Skip to main content

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

  • Review Article
  • Published:

Developmental regulation of the growth plate

Abstract

Vertebrates do not look like jellyfish because the bones of their skeletons are levers that allow movement and protect vital organs. Bones come in an enormous variety of shapes and sizes to accomplish these goals, but, with few exceptions, use one process — endochondral bone formation — to generate the skeleton. The past few years have seen an enormous increase in understanding of the signalling pathways and the transcription factors that control endochondral bone development.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Endochondral bone formation.
Figure 2: Indian hedgehog (Ihh)/parathyroid hormone-related protein (PTHrP) negative-feedback loop.
Figure 3: Fibroblast growth factor (FGF) signalling in the growth plate.
Figure 4: Opposing actions of bone morphogenetic proteins (BMPs) and fibroblast growth factors (FGFs) on the growth plate.

Similar content being viewed by others

References

  1. Hall, B. K. & Miyake, T. All for one and one for all: condensations and the initiation of skeletal development. BioEsssays 22, 138–147 (2000).

    CAS  Google Scholar 

  2. Noonan, K. J., Hunziker, E. B., Nessler, J. & Buckwalter, J. A. Changes in cell, matrix compartment, and fibrillar collagen volumes between growth-plate zones. J. Orthop. Res. 16, 500–508 (1998).

    CAS  PubMed  Google Scholar 

  3. St-Jacques, B., Hammerschmidt, M. & McMahon, A. P. Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev. 13, 2072–2086 (1999). [Published erratum appears in Genes Dev. 13, 2617 (1999).]

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Long, F., Zhang, X. M., Karp, S., Yang, Y. & McMahon, A. P. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 128, 5099–5108 (2001).

    CAS  PubMed  Google Scholar 

  5. Karaplis, A. C. et al. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 8, 277–289 (1994).

    CAS  PubMed  Google Scholar 

  6. Lanske, B. et al. PTH/PTHrP receptor in early development and Indian hedgehog-regulated bone growth. Science 273, 663–666 (1996).

    ADS  CAS  PubMed  Google Scholar 

  7. Weir, E. C. et al. Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation. Proc. Natl Acad. Sci. USA 93, 10240–10245 (1996).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  8. Schipani, E. et al. Targeted expression of constitutively active receptors for parathyroid hormone and parathyroid hormone-related peptide delays endochondral bone formation and rescues mice that lack parathyroid hormone-related peptide. Proc. Natl Acad. Sci. USA 94, 13689–13694 (1997).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Karp, S. J. et al. Indian Hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent. Development 127, 543–548 (2000).

    CAS  PubMed  Google Scholar 

  10. Vortkamp, A. et al. Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein. Science 273, 613–622 (1996).

    ADS  CAS  PubMed  Google Scholar 

  11. Chung, U. I., Lanske, B., Lee, K., Li, E. & Kronenberg, H. The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation. Proc. Natl Acad. Sci. USA 95, 13030–13035 (1998).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chung, U. I., Schipani, E., McMahon, A. P. & Kronenberg, H. M. Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. J. Clin. Invest. 107, 295–304 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Ornitz, D. M. & Marie, P. J. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 16, 1446–1465 (2002).

    CAS  PubMed  Google Scholar 

  14. Murakami, S., Kan, M., McKeehan, W. L. & de Crombrugghe, B. 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, 1113–1118 (2000).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. Deng, C., Wynshaw-Boris, A., Zhou, F., Kuo, A. & Leder, P. Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911–921 (1996).

    CAS  PubMed  Google Scholar 

  16. Colvin, J. S., Bohne, B. A., Harding, G. W., McEwen, D. G. & Ornitz, D. M. Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genet. 12, 390–397 (1996).

    CAS  PubMed  Google Scholar 

  17. Naski, M. C., Colvin, J. S., Coffin, J. D. & Ornitz, D. M. Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125, 4977–4988 (1998).

    CAS  PubMed  Google Scholar 

  18. Sahni, M. et al. FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes Dev. 13, 1361–1366 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Liu, Z., Xu, J., Colvin, J. S. & Ornitz, D. M. Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev. 16, 859–869 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Ohbayashi, N. et al. FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes Dev. 16, 870–879 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Minina, E., Kreschel, C., Naski, M. C., Ornitz, D. M. & Vortkamp, A. Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Dev. Cell 3, 439–449 (2002).

    CAS  PubMed  Google Scholar 

  22. Rosen, V. & Wozney, J. M. in Principles of Bone Biology (eds Bilezikian, J. P., Raisz, L. G. & Rodan, G. A.) 919–928 (Academic, San Diego, 2002).

    Google Scholar 

  23. Pizette, S. & Niswander, L. BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes. Dev. Biol. 219, 237–249 (2000).

    CAS  PubMed  Google Scholar 

  24. Brunet, L. J., McMahon, J. A., McMahon, A. P. & Harland, R. M. Noggin, cartilage morphogenesis, and joint formation in the mammalian skeleton. Science 280, 1455–1458 (1998).

    ADS  CAS  PubMed  Google Scholar 

  25. Kingsley, D. M. et al. The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGF beta superfamily. Cell 71, 399–410 (1992).

    CAS  PubMed  Google Scholar 

  26. Storm, E. E. & Kingsley, D. M. GDF5 coordinates bone and joint formation during digit development. Dev. Biol. 209, 11–27 (1999).

    CAS  PubMed  Google Scholar 

  27. Yi, S. E., Daluiski, A., Pederson, R., Rosen, V. & Lyons, K. M. The type I BMP receptor BMPRIB is required for chondrogenesis in the mouse limb. Development 127, 621–630 (2000).

    CAS  PubMed  Google Scholar 

  28. Baur, S. T., Mai, J. J. & Dymecki, S. M. Combinatorial signaling through BMP receptor IB and GDF5: shaping of the distal mouse limb and the genetics of distal limb diversity. Development 127, 605–619 (2000).

    CAS  PubMed  Google Scholar 

  29. Minina, E. et al. BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. Development 128, 4523–4534 (2001).

    CAS  PubMed  Google Scholar 

  30. Bi, W., Deng, J. M., Zhang, Z., Behringer, R. R. & de Crombrugghe, B. Sox9 is required for cartilage formation. Nature Genet. 22, 85–89 (1999).

    CAS  PubMed  Google Scholar 

  31. Akiyama, H., Chaboissier, M. C., Martin, J. F., Schedl, A. & de Crombrugghe, B. 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, 2813–2828 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Smits, P. et al. The transcription factors L-Sox5 and Sox6 are essential for cartilage formation. Dev. Cell 1, 277–290 (2001).

    CAS  PubMed  Google Scholar 

  33. Otto, F. et al. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell 89, 765–771 (1997).

    CAS  PubMed  Google Scholar 

  34. Komori, T. et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89, 755–764 (1997).

    CAS  PubMed  Google Scholar 

  35. Inada, M. et al. Maturational disturbance of chondrocytes in Cbfa1-deficient mice. Dev. Dyn. 214, 279–290 (1999).

    CAS  PubMed  Google Scholar 

  36. Takeda, S., Bonnamy, J. P., Owen, M. J., Ducy, P. & Karsenty, G. Continuous expression of Cbfa1 in nonhypertrophic chondrocytes uncovers its ability to induce hypertrophic chondrocyte differentiation and partially rescues Cbfa1-deficient mice. Genes Dev. 15, 467–481 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Ueta, C. et al. Skeletal malformations caused by overexpression of Cbfa1 or its dominant negative form in chondrocytes. J. Cell Biol. 153, 87–100 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

I thank A. McMahon for a careful review of this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Henry M. Kronenberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kronenberg, H. Developmental regulation of the growth plate. Nature 423, 332–336 (2003). https://doi.org/10.1038/nature01657

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01657

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

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

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