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Hedgehog (Hh) signaling plays important roles in various development processes. This signaling is necessary for osteoblast formation during endochondral ossification. In contrast to the established roles of Hh signaling in embryonic bone formation, evidence of its roles in adult bone homeostasis is not complete. Here we report the involvement of  Gli1 , a transcriptional activator induced by Hh signaling activation, in postnatal bone homeostasis under physiological and pathological conditions. Skeletal analyses of  Gli1   +/−  adult mice revealed that  Gli1  haploinsufficiency caused decreased bone mass with reduced bone formation and accelerated bone resorption, suggesting an uncoupling of bone metabolism. Hh-mediated osteoblast differentiation was largely impaired in cultures of  Gli1   +/−  precursors, and the impairment was rescued by  Gli1  expression via adenoviral transduction. In addition,  Gli1   +/−  precursors showed premature differentiation into osteocytes and increased ability to support osteoclastogenesis. When we compared fracture healing between wild-type and  Gli1   +/−  adult mice, we found that the  Gli1   +/−  mice exhibited impaired fracture healing with insufficient soft callus formation. These data suggest that  Gli1 , acting downstream of Hh signaling, contributes to adult bone metabolism, in which this molecule not only promotes osteoblast differentiation but also represses osteoblast maturation toward osteocytes to maintain normal bone homeostasis.

Gli1 Haploinsufficiency Leads to Decreased Bone Mass with an Uncoupling of Bone Metabolism in Adult Mice