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Science 2 August 1996:
Vol. 273. no. 5275, pp. 613 - 622
DOI: 10.1126/science.273.5275.613
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Research Articles

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Regulation of Rate of Cartilage Differentiation by Indian Hedgehog and PTH-Related Protein

Andrea Vortkamp, * Kaechoong Lee, * Beate Lanske, Gino V. Segre, Henry M. Kronenberg, Clifford J. Tabin dagger

Proper regulation of chondrocyte differentiation is necessary for the morphogenesis of skeletal elements, yet little is known about the molecular regulation of this process. A chicken homolog of Indian hedgehog (Ihh), a member of the conserved Hedgehog family of secreted proteins that is expressed during bone formation, has now been isolated. Ihh has biological properties similar to those of Sonic hedgehog (Shh), including the ability to regulate the conserved targets Patched (Ptc) and Gli. Ihh is expressed in the prehypertrophic chondrocytes of cartilage elements, where it regulates the rate of hypertrophic differentiation. Misexpression of Ihh prevents proliferating chondrocytes from initiating the hypertrophic differentiation process. The direct target of Ihh signaling is the perichondrium, where Gli and Ptc flank the expression domain of Ihh. Ihh induces the expression of a second signal, parathyroid hormone--related protein (PTHrP), in the periarticular perichondrium. Analysis of PTHrP (-/-) mutant mice indicated that the PTHrP protein signals to its receptor in the prehypertrophic chondrocytes, thereby blocking hypertrophic differentiation. In vitro application of Hedgehog or PTHrP protein to normal or PTHrP (-/-) limb explants demonstrated that PTHrP mediates the effects of Ihh through the formation of a negative feedback loop that modulates the rate of chondrocyte differentiation.

A. Vortkamp and C. J. Tabin are in the Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. K. Lee, B. Lanske, G. V. Segre, and H. M. Kronenberg are in the Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed.


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Expression of Galectin-3 in Skeletal Tissues Is Controlled by Runx2.
M. Stock, H. Schafer, S. Stricker, G. Gross, S. Mundlos, and F. Otto (2003)
J. Biol. Chem. 278, 17360-17367
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Positive Regulation of Endochondral Cartilage Growth by Perichondrial and Periosteal Calcitonin.
D. L. Di Nino and T. F. Linsenmayer (2003)
Endocrinology 144, 1979-1983
   Abstract »    Full Text »    PDF »
The Biology of the Growth Plate.
R. T. Ballock and R. J. O'Keefe (2003)
J. Bone Joint Surg. Am. 85, 715-726
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Wnt regulation of chondrocyte differentiation.
V. Church, T. Nohno, C. Linker, C. Marcelle, and P. Francis-West (2003)
J. Cell Sci. 115, 4809-4818
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growth arrest specific gene 1 acts as a region-specific mediator of the Fgf10/Fgf8 regulatory loop in the limb.
Y. Liu, C. Liu, Y. Yamada, and C.-M. Fan (2003)
Development 129, 5289-5300
   Abstract »    Full Text »    PDF »
Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation.
Y. Yang, L. Topol, H. Lee, and J. Wu (2003)
Development 130, 1003-1015
   Abstract »    Full Text »    PDF »
Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development.
H. Chen, S. A. Detmer, A. J. Ewald, E. E. Griffin, S. E. Fraser, and D. C. Chan (2003)
J. Cell Biol. 160, 189-200
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The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6.
H. Akiyama, M.-C. Chaboissier, J. F. Martin, A. Schedl, and B. de Crombrugghe (2002)
Genes & Dev. 16, 2813-2828
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Anabolic Actions of Parathyroid Hormone during Bone Growth Are Dependent on c-fos.
B. Demiralp, H.-L. Chen, A. J. Koh, E. T. Keller, and L. K. McCauley (2002)
Endocrinology 143, 4038-4047
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Functions of Transforming Growth Factor-beta Family Type I Receptors and Smad Proteins in the Hypertrophic Maturation and Osteoblastic Differentiation of Chondrocytes.
U. Valcourt, J. Gouttenoire, A. Moustakas, D. Herbage, and F. Mallein-Gerin (2002)
J. Biol. Chem. 277, 33545-33558
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Cyclic GMP-Dependent Protein Kinase II Plays a Critical Role in C-Type Natriuretic Peptide-Mediated Endochondral Ossification.
T. Miyazawa, Y. Ogawa, H. Chusho, A. Yasoda, N. Tamura, Y. Komatsu, A. Pfeifer, F. Hofmann, and K. Nakao (2002)
Endocrinology 143, 3604-3610
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The Cyclin D1 and Cyclin A Genes Are Targets of Activated PTH/PTHrP Receptors in Jansen's Metaphyseal Chondrodysplasia.
F. Beier and P. LuValle (2002)
Mol. Endocrinol. 16, 2163-2173
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Positional cloning of the gene LIMBIN responsible for bovine chondrodysplastic dwarfism.
H. Takeda, M. Takami, T. Oguni, T. Tsuji, K. Yoneda, H. Sato, N. Ihara, T. Itoh, S. R. Kata, Y. Mishina, et al. (2002)
PNAS 99, 10549-10554
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Shh establishes an Nkx3.2/Sox9 autoregulatory loop that is maintained by BMP signals to induce somitic chondrogenesis.
L. Zeng, H. Kempf, L. C. Murtaugh, M. E. Sato, and A. B. Lassar (2002)
Genes & Dev. 16, 1990-2005
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