• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of pnasPNASInfo for AuthorsSubscriptionsAboutThis Article
Proc Natl Acad Sci U S A. Sep 17, 1996; 93(19): 10240–10245.
PMCID: PMC38368

Targeted overexpression of parathyroid hormone-related peptide in chondrocytes causes chondrodysplasia and delayed endochondral bone formation.

Abstract

Parathyroid hormone-related peptide (PTHrP) was initially identified as a product of malignant tumors that mediates paraneoplastic hypercalcemia. It is now known that the parathyroid hormone (PTH) and PTHrP genes are evolutionarily related and that the products of these two genes share a common receptor, the PTH/PTHrP receptor. PTHrP and the PTH/PTHrP receptor are widely expressed in both adult and fetal tissues, and recent gene-targeting and disruption experiments have implicated PTHrP as a developmental regulatory molecule. Apparent PTHrP functions include the regulation of endochondral bone development, of hair follicle formation, and of branching morphogenesis in the breast. Herein, we report that overexpression of PTHrP in chondrocytes using the mouse type II collagen promoter induces a novel form of chondrodysplasia characterized by short-limbed dwarfism and a delay in endochondral ossification. This features a delay in chondrocyte differentiation and in bone collar formation and is sufficiently marked that the mice are born with a cartilaginous endochondral skeleton. In addition to the delay, chondrocytes in the transgenic mice initially become hypertrophic at the periphery of the developing long bones rather than in the middle, leading to a seeming reversal in the pattern of chondrocyte differentiation and ossification. By 7 weeks, the delays in chondrocyte differentiation and ossification have largely corrected, leaving foreshortened and misshapen but histologically near-normal bones. These findings confirm a role for PTHrP as an inhibitor of the program of chondrocyte differentiation. PTHrP may function in this regard to maintain the stepwise differentiation of chondrocytes that initiates endochondral ossification in the midsection of endochondral bones early in development and that also permits linear growth at the growth plate later in development.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (2.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Martin TJ. Properties of parathyroid hormone-related protein and its role in malignant hypercalcaemia. Q J Med. 1990 Aug;76(280):771–786. [PubMed]
  • Strewler GJ, Nissenson RA. Hypercalcemia in malignancy. West J Med. 1990 Dec;153(6):635–640. [PMC free article] [PubMed]
  • Jüppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF, Jr, Hock J, Potts JT, Jr, Kronenberg HM, et al. A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science. 1991 Nov 15;254(5034):1024–1026. [PubMed]
  • Lee K, Deeds JD, Segre GV. Expression of parathyroid hormone-related peptide and its receptor messenger ribonucleic acids during fetal development of rats. Endocrinology. 1995 Feb;136(2):453–463. [PubMed]
  • Wysolmerski JJ, Broadus AE, Zhou J, Fuchs E, Milstone LM, Philbrick WM. Overexpression of parathyroid hormone-related protein in the skin of transgenic mice interferes with hair follicle development. Proc Natl Acad Sci U S A. 1994 Feb 1;91(3):1133–1137. [PMC free article] [PubMed]
  • Wysolmerski JJ, McCaughern-Carucci JF, Daifotis AG, Broadus AE, Philbrick WM. Overexpression of parathyroid hormone-related protein or parathyroid hormone in transgenic mice impairs branching morphogenesis during mammary gland development. Development. 1995 Nov;121(11):3539–3547. [PubMed]
  • Karaplis AC, Luz A, Glowacki J, Bronson RT, Tybulewicz VL, Kronenberg HM, Mulligan RC. Lethal skeletal dysplasia from targeted disruption of the parathyroid hormone-related peptide gene. Genes Dev. 1994 Feb 1;8(3):277–289. [PubMed]
  • Metsäranta M, Toman D, de Crombrugghe B, Vuorio E. Mouse type II collagen gene. Complete nucleotide sequence, exon structure, and alternative splicing. J Biol Chem. 1991 Sep 5;266(25):16862–16869. [PubMed]
  • Savagner P, Miyashita T, Yamada Y. Two silencers regulate the tissue-specific expression of the collagen II gene. J Biol Chem. 1990 Apr 25;265(12):6669–6674. [PubMed]
  • Wang LQ, Balakir R, Horton WE., Jr Identification of a cis-acting sequence in the collagen II enhancer required for chondrocyte expression and the binding of a chondrocyte nuclear factor. J Biol Chem. 1991 Oct 25;266(30):19878–19881. [PubMed]
  • Vikkula M, Metsäranta M, Syvänen AC, Ala-Kokko L, Vuorio E, Peltonen L. Structural analysis of the regulatory elements of the type-II procollagen gene. Conservation of promoter and first intron sequences between human and mouse. Biochem J. 1992 Jul 1;285(Pt 1):287–294. [PMC free article] [PubMed]
  • Horton W, Miyashita T, Kohno K, Hassell JR, Yamada Y. Identification of a phenotype-specific enhancer in the first intron of the rat collagen II gene. Proc Natl Acad Sci U S A. 1987 Dec;84(24):8864–8868. [PMC free article] [PubMed]
  • Metsäranta M, Garofalo S, Smith C, Niederreither K, de Crombrugghe B, Vuorio E. Developmental expression of a type II collagen/beta-galactosidase fusion gene in transgenic mice. Dev Dyn. 1995 Oct;204(2):202–210. [PubMed]
  • Cheah KS, Lau ET, Au PK, Tam PP. Expression of the mouse alpha 1(II) collagen gene is not restricted to cartilage during development. Development. 1991 Apr;111(4):945–953. [PubMed]
  • Wood A, Ashhurst DE, Corbett A, Thorogood P. The transient expression of type II collagen at tissue interfaces during mammalian craniofacial development. Development. 1991 Apr;111(4):955–968. [PubMed]
  • Sandberg M, Vuorio E. Localization of types I, II, and III collagen mRNAs in developing human skeletal tissues by in situ hybridization. J Cell Biol. 1987 Apr;104(4):1077–1084. [PMC free article] [PubMed]
  • McLeod MJ. Differential staining of cartilage and bone in whole mouse fetuses by alcian blue and alizarin red S. Teratology. 1980 Dec;22(3):299–301. [PubMed]
  • Weir EC, Horowitz MC, Baron R, Centrella M, Kacinski BM, Insogna KL. Macrophage colony-stimulating factor release and receptor expression in bone cells. J Bone Miner Res. 1993 Dec;8(12):1507–1518. [PubMed]
  • Gardner E. The embryology of the clavicle. Clin Orthop Relat Res. 1968 May-Jun;58:9–16. [PubMed]
  • Erlebacher A, Filvaroff EH, Gitelman SE, Derynck R. Toward a molecular understanding of skeletal development. Cell. 1995 Feb 10;80(3):371–378. [PubMed]
  • Iwamoto M, Jikko A, Murakami H, Shimazu A, Nakashima K, Iwamoto M, Takigawa M, Baba H, Suzuki F, Kato Y. Changes in parathyroid hormone receptors during chondrocyte cytodifferentiation. J Biol Chem. 1994 Jun 24;269(25):17245–17251. [PubMed]
  • Henderson JE, Amizuka N, Warshawsky H, Biasotto D, Lanske BM, Goltzman D, Karaplis AC. Nucleolar localization of parathyroid hormone-related peptide enhances survival of chondrocytes under conditions that promote apoptotic cell death. Mol Cell Biol. 1995 Aug;15(8):4064–4075. [PMC free article] [PubMed]
  • Amizuka N, Warshawsky H, Henderson JE, Goltzman D, Karaplis AC. Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation. J Cell Biol. 1994 Sep;126(6):1611–1623. [PMC free article] [PubMed]
  • Schipani E, Kruse K, Jüppner H. A constitutively active mutant PTH-PTHrP receptor in Jansen-type metaphyseal chondrodysplasia. Science. 1995 Apr 7;268(5207):98–100. [PubMed]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...