesenchymal stem cells through NF-kappaB-dependent pathways. Arthritis Rheum 60(3):801–812. doi:10.1002/art.24352

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  193. Heldens GT, Blaney Davidson EN, Vitters EL, Schreurs BW, Piek E, van den Berg WB, van der Kraan PM (2012) Catabolic factors and osteoarthritis-conditioned medium inhibit chondrogenesis of human mesenchymal stem cells. Tissue Eng Part A 18(1–2):45–54. doi:10.1089/ten.TEA.2011.0083

    Article  CAS  PubMed  Google Scholar 

  194. Montaseri A, Busch F, Mobasheri A, Buhrmann C, Aldinger C, Rad JS, Shakibaei M (2011) IGF-1 and PDGF-bb suppress IL-1beta-induced cartilage degradation through down-regulation of NF-kappaB signaling: involvement of Src/PI-3K/AKT pathway. PLoS One 6(12):e28663. doi:10.1371/journal.pone.0028663

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  195. Majumdar MK, Wang E, Morris EA (2001) BMP-2 and BMP-9 promotes chondrogenic differentiation of human multipotential mesenchymal cells and overcomes the inhibitory effect of IL-1. J Cell Physiol 189(3):275–284. doi:10.1002/jcp.10025

    Article  CAS  PubMed  Google Scholar 

  196. Henrotin Y, Lambert C, Richette P (2014) Importance of synovitis in osteoarthritis: evidence for the use of glycosaminoglycans against synovial inflammation. Semin Arthritis Rheum 43(5):579–587. doi:10.1016/j.semarthrit.2013.10.005

    Article  CAS  PubMed  Google Scholar 

  197. Chen WH, Lo WC, Hsu WC, Wei HJ, Liu HY, Lee CH, Tina Chen SY, Shieh YH, Williams DF, Deng WP (2014) Synergistic anabolic actions of hyaluronic acid and platelet-rich plasma on cartilage regeneration in osteoarthritis therapy. Biomaterials 35(36):9599–9607. doi:10.1016/j.biomaterials.2014.07.058

    Article  CAS  PubMed  Google Scholar 

  198. Andia I, Maffulli N (2013) Platelet-rich plasma for managing pain and inflammation in osteoarthritis. Nat Rev Rheumatol 9(12):721–730. doi:10.1038/nrrheum.2013.141

    Article  CAS  PubMed  Google Scholar 

  199. Zhu Y, Yuan M, Meng HY, Wang AY, Guo QY, Wang Y, Peng J (2013) Basic science and clinical application of platelet-rich plasma for cartilage defects and osteoarthritis: a review. Osteoarthritis Cartilage 21(11):1627–1637. doi:10.1016/j.joca.2013.07.017

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to acknowledge funding by NIH R01 AR067821, AR061496, and CIRM TR3-05709.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, University of California Davis, One Shields Avenue, Davis, CA, 95616, USA

    Heenam Kwon, Nikolaos K. Paschos, Jerry C. Hu & Kyriacos Athanasiou

  2. Department of Orthopaedic Surgery, University of California Davis Medical Center, Sacramento, CA, USA

    Kyriacos Athanasiou

Authors
  1. Heenam Kwon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nikolaos K. Paschos
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jerry C. Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyriacos Athanasiou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kyriacos Athanasiou.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kwon, H., Paschos, N.K., Hu, J.C. et al. Articular cartilage tissue engineering: the role of signaling molecules. Cell. Mol. Life Sci. 73, 1173–1194 (2016). https://doi.org/10.1007/s00018-015-2115-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-015-2115-8

Keywords

Search

Navigation