The fully linked HTML version of this article has now been published.
Development ePress online publication date 18 Feb 2004
doi: 10.1242/dev.01006
Research article
Ihh signaling is directly required for the osteoblast lineage in the endochondral skeleton
Fanxin Long,
Ung-il Chung,
Shinsuke Ohba,
Jill McMahon,
Henry M. Kronenberg,
and
Andrew P. McMahon*
* Author for correspondence (e-mail: amcmahon{at}mcb.harvard.edu)
Indian hedgehog (Ihh) is indispensable for development of the osteoblast lineage in the endochondral skeleton. In order to determine whether Ihh is directly required for osteoblast differentiation, we have genetically manipulated smoothened (Smo), which encodes a transmembrane protein that is essential for transducing all Hedgehog (Hh) signals. Removal of Smo from perichondrial cells by the Cre-LoxP approach prevents formation of a normal bone collar and also abolishes development of the primary spongiosa. Analysis of chimeric embryos composed of wild-type and Smon/n cells indicates that Smon/n cells fail to contribute to osteoblasts in either the bone collar or the primary spongiosa but generate ectopic chondrocytes. In order to assess whether Ihh is sufficient to induce bone formation in vivo, we have analyzed the bone collar in the long bones of embryos in which Ihh was artificially expressed in all chondrocytes by the UAS-GAL4 bigenic system. Although ectopic Ihh does not induce overt ossification along the entire cartilage anlage, it promotes progression of the bone collar toward the epiphysis, suggesting a synergistic effect between ectopic Ihh and endogenous factors such as the bone morphogenetic proteins (BMPs). In keeping with this model, Hh signaling is further found to be required in BMP-induced osteogenesis in cultures of a limb-bud cell line. Taken together, these results demonstrate that Ihh signaling is directly required for the osteoblast lineage in the developing long bones and that Ihh functions in conjunction with other factors such as BMPs to induce osteoblast differentiation. We suggest that Ihh acts in vivo on a potential progenitor cell to promote osteoblast and prevent chondrocyte differentiation.

CiteULike
Complore
Connotea
Del.icio.us
Digg
Reddit
Technorati
Twitter What's this?
This article has been cited by other articles:

|
 |

|
 |
 
K. S. Joeng and F. Long
The Gli2 transcriptional activator is a crucial effector for Ihh signaling in osteoblast development and cartilage vascularization
Development,
December 15, 2009;
136(24):
4177 - 4185.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. Ohba, F. Yano, and U.-i. Chung
Tissue Engineering of Bone and Cartilage
IBMS BoneKEy,
November 1, 2009;
6(11):
405 - 419.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. Matsushita, Y. Y. Chan, A. Kawanami, G. Balmes, G. E. Landreth, and S. Murakami
Extracellular Signal-Regulated Kinase 1 (ERK1) and ERK2 Play Essential Roles in Osteoblast Differentiation and in Supporting Osteoclastogenesis
Mol. Cell. Biol.,
November 1, 2009;
29(21):
5843 - 5857.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
W.-K. Kim, V. Meliton, K. W. Park, C. Hong, P. Tontonoz, P. Niewiadomski, J. A. Waschek, S. Tetradis, and F. Parhami
Negative Regulation of Hedgehog Signaling by Liver X Receptors
Mol. Endocrinol.,
October 1, 2009;
23(10):
1532 - 1543.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
G. W. Calloni, N. M. Le Douarin, and E. Dupin
High frequency of cephalic neural crest cells shows coexistence of neurogenic, melanogenic, and osteogenic differentiation capacities
PNAS,
June 2, 2009;
106(22):
8947 - 8952.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
F. Long
Chondrocytes: Meeting Report from the 30th Annual Meeting of the American Society for Bone and Mineral Research: September 12-16, 2008 in Montreal, Canada
IBMS BoneKEy,
September 1, 2008;
5(9):
340 - 342.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. Napierala, K. Sam, R. Morello, Q. Zheng, E. Munivez, R. A. Shivdasani, and B. Lee
Uncoupling of chondrocyte differentiation and perichondrial mineralization underlies the skeletal dysplasia in tricho-rhino-phalangeal syndrome
Hum. Mol. Genet.,
July 15, 2008;
17(14):
2244 - 2254.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
J. B. Regard and Y. Yang
Hedgehog Signaling in Postnatal Bone
IBMS BoneKEy,
July 1, 2008;
5(7):
243 - 252.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. K. Mak, H. M. Kronenberg, P.-T. Chuang, S. Mackem, and Y. Yang
Indian hedgehog signals independently of PTHrP to promote chondrocyte hypertrophy
Development,
June 1, 2008;
135(11):
1947 - 1956.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. Nagayama, M. Iwamoto, A. Hargett, N. Kamiya, Y. Tamamura, B. Young, T. Morrison, H. Takeuchi, M. Pacifici, M. Enomoto-Iwamoto, et al.
Wnt/{beta}-catenin Signaling Regulates Cranial Base Development and Growth
Journal of Dental Research,
March 1, 2008;
87(3):
244 - 249.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
T. F. Day and Y. Yang
Wnt and Hedgehog Signaling Pathways in Bone Development
J. Bone Joint Surg. Am.,
February 1, 2008;
90(Supplement_1):
19 - 24.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
G. L. Barnes, S. Kakar, S. Vora, E. F. Morgan, L. C. Gerstenfeld, and T. A. Einhorn
Stimulation of Fracture-Healing with Systemic Intermittent Parathyroid Hormone Treatment
J. Bone Joint Surg. Am.,
February 1, 2008;
90(Supplement_1):
120 - 127.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
A. Abzhanov, S. J. Rodda, A. P. McMahon, and C. J. Tabin
Regulation of skeletogenic differentiation in cranial dermal bone
Development,
September 1, 2007;
134(17):
3133 - 3144.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
V. L. Ruiz-Perez, H. J. Blair, M. E. Rodriguez-Andres, M. J. Blanco, A. Wilson, Y.-N. Liu, C. Miles, H. Peters, and J. A. Goodship
Evc is a positive mediator of Ihh-regulated bone growth that localises at the base of chondrocyte cilia
Development,
August 15, 2007;
134(16):
2903 - 2912.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. Baron and G. Rawadi
Targeting the Wnt/{beta}-Catenin Pathway to Regulate Bone Formation in the Adult Skeleton
Endocrinology,
June 1, 2007;
148(6):
2635 - 2643.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. Ohba, T. Ikeda, F. Kugimiya, F. Yano, A. C. Lichtler, K. Nakamura, T. Takato, H. Kawaguchi, and U.-i. Chung
Identification of a potent combination of osteogenic genes for bone regeneration using embryonic stem (ES) cell-based sensor
FASEB J,
June 1, 2007;
21(8):
1777 - 1787.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
R. L. Chandler, K. J. Chandler, K. A. McFarland, and D. P. Mortlock
Bmp2 Transcription in Osteoblast Progenitors Is Regulated by a Distant 3' Enhancer Located 156.3 Kilobases from the Promoter
Mol. Cell. Biol.,
April 15, 2007;
27(8):
2934 - 2951.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
Y. Maeda, E. Nakamura, M.-T. Nguyen, L. J. Suva, F. L. Swain, M. S. Razzaque, S. Mackem, and B. Lanske
Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone
PNAS,
April 10, 2007;
104(15):
6382 - 6387.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. J. Haycraft, Q. Zhang, B. Song, W. S. Jackson, P. J. Detloff, R. Serra, and B. K. Yoder
Intraflagellar transport is essential for endochondral bone formation
Development,
January 15, 2007;
134(2):
307 - 316.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
B. S. Yoon, R. Pogue, D. A. Ovchinnikov, I. Yoshii, Y. Mishina, R. R. Behringer, and K. M. Lyons
BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways
Development,
December 1, 2006;
133(23):
4667 - 4678.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
K. K. Mak, M.-H. Chen, T. F. Day, P.-T. Chuang, and Y. Yang
Wnt/{beta}-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation
Development,
September 15, 2006;
133(18):
3695 - 3707.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
S. J. Rodda and A. P. McMahon
Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors
Development,
August 15, 2006;
133(16):
3231 - 3244.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
D. Spater, T. P. Hill, R. J. O'Sullivan, M. Gruber, D. A. Conner, and C. Hartmann
Wnt9a signaling is required for joint integrity and regulation of Ihh during chondrogenesis
Development,
August 1, 2006;
133(15):
3039 - 3049.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
L. Koziel, M. Wuelling, S. Schneider, and A. Vortkamp
Gli3 acts as a repressor downstream of Ihh in regulating two distinct steps of chondrocyte differentiation
Development,
December 1, 2005;
132(23):
5249 - 5260.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
H. M. Kronenberg
How PTHrP Controls Growth Plate Chondrocytes
IBMS BoneKEy,
November 1, 2005;
2(11):
7 - 15.
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
F. Kugimiya, H. Kawaguchi, S. Kamekura, H. Chikuda, S. Ohba, F. Yano, N. Ogata, T. Katagiri, Y. Harada, Y. Azuma, et al.
Involvement of Endogenous Bone Morphogenetic Protein (BMP) 2 and BMP6 in Bone Formation
J. Biol. Chem.,
October 21, 2005;
280(42):
35704 - 35712.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
M. J. Hilton, X. Tu, J. Cook, H. Hu, and F. Long
Ihh controls cartilage development by antagonizing Gli3, but requires additional effectors to regulate osteoblast and vascular development
Development,
October 1, 2005;
132(19):
4339 - 4351.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
C. Colnot, L. de la Fuente, S. Huang, D. Hu, C. Lu, B. St-Jacques, and J. A. Helms
Indian hedgehog synchronizes skeletal angiogenesis and perichondrial maturation with cartilage development
Development,
March 1, 2005;
132(5):
1057 - 1067.
[Abstract]
[Full Text]
[PDF]
|
 |
|

|
 |

|
 |
 
H. Hu, M. J. Hilton, X. Tu, K. Yu, D. M. Ornitz, and F. Long
Sequential roles of Hedgehog and Wnt signaling in osteoblast development
Development,
January 1, 2005;
132(1):
49 - 60.
[Abstract]
[Full Text]
[PDF]
|
 |
|
© The Company of Biologists Ltd 2004