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A mutant PTH/PTHrP type I receptor in enchondromatosis

Nature Genetics volume 30, pages 306–310 (2002)Cite this article

Abstract

Enchondromas are common benign cartilage tumors of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis (Ollier and Maffucci diseases). Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to chondrosarcoma1,2,3. The extent of skeletal involvement is variable in enchondromatosis and may include dysplasia that is not directly attributable to enchondromas4. Enchondromatosis is rare, obvious inheritance of the condition is unusual and no candidate loci have been identified. Enchondromas are usually in close proximity to, or in continuity with, growth-plate cartilage. Consequently, they may result from abnormal regulation of proliferation and terminal differentiation of chondrocytes in the adjoining growth plate. In normal growth plates, differentiation of proliferative chondrocytes to post-mitotic hypertrophic chondrocytes is regulated in part by a tightly coupled signaling relay involving parathyroid hormone related protein (PTHrP) and Indian hedgehog (IHH)5,6,7,8,9. PTHrP delays the hypertrophic differentiation of proliferating chondrocytes, whereas IHH promotes chondrocyte proliferation. We identified a mutant PTH/PTHrP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice. The mutant receptor constitutively activates Hedgehog signaling, and excessive Hedgehog signaling is sufficient to cause formation of enchondroma-like lesions.

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Figure 1: PTHR1 mutation and functional analysis.
Figure 2: Newborn mouse growth plates.
Figure 3: Enchondromas in PTHR1 transgenic mice.
Figure 4: Growth plates in PTHR1 transgenic mice.
Figure 5: a, The R150C PTHR1 mutant constitutively activates a Hedghehog-responsive Gli2-luciferase reporter construct.

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References

  1. Levesque, J. et al. Enchondroma. in A Clinical Guide to Primary Bone Tumors 98–107 (Williams and Wilkins, Philadelphia, 1998).

    Google Scholar 

  2. Huvos, A.G. Solitary and multiple osteochondromas and enchondromas: jusxtacortical chondroma; maffuci's disease. in Bone Tumors, Diagnosis Treatment and Prognosis. 264–294 (WB Saunders, Philadelphia, 1991).

    Google Scholar 

  3. Schwartz, H.S. et al. The malignant potential of enchondromatosis. J. Bone Joint Surg. Am. 69, 269–274 (1987).

    Article  CAS  PubMed  Google Scholar 

  4. Zack, P. & Beighton, P. Spondyloenchondromatosis: syndromic identity and evolution of the phenotype. Am. J. Med. Genet. 55, 478–482 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  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).

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  8. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Halal, F. & Azouz, E.M. Generalized enchondromatosis in a boy with only platyspondyly in the father. Am. J. Med. Genet. 38, 588–592 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Juppner, H. et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254, 1024–1026 (1991).

    Article  CAS  PubMed  Google Scholar 

  12. Schipani, E. et al. Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia. N. Engl. J. Med. 335, 708–714 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Schipani, E., Kruse, K. & Juppner, H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science 268, 98–100 (1995).

    Article  CAS  PubMed  Google Scholar 

  14. Jobert, A.S. et al. Absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide in Blomstrand chondrodysplasia. J. Clin. Invest. 102, 34–40 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Karaplis, A.C. et al. Inactivating mutation in the human parathyroid hormone receptor type 1 gene in Blomstrand chondrodysplasia. Endocrinology 139, 5255–5258 (1998).

    Article  CAS  PubMed  Google Scholar 

  16. Guo, J., Chung, U., Bringhurst, R.F. & Kronenberg, H.M. Failure of phospholipase C activation via the PTH/PTHrP receptor leads to abnormalities in embryonic bone development. J. Bone Miner. Res. 15, S152 (2000).

  17. Jaffe, H.L. Certain other anomalies of skeletal development. in Metabolic, Degenerative, and Inflammatory Diseases of Bones and Joints 222–226 (Lea and Feibiger, Philadelphia, 1972).

    Google Scholar 

  18. Bruggeman, L.A., Xie, H.X., Brown, K.S. & Yamada, Y. Developmental regulation for collagen II gene expression in transgenic mice. Teratology 44, 203–208 (1991).

    Article  CAS  PubMed  Google Scholar 

  19. Yamada, Y. et al. Regulation of the collagen II gene in vitro and in transgenic mice. Ann. NY Acad. Sci. 580, 81–87 (1990).

    Article  CAS  PubMed  Google Scholar 

  20. O'Keefe, R.J., Puzas, J.E., Loveys, L., Hicks, D.G. & Rosier, R.N. Analysis of type II and type X collagen synthesis in cultured growth plate chondrocytes by in situ hybridization: rapid induction of type X collagen in culture. J. Bone Miner. Res. 9, 1713–1722 (1994).

    Article  CAS  PubMed  Google Scholar 

  21. Vu, T.H. et al. MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411–422 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Mo, R. et al. Specific and redundant functions of Gli2 and Gli3 zinc finger genes in skeletal patterning and development. Development 124, 113–123 (1997).

    CAS  PubMed  Google Scholar 

  23. Sasaki, H., Nishizaki, Y., Hui, C., Nakafuku, M. & Kondoh, H. Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. Development 126, 3915–3924 (1999).

    CAS  PubMed  Google Scholar 

  24. Grachtchouk, M. et al. Basal cell carcinomas in mice overexpressing Gli2 in skin. Nature Genet. 24, 216–217 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Hopyan, S. et al. Expression of osteocalcin and its transcriptional regulators core-binding factor α 1 and MSX2 in osteoid-forming tumours. J. Orthop. Res. 17, 633–638 (1999).

    Article  CAS  PubMed  Google Scholar 

  26. Xie, L.Y. & Abou-Samra, A.B. Epitope tag mapping of the extracellular and cytoplasmic domains of the rat parathyroid hormone (PTH)/PTH-related peptide receptor. Endocrinology 139, 4563–4567 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Li, C., Bapat, B. & Alman, B. A. Adenomatous polyposis coli gene mutation alters proliferation through its beta-catenin-regulatory function in aggressive fibromatosis (desmoid tumor). Am. J. Pathol. 153, 709–714 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Carter, P.H., Jüppner, H. & Gardella, T.J. Studies of the N-terminal region of a parathyroid hormone-related peptide (1-36) analog: receptor subtype-selective agonists, antagonists, and photochemical cross-linking agents. Endocrinology 140, 4972–4981 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Schipani E, et al. Pseudohypoparathyroidism type Ib is not caused by mutations in the coding exons of the human parathyroid hormone (PTH)/PTH-related peptide receptor gene. J. Clin. Endocrinol. Metab. 80, 1611–1621 (1995).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank affected individuals and their families for their cooperation, C.-C. Hui for Gli2 and Gli2-luciferase cDNA, U.-I. Chung for PTHR1−/− embryonic stem cells, Y. Yamada for Col2A1 promoter/enhancer cDNA, T. Ingolia (Ontogeny) for Shh-N protein, A. Karaplis for c-Myc–tagged PTHR1 cDNA (Hkrk), F. de Sauvage (Genentech) for Smo cDNA, S. Tondat and L. Schwartz for pronuclear microinjections, L. Morikawa for histology, M. Ho for anti-c-Myc immunohistochemistry, M. To for assistance with cAMP assays, S. Cheon for assistance with SSCP analysis, A. Davis for help with statistical analysis, J. Ahier for patient contact, members of the Andrulis and Alman labs for support, A. Gross, C. Hutchison and J. Wright for tissue specimens; and J. Aubin, U. Chung, J. Dennis, S. Egan, J. Haigh, C.-C. Hui, H. Kronenberg and J. Rossant for critical advice. This work was supported by grants from the National Cancer Institute of Canada with funds from the Terry Fox Run (to B.A.A., I.L.A. and R.S.B.), the Canadian Institutes of Health Research (to J.S.W., B.A.A. and W.G.C.) and The Hospital for Sick Children Research Institute Trainees' Start-Up Fund (to S.H.). S.H. is supported by a Clinician-Scientist Fellowship from the Research Training Centre of The Hospital for Sick Children Research Institute, and B.A.A. is supported by the Canadian Research Chair Program.

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Authors and Affiliations

  1. Program in Developmental Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada

    Sevan Hopyan, Raymond Poon, Chunying Yu & Benjamin A. Alman

  2. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, M5G1X5, Ontario, Canada

    Sevan Hopyan, Nalan Gokgoz, Irene L. Andrulis & Jay S. Wunder

  3. Department of Surgery, Division of Orthopaedics, University of Toronto, Toronto, Ontario, Canada

    Sevan Hopyan, William G. Cole, Robert S. Bell, Jay S. Wunder & Benjamin A. Alman

  4. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Sevan Hopyan, Robert S. Bell, Jay S. Wunder & Benjamin A. Alman

  5. Departments of Medicine and Pediatrics, Endocrine and Pediatric Endocrine Units, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA

    Robert C. Gensure & Harald Jüppner

  6. Division of Orthopaedics, The Hospital for Sick Children, Toronto, Ontario, Canada

    William G. Cole & Benjamin A. Alman

  7. Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada

    William G. Cole & Irene L. Andrulis

  8. University Musculoskeletal Oncology Unit and Division of Orthopaedics, Mount Sinai Hospital, Toronto, M5G1X5, Ontario, Canada

    Robert S. Bell, Irene L. Andrulis & Jay S. Wunder

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  1. Sevan Hopyan
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Correspondence to Jay S. Wunder.

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Hopyan, S., Gokgoz, N., Poon, R. et al. A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat Genet 30, 306–310 (2002). https://doi.org/10.1038/ng844

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