title: Osteocytes mediate the anabolic actions of canonical Wnt/β-catenin signaling in bone.
abstract: Osteocytes, >90% of the cells in bone, lie embedded within the mineralized matrix and coordinate osteoclast and osteoblast activity on bone surfaces by mechanisms still unclear. Bone anabolic stimuli activate Wnt signaling, and human mutations of components along this pathway underscore its crucial role in bone accrual and maintenance. However, the cell responsible for orchestrating Wnt anabolic actions has remained elusive. We show herein that activation of canonical Wnt signaling exclusively in osteocytes [dominant active (da)βcat(Ot) mice] induces bone anabolism and triggers Notch signaling without affecting survival. These features contrast with those of mice expressing the same daß-catenin in osteoblasts, which exhibit decreased resorption and perinatal death from leukemia. daßcat(Ot) mice exhibit increased bone mineral density in the axial and appendicular skeleton, and marked increase in bone volume in cancellous/trabecular and cortical compartments compared with littermate controls. daßcat(Ot) mice display increased resorption and formation markers, high number of osteoclasts and osteoblasts in cancellous and cortical bone, increased bone matrix production, and markedly elevated periosteal bone formation rate. Wnt and Notch signaling target genes, osteoblast and osteocyte markers, and proosteoclastogenic and antiosteoclastogenic cytokines are elevated in bones of daßcat(Ot) mice. Further, the increase in RANKL depends on Sost/sclerostin. Thus, activation of osteocytic β-catenin signaling increases both osteoclasts and osteoblasts, leading to bone gain, and is sufficient to activate the Notch pathway. These findings demonstrate disparate outcomes of β-catenin activation in osteocytes versus osteoblasts and identify osteocytes as central target cells of the anabolic actions of canonical Wnt/β-catenin signaling in bone.
authors.affiliation: Department of Anatomy and Cell Biology and tbellido@iupui.edu xiaolint@hotmail.com.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Tu
authors.affiliation: Department of Anatomy and Cell Biology and Roudebush Veterans Administration Medical Center and.
authors.forename: Jesus
authors.initials: J
authors.lastname: Delgado-Calle
authors.affiliation: Department of Anatomy and Cell Biology and.
authors.forename: Keith W
authors.initials: KW
authors.lastname: Condon
authors.affiliation: Department of Anatomy and Cell Biology and.
authors.forename: Marta
authors.initials: M
authors.lastname: Maycas
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46022; and.
authors.forename: Huajia
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46022; and.
authors.forename: Nadia
authors.initials: N
authors.lastname: Carlesso
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Department of Anatomy and Cell Biology and.
authors.forename: David B
authors.initials: DB
authors.lastname: Burr
authors.affiliation: Department of Anatomy and Cell Biology and Roudebush Veterans Administration Medical Center and.
authors.forename: Lilian I
authors.initials: LI
authors.lastname: Plotkin
authors.affiliation: Department of Anatomy and Cell Biology and Roudebush Veterans Administration Medical Center and Division of Endocrinology, Department of Medicine, Indiana University School of Medicine; tbellido@iupui.edu xiaolint@hotmail.com.
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
mesh_terms: D000818:Animals; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010011:Osteocytes / Q000502:physiology*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D051176:beta Catenin
keywords: beta-catenin; bone anabolism; canonical Wnt; notch signaling; osteocytes