title: Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity.
abstract: Hedgehog (Hh)-Patched1 (Ptch1) signaling plays essential roles in various developmental processes, but little is known about its role in postnatal homeostasis. Here, we demonstrate regulation of postnatal bone homeostasis by Hh-Ptch1 signaling. Ptch1-deficient (Ptch1+/-) mice and patients with nevoid basal cell carcinoma syndrome showed high bone mass in adults. In culture, Ptch1+/- cells showed accelerated osteoblast differentiation, enhanced responsiveness to the runt-related transcription factor 2 (Runx2), and reduced generation of the repressor form of Gli3 (Gli3rep). Gli3rep inhibited DNA binding by Runx2 in vitro, suggesting a mechanism that could contribute to the bone phenotypes seen in the Ptch1 heterozygotes. Moreover, systemic administration of the Hh signaling inhibitor cyclopamine decreased bone mass in adult mice. These data provide evidence that Hh-Ptch1 signaling plays a crucial role in postnatal bone homeostasis and point to Hh-Ptch1 signaling as a potential molecular target for the treatment of osteoporosis.
authors.affiliation: Department of Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan. shin-o@umin.ac.jp
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Ohba
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawaguchi
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Kugimiya
authors.forename: Toru
authors.initials: T
authors.lastname: Ogasawara
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kawamura
authors.forename: Taku
authors.initials: T
authors.lastname: Saito
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Katsunori
authors.initials: K
authors.lastname: Fujii
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Miyajima
authors.forename: Akira
authors.initials: A
authors.lastname: Kuramochi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miyashita
authors.forename: Hiromi
authors.initials: H
authors.lastname: Oda
authors.forename: Kozo
authors.initials: K
authors.lastname: Nakamura
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Takato
authors.forename: Ung-Il
authors.initials: UI
authors.lastname: Chung
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D005786:Gene Expression Regulation; D006238:Haploidy; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011485:Protein Binding; D011859:Radiography; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D000074290:Zinc Finger Protein Gli3
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D000074290:Zinc Finger Protein Gli3; D004247:DNA