title: Constitutive activity of the osteoblast Ca2+-sensing receptor promotes loss of cancellous bone.
abstract: Changes in extracellular [Ca2+] modulate the function of bone cells in vitro via the extracellular Ca2+-sensing receptor (CaR). Within bone microenvironments, resorption increases extracellular [Ca2+] locally. To determine whether enhanced CaR signaling could modulate remodeling and thereby bone mass in vivo, we generated transgenic mice with a constitutively active mutant CaR (Act-CaR) targeted to their mature osteoblasts by the 3.5 kb osteocalcin promoter. Longitudinal microcomputed tomography of cancellous bone revealed reduced bone volume and density, accompanied by a diminished trabecular network, in the Act-CaR mice. The bone loss was secondary to an increased number and activity of osteoclasts, demonstrated by histomorphometry of secondary spongiosa. Histomorphometry, conversely, indicates that bone formation rates were unchanged in the transgenic mice. Constitutive signaling of the CaR in mature osteoblasts resulted in increased expression of RANK-L (receptor activator of nuclear factor-kappaB ligand), the major stimulator of osteoclast differentiation and activation, which is the likely underlying mechanism for the bone loss. The phenotype of Act-CaR mice is not attributable to systemic changes in serum [Ca2+] or PTH levels. We provide the first in vivo evidence that increased signaling by the CaR in mature osteoblasts can enhance bone resorption and further propose that fluctuations in the [Ca2+] within the bone microenvironment may modulate remodeling via the CaR.
authors.affiliation: Endocrine Research Unit, Department of Veterans Affairs Medical Center, 4150 Clement Street, University of California, San Francisco, California 94121, USA.
authors.forename: Melita M
authors.initials: MM
authors.lastname: Dvorak
authors.forename: Tsui-Hua
authors.initials: TH
authors.lastname: Chen
authors.forename: Benjamin
authors.initials: B
authors.lastname: Orwoll
authors.forename: Caitlin
authors.initials: C
authors.lastname: Garvey
authors.forename: Wenhan
authors.initials: W
authors.lastname: Chang
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.forename: Dolores M
authors.initials: DM
authors.lastname: Shoback
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D001862:Bone Resorption / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D002118:Calcium / Q000097:blood; D002417:Cattle; D002478:Cells, Cultured; D005260:Female; D015151:Immunoblotting; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000097:blood; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D044169:Receptors, Calcium-Sensing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014057:Tomography, X-Ray Computed
chemical_list: D007295:Inositol Phosphates; D010281:Parathyroid Hormone; D053245:RANK Ligand; D044169:Receptors, Calcium-Sensing; D002118:Calcium