Abstract
Indian hedgehog (Ihh) signaling is indispensable for osteoblast differentiation during endochondral bone development in the mouse embryo. We have previously shown that the Gli2 transcription activator critically mediates Ihh function in osteoblastogenesis. To explore the possibility that activation of Hedgehog (Hh) signaling may enhance bone formation, we generated mice that expressed a constitutively active form of Gli2 in the Osx-lineage cells. Unexpectedly, these mice exhibited severe osteopenia due to a marked decrease in osteoblast number and function, although bone resorption was not affected. Quantitative analyses of the molecular markers indicated that osteoblast differentiation was impaired in the mutant mouse. However, the osteoblast-lineage cells isolated from these mice exhibited more robust osteoblast differentiation than normal in vitro. Similarly, pharmacological stimulation of Hh signaling enhanced osteoblast differentiation from Osx-expressing cells isolated from the wild-type mouse. Thus, even though Hh signaling directly promotes osteoblast differentiation in vitro, constitutive activation of this pathway impairs bone formation in vivo, perhaps through an indirect mechanism.
Highlights
The Hedgehog (Hh) family of secreted proteins critically regulates developmental processes from flies to humans [1]
Whereas derepression of the Gli3 repressor is primarily responsible for Indian hedgehog (Ihh) function in chondrocyte proliferation and maturation, activation of the Gli2 transcription factor is critical for Ihh-induced osteoblast differentiation [10,11,12,13]
We activate Hh signaling in the osteoblast lineage by expressing a constitutively activated form of the Gli2 transcription factor (DNGli2)
Summary
The Hedgehog (Hh) family of secreted proteins critically regulates developmental processes from flies to humans [1]. Ihh critically controls endochondral skeletal development in the chicken embryo [3]. Mouse genetic experiments with Smoothened, which encodes a sevenpass transmembrane protein indispensable for transducing intracellular Hh signaling, have demonstrated that Ihh directly controls chondrocyte proliferation as well as osteoblast differentiation from the perichondrial progenitors [4,5]. Whereas derepression of the Gli repressor is primarily responsible for Ihh function in chondrocyte proliferation and maturation, activation of the Gli transcription factor is critical for Ihh-induced osteoblast differentiation [10,11,12,13]. Extensive studies in the mouse embryo have established that Ihh critically controls osteoblast differentiation during endochondral skeletal development
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