title: Constitutive activation of smoothened leads to impaired developments of postnatal bone in mice.
abstract: Sonic hedgehog (Shh) signaling regulates patterning, proliferation, and stem cell self-renewal in many organs. Smoothened (Smo) plays a key role in transducing Shh signaling into the nucleus by activating a glioma family of transcription factors; however, the cellular and molecular mechanisms underlying the role of sustained Smo activation in postnatal development are still unclear. In this study, we explored the effects of Shh signaling on bone development using a conditional knock-in mouse model that expresses a constitutively activated form of Smo (SmoM2) upon osteocalcin (OCN)-Cre-mediated recombination (SmoM2; OCN-Cre mice). We also evaluated the expression pattern of bone formation-related factors in primary calvarial cultures of mutant and control mice. The SmoM2; OCN-Cre mutant showed growth retardation and reduction of bone mineral density compared to control mice. Constitutively activated SmoM2 also repressed mRNA expression of Runx2, osterix, type I collagen, and osteocalcin. Further, sustained SmoM2 induction suppressed mineralization in calvarial primary osteoblasts cultures, whereas such induction did not affect cell proliferation in the mutant cultures as compared with SmoM2 only control cultures. These results suggest that sustained Smo activation inhibits postnatal development of bone by suppressing gene expression of bone formation regulatory factors in mice.
authors.affiliation: Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences and Brain Korea 21 Program, Chonbuk National University, Jeonju 561-756, Korea.
authors.forename: Eui-Sic
authors.initials: ES
authors.lastname: Cho
authors.forename: Shin-Saeng
authors.initials: SS
authors.lastname: Lim
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Hwang
authors.forename: Jeong-Chae
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000375:Aging / Q000235:genetics; D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D015519:Bone Density / Q000235:genetics; D001846:Bone Development / Q000235:genetics; D002113:Calcification, Physiologic / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D019426:Integrases / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D009928:Organ Specificity / Q000235:genetics; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D015675:Osteocalcin / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000072086:Smoothened Receptor; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C493716:Runx2 protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D015675:Osteocalcin; C045073:Cre recombinase; D019426:Integrases; D000469:Alkaline Phosphatase; D002118:Calcium