Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone

doi:10.1073/pnas.0608449104

Indian Hedgehog produced by postnatal chondrocytes is essential for maintaining a growth plate and trabecular bone

^†Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115;
^‡National Cancer Institute, Bethesda, MD 20892; and
^§Department of Orthopedic Surgery, Center for Orthopedic Research, University of Arkansas for Medical Sciences, Little Rock, AR 72205

Edited by Kathryn V. Anderson, Sloan–Kettering Cancer Institute, New York, NY, and approved February 9, 2007 (received for review September 26, 2006)

Abstract

Indian hedgehog (Ihh) is essential for chondrocyte and osteoblast proliferation/differentiation during prenatal endochondral bone formation. The early lethality of various Ihh-ablated mutant mice, however, prevented further analysis of its role in postnatal bone growth and development. In this study, we describe the generation and characterization of a mouse model in which the Ihh gene was successfully ablated from postnatal chondrocytes in a temporal/spatial-specific manner; postnatal deletion of Ihh resulted in loss of columnar structure, premature vascular invasion, and formation of ectopic hypertrophic chondrocytes in the growth plate. Furthermore, destruction of the articular surface in long bones and premature fusion of growth plates of various endochondral bones was evident, resulting in dwarfism in mutant mice. More importantly, these mutant mice exhibited continuous loss of trabecular bone over time, which was accompanied by reduced Wnt signaling in the osteoblastic cells. These results demonstrate, for the first time, that postnatal chondrocyte-derived Ihh is essential for maintaining the growth plate and articular surface and is required for sustaining trabecular bone and skeletal growth.

Footnotes

^¶To whom correspondence should be addressed at:
Department of Developmental Biology, Harvard School of Dental Medicine, REB 303, 188 Longwood Avenue, Boston, MA 02115.
E-mail: beate_lanske{at}hsdm.harvard.edu
Author contributions: Y.M. and B.L. designed research; Y.M., L.J.S., and F.L.S. performed research; E.N., M.-T.N., and S.M. contributed new reagents/analytic tools; Y.M., L.J.S., F.L.S., M.S.R., and B.L. analyzed data; and Y.M., M.S.R., and B.L. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0608449104/DC1.
Abbreviations:

PCNA,

proliferating cell nuclear antigen;

Pn,

postnatal day n;

PTHrP,

parathyroid hormone-related peptide.