title: PTH receptor signaling in osteocytes governs periosteal bone formation and intracortical remodeling.
abstract: The periosteal and endocortical surfaces of cortical bone dictate the geometry and overall mechanical properties of bone. Yet the cellular and molecular mechanisms that regulate activity on these surfaces are far from being understood. Parathyroid hormone (PTH) has profound effects in cortical bone, stimulating periosteal expansion and at the same time accelerating intracortical bone remodeling. We report herein that transgenic mice expressing a constitutive active PTH receptor in osteocytes (DMP1-caPTHR1 mice) exhibit increased cortical bone area and an elevated rate of periosteal and endocortical bone formation. In addition, DMP1-caPTHR1 mice display a marked increase in intracortical remodeling and cortical porosity. Crossing DMP1-caPTHR1 mice with mice lacking the Wnt coreceptor, LDL-related receptor 5 (LRP5), or with mice overexpressing the Wnt antagonist Sost in osteocytes (DMP1-Sost mice) reduced or abolished, respectively, the increased cortical bone area, periosteal bone formation rate, and expression of osteoblast markers and Wnt target genes exhibited by the DMP1-caPTHR1 mice. In addition, DMP1-caPTHR1 lacking LRP5 or double transgenic DMP1-caPTHR1;DMP1-Sost mice exhibit exacerbated intracortical remodeling and increased osteoclast numbers, and markedly decreased expression of the RANK decoy receptor osteoprotegerin. Thus, whereas Sost downregulation and the consequent Wnt activation is required for the stimulatory effect of PTH receptor signaling on periosteal bone formation, the Wnt-independent increase in osteoclastogenesis induced by PTH receptor activation in osteocytes overrides the effect on Sost. These findings demonstrate that PTH receptor signaling influences cortical bone through actions on osteocytes and defines the role of Wnt signaling in PTH receptor action.
authors.affiliation: Department of Anatomy and Cell Biology, Division of Endocrinology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Yumie
authors.initials: Y
authors.lastname: Rhee
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Allen
authors.forename: Keith
authors.initials: K
authors.lastname: Condon
authors.forename: Virginia
authors.initials: V
authors.lastname: Lezcano
authors.forename: Ana C
authors.initials: AC
authors.lastname: Ronda
authors.forename: Carlo
authors.initials: C
authors.lastname: Galli
authors.forename: Naomi
authors.initials: N
authors.lastname: Olivos
authors.forename: Giovanni
authors.initials: G
authors.lastname: Passeri
authors.forename: Charles A
authors.initials: CA
authors.lastname: O'Brien
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Bivi
authors.forename: Lilian I
authors.initials: LI
authors.lastname: Plotkin
authors.forename: Teresita
authors.initials: T
authors.lastname: Bellido
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D016723:Bone Remodeling / Q000502:physiology*; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism / Q000473:pathology; D010011:Osteocytes / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D010521:Periosteum / Q000473:pathology / Q000502:physiology*; D010641:Phenotype; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D012886:Skull / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015415:Biomarkers; D016207:Cytokines; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D044168:Receptor, Parathyroid Hormone, Type 1; C486030:Sost protein, mouse; D051153:Wnt Proteins