Control of bone mass and remodeling by PTH receptor signaling in osteocytes.
Osteocytes, former osteoblasts buried within bone, are thought to orchestrate skeletal adaptation to mechanical stimuli. However, it remains unknown whether hormones control skeletal homeostasis through actions on osteocytes. Parathyroid hormone (PTH) stimulates bone remodeling and may cause bone loss or bone gain depending on the balance between bone resorption and formation. Herein, we demonstrate that transgenic mice expressing a constitutively active PTH receptor exclusively in osteocytes exhibit increased bone mass and bone remodeling, as well as reduced expression of the osteocyte-derived Wnt antagonist sclerostin, increased Wnt signaling, increased osteoclast and osteoblast number, and decreased osteoblast apoptosis. Deletion of the Wnt co-receptor LDL related receptor 5 (LRP5) attenuates the high bone mass phenotype but not the increase in bone remodeling induced by the transgene. These findings demonstrate that PTH receptor signaling in osteocytes increases bone mass and the rate of bone remodeling through LRP5-dependent and -independent mechanisms, respectively.
O'Brien
Charles A
CA
Division of Endocrinology, Center for Osteoporosis and Metabolic Bone Diseases, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America. caobrien@uams.edu
Plotkin
Lilian I
LI
Galli
Carlo
C
Goellner
Joseph J
JJ
Gortazar
Arancha R
AR
Allen
Matthew R
MR
Robling
Alexander G
AG
Bouxsein
Mary
M
Schipani
Ernestina
E
Turner
Charles H
CH
Jilka
Robert L
RL
Weinstein
Robert S
RS
Manolagas
Stavros C
SC
Bellido
Teresita
T
D000818:Animals; D016723:Bone Remodeling / Q000502:physiology*; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology; D010010:Osteoclasts / Q000166:cytology; D010011:Osteocytes / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics*; D018016:Receptors, Parathyroid Hormone / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
C513309:DMP1 protein, human; D016326:Extracellular Matrix Proteins; C473449:PTH1R protein, human; D010750:Phosphoproteins; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone