Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity

Shinsuke Ohba; Hiroshi Kawaguchi; Fumitaka Kugimiya; Toru Ogasawara; Naohiro Kawamura; Taku Saito; Toshiyuki Ikeda; Katsunori Fujii; Tsuyoshi Miyajima; Akira Kuramochi; Toshiyuki Miyashita; Hiromi Oda; Kozo Nakamura; Tsuyoshi Takato; Ung-Il Chung

doi:10.1016/j.devcel.2008.03.007

Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity

Dev Cell. 2008 May;14(5):689-99. doi: 10.1016/j.devcel.2008.03.007.

Authors

Shinsuke Ohba¹, Hiroshi Kawaguchi, Fumitaka Kugimiya, Toru Ogasawara, Naohiro Kawamura, Taku Saito, Toshiyuki Ikeda, Katsunori Fujii, Tsuyoshi Miyajima, Akira Kuramochi, Toshiyuki Miyashita, Hiromi Oda, Kozo Nakamura, Tsuyoshi Takato, Ung-Il Chung

Affiliation

¹ 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

PMID: 18477452
DOI: 10.1016/j.devcel.2008.03.007

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone and Bones / diagnostic imaging
Bone and Bones / pathology*
Cell Differentiation
Cells, Cultured
Core Binding Factor Alpha 1 Subunit / genetics
Core Binding Factor Alpha 1 Subunit / metabolism
DNA / metabolism
Gene Expression Regulation
Haploidy*
Hedgehog Proteins / metabolism
Humans
Kruppel-Like Transcription Factors / genetics
Kruppel-Like Transcription Factors / metabolism*
Mice
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Organ Size
Osteoblasts / metabolism
Osteoblasts / pathology
Patched Receptors
Patched-1 Receptor
Protein Binding
Radiography
Receptors, Cell Surface / deficiency*
Receptors, Cell Surface / genetics
Receptors, Cell Surface / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Signal Transduction
Stem Cells / metabolism
Stem Cells / pathology
Transcription, Genetic
Zinc Finger Protein Gli3

Substances

Core Binding Factor Alpha 1 Subunit
Gli3 protein, mouse
Hedgehog Proteins
Kruppel-Like Transcription Factors
Nerve Tissue Proteins
PTCH1 protein, human
Patched Receptors
Patched-1 Receptor
Ptch1 protein, mouse
Receptors, Cell Surface
Repressor Proteins
Zinc Finger Protein Gli3
DNA