Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development
Ung-il Chung, … , Andrew P. McMahon, Henry M. Kronenberg
Ung-il Chung, … , Andrew P. McMahon, Henry M. Kronenberg
Published February 1, 2001
Citation Information: J Clin Invest. 2001;107(3):295-304. https://doi.org/10.1172/JCI11706.
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Article

Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development

Abstract

Vertebrate skeletogenesis requires a well-coordinated transition from chondrogenesis to osteogenesis. Hypertrophic chondrocytes in the growth plate play a pivotal role in this transition. Parathyroid hormone–related peptide (PTHrP), synthesized in the periarticular growth plate, regulates the site at which hypertrophy occurs. By comparing PTH/PTHrP receptor–/–/wild-type (PPR–/–/wild-type) chimeric mice with Ihh–/–;PPR–/–/wild-type chimeric and Ihh–/–/wild-type chimeric mice, we provide in vivo evidence that Indian hedgehog (Ihh), synthesized by prehypertrophic and hypertrophic chondrocytes, regulates the site of hypertrophic differentiation by signaling to the periarticular growth plate and also determines the site of bone collar formation in the adjacent perichondrium. By providing crucial local signals from prehypertrophic and hypertrophic chondrocytes to both chondrocytes and preosteoblasts, Ihh couples chondrogenesis to osteogenesis in endochondral bone development.

Authors

Ung-il Chung, Ernestina Schipani, Andrew P. McMahon, Henry M. Kronenberg

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Ihh signaling by ectopically hypertrophied PPR–/– and Ihh–/–;PPR–/– chon...
Ihh signaling by ectopically hypertrophied PPR–/– and Ihh–/–;PPR–/– chondrocytes. (a–c) In situ hybridization of the sections of the tibiae from d17.5 embryos with a mouse Ihh antisense probe. In the wild-type growth plate (a), Ihh mRNA is expressed in prehypertrophic and hypertrophic chondrocytes. In the chimeric growth plates, ectopically differentiated PPR–/– chondrocytes also express Ihh mRNA (b, asterisk), whereas ectopically differentiated Ihh–/–;PPR–/– cells do not (c). (d–f) In situ hybridization of the sections of the tibiae from d17.5 embryos with a mouse Ptc1 antisense probe. Ptc1 is a transcriptional target of Ihh signaling. In the wild-type growth plate (d), Ptc1 mRNA is expressed most strongly in columnar proliferating chondrocytes adjacent to prehypertrophic chondrocytes with the expression decreasing toward the end of bone. Ptc1 mRNA is also expressed in the perichondrium and the primary spongiosa. In the PPR–/–/wild-type chimeric growth plate (e), periarticular and columnar proliferating chondrocytes surrounding ectopic prehypertrophic/hypertrophic chondrocytes overexpress Ptc1 mRNA (bracket), reflecting ectopic actions of Ihh. In contrast, in the Ihh–/–;PPR–/–/wild-type chimeric growth plate (f), there is no ectopic expression of Ptc1 mRNA despite the presence of ectopic prehypertrophic/hypertrophic chondrocytes. Left, bright field; right, dark field. Horizontal bar = 100 μm.