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Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity.
Dev Cell 2008; 14(5):689-99DC

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+Show Affiliations

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.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

18477452

Citation

Ohba, Shinsuke, et al. "Patched1 Haploinsufficiency Increases Adult Bone Mass and Modulates Gli3 Repressor Activity." Developmental Cell, vol. 14, no. 5, 2008, pp. 689-99.
Ohba S, Kawaguchi H, Kugimiya F, et al. Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity. Dev Cell. 2008;14(5):689-99.
Ohba, S., Kawaguchi, H., Kugimiya, F., Ogasawara, T., Kawamura, N., Saito, T., ... Chung, U. I. (2008). Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity. Developmental Cell, 14(5), pp. 689-99. doi:10.1016/j.devcel.2008.03.007.
Ohba S, et al. Patched1 Haploinsufficiency Increases Adult Bone Mass and Modulates Gli3 Repressor Activity. Dev Cell. 2008;14(5):689-99. PubMed PMID: 18477452.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Patched1 haploinsufficiency increases adult bone mass and modulates Gli3 repressor activity. AU - Ohba,Shinsuke, AU - Kawaguchi,Hiroshi, AU - Kugimiya,Fumitaka, AU - Ogasawara,Toru, AU - Kawamura,Naohiro, AU - Saito,Taku, AU - Ikeda,Toshiyuki, AU - Fujii,Katsunori, AU - Miyajima,Tsuyoshi, AU - Kuramochi,Akira, AU - Miyashita,Toshiyuki, AU - Oda,Hiromi, AU - Nakamura,Kozo, AU - Takato,Tsuyoshi, AU - Chung,Ung-Il, PY - 2007/09/13/received PY - 2008/01/13/revised PY - 2008/03/12/accepted PY - 2008/5/15/pubmed PY - 2008/5/30/medline PY - 2008/5/15/entrez SP - 689 EP - 99 JF - Developmental cell JO - Dev. Cell VL - 14 IS - 5 N2 - 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. SN - 1878-1551 UR - https://www.unboundmedicine.com/medline/citation/18477452/Patched1_haploinsufficiency_increases_adult_bone_mass_and_modulates_Gli3_repressor_activity_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1534-5807(08)00115-9 DB - PRIME DP - Unbound Medicine ER -