Abstract
Hedgehog (Hh) signaling is highly conserved among species and plays indispensable roles in various developmental processes. There are three Hh members in mammals; one of them, Indian hedgehog (Ihh), is expressed in prehypertrophic and hypertrophic chondrocytes during endochondral ossification. Based on mouse genetic studies, three major functions of Ihh have been proposed: (1) Regulation of chondrocyte differentiation via a negative feedback loop formed together with parathyroid hormone-related protein (PTHrP), (2) promotion of chondrocyte proliferation, and (3) specification of bone-forming osteoblasts. Gli transcription factors mediate the major aspect of Hh signaling in this context. Gli3 has dominant roles in the growth plate chondrocytes, whereas Gli1, Gli2, and Gli3 collectively mediate biological functions of Hh signaling in osteoblast specification. Recent studies have also highlighted postnatal roles of the signaling in maintenance and repair of skeletal tissues.
Highlights
Hedgehog (Hh) signaling plays essential roles in various developmental process in vertebrates and insects, and is a highly conserved pathway among species
Activation of parathyroid hormone-related protein (PTHrP) signaling in the Indian hedgehog (Ihh)−/− mutant background cancelled the premature hypertrophy of Ihh−/− chondrocytes, but did not increase the number of mitotically active chondrocytes [23]. These results suggest that: (1) Ihh is required for both the differentiation and the proliferation of growth plate chondrocytes; (2) PTHrP partly mediates the Ihh function in maintaining a pool of proliferating chondrocytes; and (3) Ihh positively regulates chondrocyte proliferation in a PTHrP-independent manner
The above-described studies demonstrate that Ihh produced by pre- and hypertrophic chondrocytes is essential for osteoblastogenesis in the perichondrium and the primary spongiosa during endochondral ossification (Figure 3)
Summary
Hedgehog (Hh) signaling plays essential roles in various developmental process in vertebrates and insects, and is a highly conserved pathway among species. Shh is involved in the L-R axis determination, the patterning of body segments, the neural tube, and limbs and morphogenesis of the hair, teeth, lungs, gut, and muscle. Shh expressed in the zone of polarizing activity in developing limbs and in the notochord and floor plate of the neural tube determines the patterning of digits and cell fates of neural progenitors, respectively. A large number of studies have revealed various and indispensable functions of Hh signaling for the development and maintenance of skeletal tissues, as several concise and comprehensive reviews recently overviewed [3,4,5]. This review aims to organize and summarize the functions of Hh signaling and the mode of Hh action in skeletal development, based mainly on the findings of mouse genetic studies
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