title: Osteocyte-derived insulin-like growth factor I is essential for determining bone mechanosensitivity.
abstract: This study sought to determine whether deficient Igf1 expression in osteocytes would affect loading-induced osteogenic response. Tibias of osteocyte Igf1 conditional knockout (KO) mice (generated by cross-breeding Igf1 floxed mice with Dmp1-Cre transgenic mice) and wild-type (WT) littermates were subjected to four-point bending for 2 wk. Microcomputed tomography confirmed that the size of tibias of conditional mutants was smaller. Loading with an equivalent loading strain increased periosteal woven bone and endosteal lamellar bone formation in WT mice but not in conditional KO mice. Consistent with the lack of an osteogenic response, the loading failed to upregulate expression of early mechanoresponsive genes (Igf1, Cox-2, c-fos) or osteogenic genes (Cbfa-1, and osteocalcin) in conditional KO bones. The lack of osteogenic response was not due to reduced osteocyte density or insufficient loading strain. Deficient osteocyte Igf1 expression reduced the loading-induced upregulation of expression of canonical Wnt signaling genes (Wnt10b, Lrp5, Dkk1, sFrp2). The loading also reduced (by 40%) Sost expression in WT mice, but the loading not only did not reduce but upregulated (~1.5-fold) Sost expression in conditional KO mice. Conditional disruption of Igf1 in osteocytes also abolished the loading-induced increase in the bone β-catenin protein level. These findings suggest an impaired response in the loading-induced upregulation of the Wnt signaling in conditional KO mice. In summary, conditional disruption of Igf1 in osteocytes abolished the loading-induced activation of the Wnt signaling and the corresponding osteogenic response. In conclusion, osteocyte-derived IGF-I plays a key determining role in bone mechanosensitivity.
authors.affiliation: Division of Regenerative Medicine, Department of Medicine, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
authors.forename: K-H William
authors.initials: KH
authors.lastname: Lau
authors.forename: David J
authors.initials: DJ
authors.lastname: Baylink
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhou
authors.forename: Denise
authors.initials: D
authors.lastname: Rodriguez
authors.forename: Lynda F
authors.initials: LF
authors.lastname: Bonewald
authors.forename: Zihui
authors.initials: Z
authors.lastname: Li
authors.forename: Davide
authors.initials: D
authors.lastname: Ruffoni
authors.forename: Ralph
authors.initials: R
authors.lastname: Müller
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Kesavan
authors.forename: Matilda H-C
authors.initials: MH
authors.lastname: Sheng
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015153:Blotting, Western; D001846:Bone Development / Q000235:genetics / Q000502:physiology; D001842:Bone and Bones / Q000033:anatomy & histology / Q000000981:diagnostic imaging / Q000502:physiology*; D004247:DNA / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005838:Genotype; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010011:Osteocytes / Q000502:physiology*; D010716:Phosphatidylinositols / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013977:Tibia / Q000502:physiology; D014057:Tomography, X-Ray Computed; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: D010716:Phosphatidylinositols; D051176:beta Catenin; C078629:dimyristoylphosphatidylinositol; D007334:Insulin-Like Growth Factor I; D004247:DNA; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Wnt; insulin-like growth factor I; mechanical loading; mechanotransduction; osteocytes