title: Gli1 haploinsufficiency leads to decreased bone mass with an uncoupling of bone metabolism in adult mice.
abstract: 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.
authors.affiliation: Department of Sensory and Motor System Medicine, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan; Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kitaura
authors.affiliation: Department of Sensory and Motor System Medicine, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan; Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hironori
authors.initials: H
authors.lastname: Hojo
authors.affiliation: Department of Sensory and Motor System Medicine, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan; Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yuske
authors.initials: Y
authors.lastname: Komiyama
authors.affiliation: Department of Sensory and Motor System Medicine, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takato
authors.affiliation: Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan; Department of Bioengineering, The University of Tokyo Graduate School of Engineering, Bunkyo-ku, Tokyo, Japan.
authors.forename: Ung-il
authors.initials: UI
authors.lastname: Chung
authors.affiliation: Division of Clinical Biotechnology, The University of Tokyo Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan; Department of Bioengineering, The University of Tokyo Graduate School of Engineering, Bunkyo-ku, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ohba
mesh_terms: D000818:Animals; D015519:Bone Density; D001854:Bone Marrow Cells / Q000166:cytology; D002454:Cell Differentiation; D002478:Cells, Cultured; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D050723:Fractures, Bone / Q000473:pathology; D005786:Gene Expression Regulation; D005838:Genotype; D057895:Haploinsufficiency; D053823:Hedgehog Proteins / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis; D011859:Radiography; D015398:Signal Transduction; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000071676:Zinc Finger Protein GLI1
chemical_list: D053823:Hedgehog Proteins; D015513:Oncogene Proteins; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1