Departmental Papers (Dental)

Document Type

Journal Article

Date of this Version

4-2019

Publication Source

Journal of Bone and Mineral Research

Volume

34

Issue

4

Start Page

752

Last Page

764

DOI

10.1002/jbmr.3645

Abstract

Bone homeostasis intimately relies on the balance between osteoblasts (OBs) and osteoclasts (OCs). Our previous studies have revealed that regulator of G protein signaling protein 12 (Rgs12), the largest protein in the Rgs super family, is essential for osteoclastogenesis from hematopoietic cells and OC precursors. However, how Rgs12 regulates OB differentiation and function is still unknown. To understand that, we generated an OB-targeted Rgs12 conditional knockout (CKO) mice model by crossing Rgs12 fl/fl mice with Osterix (Osx)-Cre transgenic mice. We found that Rgs12 was highly expressed in both OB precursor cells (OPCs) and OBs of wild-type (WT) mice, and gradually increased during OB differentiation, whereas Rgs12-CKO mice (Osx Cre/+ ; Rgs12 fl/fl ) exhibited a dramatic decrease in both trabecular and cortical bone mass, with reduced numbers of OBs and increased apoptotic cell population. Loss of Rgs12 in OPCs in vitro significantly inhibited OB differentiation and the expression of OB marker genes, resulting in suppression of OB maturation and mineralization. Further mechanism study showed that deletion of Rgs12 in OPCs significantly inhibited guanosine triphosphatase (GTPase) activity and cyclic adenosine monophosphate (cAMP) level, and impaired Calcium (Ca 2+ ) oscillations via restraints of major Ca 2+ entry sources (extracellular Ca 2+ influx and intracellular Ca 2+ release from endoplasmic reticulum), partially contributed by the blockage of L-type Ca 2+ channel mediated Ca 2+ influx. Downstream mediator extracellular signal-related protein kinase (ERK) was found inactive in OBs of Osx Cre/+ ; Rgs12 fl/fl mice and in OPCs after Rgs12 deletion, whereas application of pertussis toxin (PTX) or overexpression of Rgs12 could rescue the defective OB differentiation via restoration of ERK phosphorylation. Our findings reveal that Rgs12 is an important regulator during osteogenesis and highlight Rgs12 as a potential therapeutic target for bone disorders. © 2018 American Society for Bone and Mineral Research. © 2018 American Society for Bone and Mineral Research

Keywords

CALCIUM CHANNEL/OSCILLATION, GαI SIGNALING, OSTEOBLASTS, RGS12, Animals, Calcium Channels, L-Type, Calcium Signaling, Cell Differentiation, Female, GTP-Binding Protein alpha Subunits, Male, MAP Kinase Signaling System, Mice, Mice, Knockout, Osteoblasts, Osteogenesis, RGS Proteins, calcium channel, calcium channel L type, cyclic AMP, guanosine triphosphatase, mitogen activated protein kinase, pertussis toxin, regulator of g protein signaling protein 12, RGS protein, transcription factor osterix, unclassified drug, calcium channel L type, guanine nucleotide binding protein alpha subunit, RGS protein, RGS12 protein, mouse, animal experiment, Article, bone development, bone mass, bone maturation, bone mineralization, calcium signaling, calcium transport, cell differentiation, controlled study, cortical bone, endoplasmic reticulum, extracellular calcium, gene overexpression, in vitro study, knockout mouse, MAPK signaling, marker gene, mouse, nonhuman, osteoblast, trabecular bone, transgenic mouse, wild type mouse, animal, cell differentiation, female, genetics, male, metabolism, osteoblast

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Date Posted:30 June 2022

This document has been peer reviewed.