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A Second Career for Chondrocytes—Transformation into Osteoblasts

  • Skeletal Development (R Marcucio and J Feng, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The goal of the review is to summarize the current knowledge on the process of chondrocyte-to-osteoblast transdifferentiation during endochondral bone formation and its potential implications in fracture healing and disease.

Recent Findings

Lineage tracing experiments confirmed the transdifferentiation of chondrocytes into osteoblasts. More recent studies lead to the discovery of molecules involved in this process, as well as to the hypothesis that these cells may re-enter a stem cell-like phase prior to their osteoblastic differentiation.

Summary

This review recapitulates the current knowledge regarding chondrocyte transdifferentiating into osteoblasts, the developmental and postnatal events where transdifferentiation appears to be relevant, and the molecules implicated in this process.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Farnum CE, Lee R, O’Hara K, Urban JP. Volume increase in growth plate chondrocytes during hypertrophy: the contribution of organic osmolytes. Bone. 2002;30(4):574–81.

    Article  CAS  Google Scholar 

  2. Miller JP, Yeh N, Vidal A, Koff A. Interweaving the cell cycle machinery with cell differentiation. Cell Cycle. 2007;6(23):2932–8. https://doi.org/10.4161/cc.6.23.5042.

    Article  CAS  PubMed  Google Scholar 

  3. Cooper KL, Oh S, Sung Y, Dasari RR, Kirschner MW, Tabin CJ. Multiple phases of chondrocyte enlargement underlie differences in skeletal proportions. Nature. 2013;495(7441):375–8. https://doi.org/10.1038/nature11940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schmid TM, Conrad HE. A unique low molecular weight collagen secreted by cultured chick embryo chondrocytes. J Biol Chem. 1982;257(20):12444–50.

    CAS  PubMed  Google Scholar 

  5. Grant WT, Sussman MD, Balian G. A disulfide-bonded short chain collagen synthesized by degenerative and calcifying zones of bovine growth plate cartilage. J Biol Chem. 1985;260(6):3798–803.

    CAS  PubMed  Google Scholar 

  6. Aghajanian P, Mohan S. The art of building bone: emerging role of chondrocyte-to-osteoblast transdifferentiation in endochondral ossification. Bone Res. 2018;6:19. https://doi.org/10.1038/s41413-018-0021-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. St-Jacques B, Hammerschmidt M, McMahon AP. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 1999;13(16):2072–86.

    Article  CAS  Google Scholar 

  8. Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423(6937):332–6. https://doi.org/10.1038/nature01657.

    Article  CAS  PubMed  Google Scholar 

  9. Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999;5(6):623–8. https://doi.org/10.1038/9467.

    Article  CAS  PubMed  Google Scholar 

  10. Maes C, Kobayashi T, Selig MK, Torrekens S, Roth SI, Mackem S, et al. Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. Dev Cell. 2010;19(2):329–44. https://doi.org/10.1016/j.devcel.2010.07.010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108(1):17–29.

    Article  CAS  Google Scholar 

  12. Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell. 2005;8(5):739–50. https://doi.org/10.1016/j.devcel.2005.03.016.

    Article  CAS  PubMed  Google Scholar 

  13. Hill TP, Spater D, Taketo MM, Birchmeier W, Hartmann C. Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. Dev Cell. 2005;8(5):727–38. https://doi.org/10.1016/j.devcel.2005.02.013.

    Article  CAS  PubMed  Google Scholar 

  14. Rodda SJ, McMahon AP. Distinct roles for hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors. Development. 2006;133(16):3231–44. https://doi.org/10.1242/dev.02480.

    Article  CAS  PubMed  Google Scholar 

  15. Blumer MJ, Longato S, Fritsch H. Structure, formation and role of cartilage canals in the developing bone. Ann Anat. 2008;190(4):305–15. https://doi.org/10.1016/j.aanat.2008.02.004.

    Article  PubMed  Google Scholar 

  16. Blumer MJ, Longato S, Schwarzer C, Fritsch H. Bone development in the femoral epiphysis of mice: the role of cartilage canals and the fate of resting chondrocytes. Dev Dyn. 2007;236(8):2077–88. https://doi.org/10.1002/dvdy.21228.

    Article  PubMed  Google Scholar 

  17. Hung RW, Chow AW. Apoptosis: molecular mechanisms, regulation and role in pathogenesis. Can J Infect Dis. 1997;8(2):103–9.

    Article  CAS  Google Scholar 

  18. Gibson G. Active role of chondrocyte apoptosis in endochondral ossification. Microsc Res Tech. 1998;43(2):191–204. https://doi.org/10.1002/(SICI)1097-0029(19981015)43:2<191::AID-JEMT10>3.0.CO;2-T.

    Article  CAS  PubMed  Google Scholar 

  19. Schweichel JU, Merker HJ. The morphology of various types of cell death in prenatal tissues. Teratology. 1973;7(3):253–66. https://doi.org/10.1002/tera.1420070306.

    Article  CAS  PubMed  Google Scholar 

  20. Roach HI, Clarke NM. Physiological cell death of chondrocytes in vivo is not confined to apoptosis. New observations on the mammalian growth plate. J Bone Joint Surg Br. 2000;82(4):601–13.

    Article  CAS  Google Scholar 

  21. Roach HI, Aigner T, Kouri JB. Chondroptosis: a variant of apoptotic cell death in chondrocytes? Apoptosis. 2004;9(3):265–77.

    Article  CAS  Google Scholar 

  22. Ahmed YA, Tatarczuch L, Pagel CN, Davies HM, Mirams M, Mackie EJ. Physiological death of hypertrophic chondrocytes. Osteoarthr. Cartil. 2007;15(5):575–86. https://doi.org/10.1016/j.joca.2006.10.016.

  23. Hunziker EB, Schenk RK. Cartilage ultrastructure after high pressure freezing, freeze substitution, and low temperature embedding. II. Intercellular matrix ultrastructure—preservation of proteoglycans in their native state. J Cell Biol. 1984;98(1):277–82.

    Article  CAS  Google Scholar 

  24. Farnum CE, Turgai J, Wilsman NJ. Visualization of living terminal hypertrophic chondrocytes of growth plate cartilage in situ by differential interference contrast microscopy and time-lapse cinematography. J Orthop Res. 1990;8(5):750–63. https://doi.org/10.1002/jor.1100080517.

    Article  CAS  PubMed  Google Scholar 

  25. Takechi M, Itakura C. Ultrastructural and histochemical studies of the epiphyseal plate in normal chicks. Anat Rec. 1995;242(1):29–39. https://doi.org/10.1002/ar.1092420105.

    Article  CAS  PubMed  Google Scholar 

  26. Cancedda R, Descalzi Cancedda F, Castagnola P. Chondrocyte differentiation. Int Rev Cytol. 1995;159:265–358.

    Article  CAS  Google Scholar 

  27. Tsang KY, Chan D, Cheah KS. Fate of growth plate hypertrophic chondrocytes: death or lineage extension? Develop Growth Differ. 2015;57(2):179–92. https://doi.org/10.1111/dgd.12203.

    Article  CAS  Google Scholar 

  28. Hinton RJ, Jing Y, Jing J, Feng JQ. Roles of chondrocytes in endochondral bone formation and fracture repair. J Dent Res. 2017;96(1):23–30. https://doi.org/10.1177/0022034516668321.

    Article  CAS  PubMed  Google Scholar 

  29. Galotto M, Campanile G, Robino G, Cancedda FD, Bianco P, Cancedda R. Hypertrophic chondrocytes undergo further differentiation to osteoblast-like cells and participate in the initial bone formation in developing chick embryo. J Bone Miner Res. 1994;9(8):1239–49. https://doi.org/10.1002/jbmr.5650090814.

    Article  CAS  PubMed  Google Scholar 

  30. Bianco P, Cancedda FD, Riminucci M, Cancedda R. Bone formation via cartilage models: the “borderline” chondrocyte. Matrix Biol. 1998;17(3):185–92.

    Article  CAS  Google Scholar 

  31. Holtrop ME. The potencies of the epiphyseal cartilage in endochondral ossification. Proc K Ned Akad Wet C. 1967;70(1):21–8.

    CAS  PubMed  Google Scholar 

  32. Kahn AJ, Simmons DJ. Chondrocyte-to-osteocyte transformation in grafts of perichondrium-free epiphyseal cartilage. Clin Orthop Relat Res. 1977;129:299–304.

    Article  Google Scholar 

  33. Descalzi Cancedda F, Gentili C, Manduca P, Cancedda R. Hypertrophic chondrocytes undergo further differentiation in culture. J Cell Biol. 1992;117(2):427–35.

    Article  CAS  Google Scholar 

  34. Dy P, Wang W, Bhattaram P, Wang Q, Wang L, Ballock RT, et al. Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell. 2012;22(3):597–609. https://doi.org/10.1016/j.devcel.2011.12.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. •• Yang L, Tsang KY, Tang HC, Chan D, Cheah KS. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci U S A. 2014;111(33):12097–102. https://doi.org/10.1073/pnas.1302703111 The use of a tamoxifen-inducible Col10a1-Cre line being exclusively active in hypertrophic chondrocytes enabled the authors to trace the fate of hypertrophic chondrocytes at different stages of development. Furthermore, grafting experiments showed that descendents of hypertrophic chondrocytes contributed to bone repair.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. •• Yang G, Zhu L, Hou N, Lan Y, Wu XM, Zhou B, et al. Osteogenic fate of hypertrophic chondrocytes. Cell Res. 2014. https://doi.org/10.1038/cr.2014.111 The results from this study using the confetti mouse in combination with an inducible Col2Cre mouse line to trace the fate of chondrocytes allowed to follow the clonal progeny of a chondrocyte showing the presence of chondrocyte-derived clones in the bone marrow cavity.

  37. •• Zhou X, von der Mark K, Henry S, Norton W, Adams H, de Crombrugghe B. Chondrocytes transdifferentiate into osteoblasts in endochondral bone during development, postnatal growth and fracture healing in mice. PLoS genetics. 2014;10(12):e1004820. https://doi.org/10.1371/journal.pgen.1004820 This study showed that chondrocyte-to-osteoblast transdifferentiation occurred not only during normal endochondral bone formation but also in the bone repair callus.

    Article  PubMed  PubMed Central  Google Scholar 

  38. •• Park J, Gebhardt M, Golovchenko S, Branguli F, Hattori T, Hartmann C, et al. Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage. Biol Open. 2015;4(5). https://doi.org/10.1242/bio.201411031 The results from this study suggest that transdifferentiating chondrocytes reenter the cell cycle at the chondro-osseous border and are immunopositive for the mesenchymal stem cell marker Sca1.

  39. •• Houben A, Kostanova-Poliakova D, Weissenbock M, Graf J, Teufel S, von der Mark K, et al. Beta-catenin activity in late hypertrophic chondrocytes locally orchestrates osteoblastogenesis and osteoclastogenesis. Development. 2016;143(20):3826–38. https://doi.org/10.1242/dev.137489 The results from this study revealed an essential role for beta-catenin in chondrocyte-to-osteoblast transdifferentiation and suggested that β-catenin must act via a mechanism different from the one described for perichondrial osteoblastogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids. Potential mechanisms of their deleterious effects on bone. J Clin Invest. 1998;102(2):274–82. https://doi.org/10.1172/JCI2799.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Maye P, Fu Y, Butler DL, Chokalingam K, Liu Y, Floret J, et al. Generation and characterization of Col10a1-mcherry reporter mice. Genesis. 2011;49(5):410–8. https://doi.org/10.1002/dvg.20733.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. •• Aghajanian P, Xing W, Cheng S, Mohan S. Epiphyseal bone formation occurs via thyroid hormone regulation of chondrocyte to osteoblast transdifferentiation. Sci Rep. 2017;7(1):10432. https://doi.org/10.1038/s41598-017-11050-1 The results from this study suggest that in the SOC, thyroid hormone regulates chondrocyte-derived osteoblastogenesis via opposing Ihh- and Shh-mediated signaling pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Shapiro F, Flynn E, Calicchio ML. Molecular differentiation in epiphyseal and physeal cartilage. Prominent role for gremlin in maintaining hypertrophic chondrocytes in epiphyseal cartilage. Biochem Biophys Res Commun. 2009;390(3):570–6. https://doi.org/10.1016/j.bbrc.2009.10.006.

    Article  CAS  PubMed  Google Scholar 

  44. Worthley DL, Churchill M, Compton JT, Tailor Y, Rao M, Si Y, et al. Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell. 2015;160(1–2):269–84. https://doi.org/10.1016/j.cell.2014.11.042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. •• Jing Y, Zhou X, Han X, Jing J, von der Mark K, Wang J, et al. Chondrocytes directly transform into bone cells in mandibular condyle growth. J Dent Res. 2015;94(12):1668–75. https://doi.org/10.1177/0022034515598135 This study shows that chondrocyte-to-osteoblast transdifferentiation also occurs during bone formation in secondary cartilage.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Durkin JF. Secondary cartilage: a misnomer? Am J Orthod. 1972;62(1):15–41.

    Article  CAS  Google Scholar 

  47. Holmbeck K, Bianco P, Chrysovergis K, Yamada S, Birkedal-Hansen H. MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage: a critical process in skeletal growth. J Cell Biol. 2003;163(3):661–71. https://doi.org/10.1083/jcb.200307061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Scammell BE, Roach HI. A new role for the chondrocyte in fracture repair: endochondral ossification includes direct bone formation by former chondrocytes. J Bone Miner Res. 1996;11(6):737–45. https://doi.org/10.1002/jbmr.5650110604.

    Article  CAS  PubMed  Google Scholar 

  49. Bahney CS, Hu DP, Taylor AJ, Ferro F, Britz HM, Hallgrimsson B, et al. Stem cell-derived endochondral cartilage stimulates bone healing by tissue transformation. J Bone Miner Res Off J Am Soc Bone Miner Res. 2014;29(5):1269–82. https://doi.org/10.1002/jbmr.2148.

    Article  CAS  Google Scholar 

  50. Wong SA, Hu D, Miclau T, Bahney C, Marcucio R. Trans differentiation of chondrocytes to osteoblasts during endochondral ossification in the healing mandible. FASEB J. 2016;30. (1) Supplement, Abstract Number:1039.11

  51. Marcucio R, Hu D, Yang F, Bahney C, Miclau T. Transdifferentiation of chondrocytes to osteoblasts during bone fracture healing. FASEB J. 2016;30. (1) Supplement. Abstract Number:223.1

  52. •• Hu DP, Ferro F, Yang F, Taylor AJ, Chang W, Miclau T, et al. Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes. Development. 2017;144(2):221–34. https://doi.org/10.1242/dev.130807 The results from this study suggest that during fracture repair chondrocytes are induced to dedifferentiate into a pluripotent state prior to differentiating into osteoblasts.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Roach HI, Erenpreisa J, Aigner T. Osteogenic differentiation of hypertrophic chondrocytes involves asymmetric cell divisions and apoptosis. J Cell Biol. 1995;131(2):483–94.

    Article  CAS  Google Scholar 

  54. Roach HI, Erenpreisa J. The phenotypic switch from chondrocytes to bone-forming cells involves asymmetric cell division and apoptosis. Connect Tissue Res. 1996;35(1–4):85–91.

    Article  CAS  Google Scholar 

  55. Roach HI. Trans-differentiation of hypertrophic chondrocytes into cells capable of producing a mineralized bone matrix. Bone Miner. 1992;19(1):1–20.

    Article  CAS  Google Scholar 

  56. Crelin ES, Koch WE. An autoradiographic study of chondrocyte transformation into chondroclasts and osteocytes during bone formation in vitro. Anat Rec. 1967;158(4):473–83. https://doi.org/10.1002/ar.1091580410.

    Article  CAS  PubMed  Google Scholar 

  57. Weiss A, von der Mark K, Silbermann M. Fully differentiated chondrocytes alter their phenotypic expression in vitro and transform into bone cells. In: Hurwitz S, Sela J, editors. Current advances in skeletogenesis 3. Jerusalem: Heiliger Publishing; 1997. p. 40–3.

    Google Scholar 

  58. Yoshioka C, Yagi T. Electron microscopic observations on the fate of hypertrophic chondrocytes in condylar cartilage of rat mandible. J Craniofac Genet Dev Biol. 1988;8(3):253–64.

    CAS  PubMed  Google Scholar 

  59. Bais M, McLean J, Sebastiani P, Young M, Wigner N, Smith T, et al. Transcriptional analysis of fracture healing and the induction of embryonic stem cell-related genes. PLoS One. 2009;4(5):e5393. https://doi.org/10.1371/journal.pone.0005393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. • Enishi T, Yukata K, Takahashi M, Sato R, Sairyo K, Yasui N. Hypertrophic chondrocytes in the rabbit growth plate can proliferate and differentiate into osteogenic cells when capillary invasion is interposed by a membrane filter. PloS one. 2014;9(8):e104638. https://doi.org/10.1371/journal.pone.0104638 The results from this study suggest that chondrocyte-to-osteoblast transdifferentiation can occur in the absence of capillary invasion.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014;507(7492):323–8. https://doi.org/10.1038/nature13145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Langen UH, Pitulescu ME, Kim JM, Enriquez-Gasca R, Sivaraj KK, Kusumbe AP, et al. Cell-matrix signals specify bone endothelial cells during developmental osteogenesis. Nat Cell Biol. 2017;19(3):189–201. https://doi.org/10.1038/ncb3476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Salter RB, Harris WR. Injuries involving the epiphyseal plate. J Bone Joint Surg Am. 1963;45(3):587–622. https://doi.org/10.2106/00004623-196345030-00019.

    Article  Google Scholar 

  64. Heuberger J, Birchmeier W. Interplay of cadherin-mediated cell adhesion and canonical Wnt signaling. Cold Spring Harb Perspect Biol. 2010;2(2):a002915. https://doi.org/10.1101/cshperspect.a002915.

    Article  PubMed  PubMed Central  Google Scholar 

  65. • Jing Y, Jing J, Wang K, Chan K, Harris SE, Hinton RJ, et al. Vital roles of beta-catenin in trans-differentiation of chondrocytes to bone cells. Int J Biol Sci. 2018;14(1):1–9. https://doi.org/10.7150/ijbs.23165 This study confirms that β-catenin plays an important role in chondrocyte-to-osteoblast transdifferentiation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. •• Wang L, Huang J, Moore DC, Zuo C, Wu Q, Xie L, et al. SHP2 Regulates the osteogenic fate of growth plate hypertrophic chondrocytes. Scientific reports. 2017;7(1):12699. https://doi.org/10.1038/s41598-017-12767-9 Results from this study implemented a role for the phosphatase SHP2 in chondrocyte-to-osteoblast transdifferentiation through inhibition of SOX9 activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Topol L, Chen W, Song H, Day TF, Yang Y. Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus. J Biol Chem. 2009;284(5):3323–33. https://doi.org/10.1074/jbc.M808048200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Akiyama H, Lyons JP, Mori-Akiyama Y, Yang X, Zhang R, Zhang Z, et al. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev. 2004;18(9):1072–87. https://doi.org/10.1101/gad.1171104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Zuo C, Wang L, Kamalesh RM, Bowen ME, Moore DC, Dooner MS, et al. SHP2 regulates skeletal cell fate by modifying SOX9 expression and transcriptional activity. Bone Res. 2018;6:12. https://doi.org/10.1038/s41413-018-0013-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. •• Jing Y, Jing J, Ye L, Liu X, Harris SE, Hinton RJ, et al. Chondrogenesis and osteogenesis are one continuous developmental and lineage defined biological process. Sci Rep. 2017;7(1):10020. https://doi.org/10.1038/s41598-017-10048-z This study shows that BMPR1 signaling plays an important role in chondrocyte-to-osteoblast diffferentiation and suggests that chondrogenesis and osteoblastogenesis are a continuous process.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Xing W, Cheng S, Wergedal J, Mohan S. Epiphyseal chondrocyte secondary ossification centers require thyroid hormone activation of Indian hedgehog and osterix signaling. J Bone Miner Res Off J Am Soc Bone Miner Res. 2014;29(10):2262–75. https://doi.org/10.1002/jbmr.2256.

    Article  CAS  Google Scholar 

  72. Kim HY, Mohan S. Role and mechanisms of actions of thyroid hormone on the skeletal development. Bone Res. 2013;1(2):146–61. https://doi.org/10.4248/BR201302004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Tavella S, Biticchi R, Schito A, Minina E, Di Martino D, Pagano A, et al. Targeted expression of SHH affects chondrocyte differentiation, growth plate organization, and Sox9 expression. J Bone Miner Res Off J Am Soc Bone Miner Res. 2004;19(10):1678–88. https://doi.org/10.1359/JBMR.040706.

    Article  CAS  Google Scholar 

  74. Mak KK, Kronenberg HM, Chuang PT, Mackem S, Yang Y. Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy. Development. 2008;135(11):1947–56. https://doi.org/10.1242/dev.018044.

    Article  CAS  PubMed  Google Scholar 

  75. Razzaque MS, Soegiarto DW, Chang D, Long F, Lanske B. Conditional deletion of Indian hedgehog from collagen type 2alpha1-expressing cells results in abnormal endochondral bone formation. J Pathol. 2005;207(4):453–61. https://doi.org/10.1002/path.1870.

    Article  CAS  PubMed  Google Scholar 

  76. Deng A, Zhang H, Hu M, Liu S, Gao Q, Wang Y, et al. Knockdown of Indian hedgehog protein induces an inhibition of cell growth and differentiation in osteoblast MC3T3E1 cells. Mol Med Rep. 2017;16(6):7987–92. https://doi.org/10.3892/mmr.2017.7669.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Maeda Y, Nakamura E, Nguyen MT, Suva LJ, Swain FL, Razzaque MS, et al. Indian hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone. Proc Natl Acad Sci U S A. 2007;104(15):6382–7. https://doi.org/10.1073/pnas.0608449104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Javaheri B, Caetano-Silva SP, Kanakis I, Bou-Gharios G, Pitsillides AA. The chondro-osseous continuum: is it possible to unlock the potential assigned within? Front Bioeng Biotechnol. 2018;6:28. https://doi.org/10.3389/fbioe.2018.00028.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Clarkin C, Olsen BR. On bone-forming cells and blood vessels in bone development. Cell Metab. 2010;12(4):314–6. https://doi.org/10.1016/j.cmet.2010.09.009.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Shah M, Gburcik V, Reilly P, Sankey RA, Emery RJ, Clarkin CE, et al. Local origins impart conserved bone type-related differences in human osteoblast behaviour. Eur Cells Mater. 2015;29:155–75 discussion 75-6.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge the contributions of all researchers regarding the fate of hypertrophic chondrocytes in the field of skeletogenesis and apologize for not citing all the original research regarding the previous in vitro observations on transdifferentiation.

Funding

Research by the authors is supported by grants from the Deutsche Forschungsgemeinschaft (HA 4767/2-1, HA 4767/4-2, HA 4767/5-1) and from the Federal Ministry of Education and Science (01EC1408E), as part of the OVERLOAD-Prev-OP consortium. The authors further acknowledge institutional support by a grant from the Interdisciplinary Center of Clinical Research (IZKF, Har2/002/14).

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  1. Institute of Musculoskeletal Medicine, Department of Bone and Skeletal Research, Medical Faculty of the Westphalian Wilhelms University Münster, Munster, Germany

    Lena Ingeborg Wolff & Christine Hartmann

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  1. Lena Ingeborg Wolff
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Correspondence to Christine Hartmann.

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Conflict of Interest

Christine Hartmann reports grants from the German research foundation (DFG) and grants from the German Federal Ministry of Education and Science, during the conduct of the study. Lena Wolff declares no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human subjects performed by the authors. Animal studies performed by the authors regarding chondrocyte-to-osteoblast transdifferentiation were in accordance with local, institutional, and national regulations and licenses (AZ: 84-02.05.2012.261; 84-02.04.2015.128; 84-02.05.50.15.022).

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Wolff, L.I., Hartmann, C. A Second Career for Chondrocytes—Transformation into Osteoblasts. Curr Osteoporos Rep 17, 129–137 (2019). https://doi.org/10.1007/s11914-019-00511-3

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