title: Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling.
abstract: Much is known regarding the role of Indian hedgehog (Ihh) in endochondral ossification, where Ihh regulates multiple steps of chondrocyte differentiation. The Ihh-/- phenotype is most notable for severely foreshortened limbs and a complete absence of mature osteoblasts. A far less explored phenotype in the Ihh-/- mutant is found in the calvaria, where bones form predominately through intramembranous ossification. We investigated the role of Ihh in calvarial bone ossification, finding that proliferation was largely unaffected. Instead, our results indicate that Ihh is a pro-osteogenic factor that positively regulates intramembranous ossification. We confirmed through histologic and quantitative gene analysis that loss of Ihh results in reduction of cranial bone size and all markers of osteodifferentiation. Moreover, in vitro studies suggest that Ihh loss reduces Bmp expression within the calvaria, an observation that may underlie the Ihh-/- calvarial phenotype. In conjunction with the newly recognized roles of Hedgehog deregulation in craniosynostosis, our study defines Ihh as an important positive regulator of cranial bone ossification.
authors.affiliation: Division of Plastic and Reconstructive Surgery, Department of Surgery, School of Medicine, Stanford University, Stanford, California 94028, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Lenton
authors.forename: Aaron W
authors.initials: AW
authors.lastname: James
authors.forename: Alina
authors.initials: A
authors.lastname: Manu
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Brugmann
authors.forename: Daniel
authors.initials: D
authors.lastname: Birker
authors.forename: Emily R
authors.initials: ER
authors.lastname: Nelson
authors.forename: Philipp
authors.initials: P
authors.lastname: Leucht
authors.forename: Jill A
authors.initials: JA
authors.lastname: Helms
authors.forename: Michael T
authors.initials: MT
authors.lastname: Longaker
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000196:embryology; D002454:Cell Differentiation; D019902:Chondrocytes / Q000378:metabolism; D053823:Hedgehog Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism; D010012:Osteogenesis; D015398:Signal Transduction; D012886:Skull / Q000196:embryology*
chemical_list: D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins