Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

Yuan, Xue; Cao, Jay; Liu, T.; Li, Y. P.; Scannapieco, Frank A.; He, Xiaoning; Oursler, Merry Jo; Zhang, X.; Vacher, Jean; Li, C.; Olson, Douglas P.; Yang, Shuying

doi:10.1038/cdd.2015.45

Cited by 37 publications

(46 citation statements)

References 61 publications

(73 reference statements)

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“…This resulted in growth retardation, increased bone mass, and reduced numbers of osteoclasts in the mice (109). Similar results were found in Rgs12 fl/fl Cd11b-cre mice, which would predominately delete Rgs12 expression in neutrophils and macrophages (110). No assessment of dendritic cell function was performed in these mice.…”

Section: G-protein Regulatory Proteinssupporting

confidence: 75%

The impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity

Kehrl

2016

Biochemical Pharmacology

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Leukocyte chemoattractant receptors are members of the G-protein coupled receptor (GPCR) family. Signaling downstream of these receptors directs the localization, positioning and homeostatic trafficking of leukocytes; as well as their recruitment to, and their retention at, inflammatory sites. Ligand induced changes in the molecular conformation of chemoattractant receptors results in the engagement of heterotrimeric G-proteins, which promotes α subunits to undergo GTP/GDP exchange. This results in the functionally release of βγ subunits from the heterotrimers, thereby activating downstream effector molecules, which initiate leukocyte polarization, gradient sensing, and directional migration. Pertussis toxin ADP ribosylates Gαi subunits and prevents chemoattractant receptors from triggering Gαi nucleotide exchange. The use of pertussis toxin revealed the essential importance of Gαi subunit nucleotide exchange for chemoattractant receptor signaling. More recent studies have identified a range of regulatory mechanisms that target these receptors and their associated heterotrimeric G-proteins, thereby helping to control the magnitude, kinetics, and duration of signaling. A failure in these regulatory pathways can lead to impaired receptor signaling and immunopathology. The analysis of mice with targeted deletions of Gαi isoforms as well as some of these G-protein regulatory proteins is providing insights into their roles in chemoattractant receptor signaling.

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Section: G-protein Regulatory Proteinssupporting

confidence: 75%

The impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity

Kehrl

2016

Biochemical Pharmacology

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“…Methodologies for generation of homozygous Rgs12 fl/fl and Osx‐Cre mice on C57BL/6J backgrounds have been described . To specifically inactivate Rgs12 in the OB lineage, we crossed Rgs12 fl/fl mice with Osx‐Cre transgenic mice (OSX1‐GFP::Cre) to generate Osx; Rgs12 fl/+ progeny, which were used for subsequent mating to produce heterozygous Osx Cre/+ ; Rgs12 fl/fl mice.…”

Section: Methodsmentioning

confidence: 99%

“…Measurements of Ca 2+ oscillation were performed as described with slight modification . OPCs after Ad‐Null or Ad‐Cre infection were reseeded at a density of 2 × 10 5 cells/35‐mm dish and induced with OS medium for 3 days.…”

Section: Methodsmentioning

confidence: 99%

“…This multidomain structure provides Rgs12 with the potential to modulate multiple signaling pathways, including the signaling mediated by Gi‐coupled GPCR, which has been reported to lead to the osteopenia phenotype through the transgenic expression of a constitutively active Gi‐coupled GPCR in OBs . Our previous studies revealed that Rgs12 plays an essential role in osteoclastogenesis through the regulation of PLCγ‐Ca 2+ channel‐Ca 2+ oscillations–nuclear factor of activated T cells 2 (NFAT2) pathways . Loss of Rgs12 impaired Ca 2+ oscillations and reduced NFAT2 expression in OCs, leading to the failure in OC differentiation and function .…”

Section: Introductionmentioning

confidence: 99%

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Regulator of G Protein Signaling Protein 12 (Rgs12) Controls Mouse Osteoblast Differentiation via Calcium Channel/Oscillation and Gαi-ERK Signaling

Liu

Gilmore

et al. 2018

Journal of Bone and Mineral Research

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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 Rgs12fl/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 (OsxCre/+; Rgs12fl/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 (Ca2+) oscillations via restraints of major Ca2+ entry sources (extracellular Ca2+ influx and intracellular Ca2+ release from endoplasmic reticulum), partially contributed by the blockage of L‐type Ca2+ channel mediated Ca2+ influx. Downstream mediator extracellular signal‐related protein kinase (ERK) was found inactive in OBs of OsxCre/+; Rgs12fl/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.

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“…Furthermore, RGS12 is essential for osteoclast differentiation through its effects on the RANKL-PLCγ-[Ca2+]i oscillations-nuclear factor of activated T cells (NFAT) 2 signaling. 22 Considering the involvement of mitogen-activated protein kinase (MAPK) signaling and NFAT2 in cardiac hypertrophy has been well documented, it is reasonable to hypothesize the regulatory effects of RGS12 on cardiac hypertrophy. Interestingly, the mRNA of RGS12 is exclusively expressed in ventricular but not in atrial cardiomyocytes.…”

mentioning

confidence: 99%

Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy

et al. 2016

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Cardiac hypertrophy is initially an adaptive response to cardiac stresses, including mechanical overload, ischemia, and endocrine disorders.1,2 At the beginning, it elicits beneficial effects by reducing ventricular wall stress and maintaining cardiac output without adverse pathology. However, sustained hypertrophy of the myocardium can progress into a decompensated state that is characterized by fetal gene expression, contractile dysfunction, and extracellular remodeling, eventually leading to heart failure. 3,4 During this complicated process, specific signaling pathways mediate the critical transition from compensated hypertrophy to decompensated hypertrophy and heart failure. 5,6 Therefore, a better understanding of the molecular mechanisms regulating the hypertrophy-related signaling pathways is important for the development of new strategies to treat pathological cardiac hypertrophy and heart failure.Regulator of G-protein signaling (RGS) proteins represent a family of proteins originally defined by the presence of a semiconserved region of ≈120 amino acids called the RGS domain. They function as GTPase-activating proteins for Gα proteins to repress G-protein-coupled receptor signaling. 7,8 To date, several members of the RGS family have been found to participate in pathological cardiac hypertrophy. [9][10][11][12][13] Recently, a growing number of studies demonstrated that RGS proteins could regulate cardiac hypertrophy independent of GTPaseactivating protein activity. Among them, RGS3, RGS5, and RGS10 protect against pressure overload-induced hypertrophic response and improve cardiac function by inhibiting MEK1/2-ERK1/2 signaling. 11,13,14 RGS12 is the largest, typical multidomain member of the RGS family. 15 In addition to a central RGS domain, RGS12 contains a PDZ (PSD-95/ discslarge/ZO-1 homology) domain, with putative CXCR2-binding properties, and a phosphotyrosine-binding domain at the N terminus, whereas a tandem repeat of Ras-binding domains and a Gai/o-Loco motif are located at the C terminus of RGS12. [16][17][18][19] This multidomain architecture contributes to the regulatory role of RGS12 in diverse signaling pathways. 18 Huang et al 20 reported that RGS12 inactivates phosphorylated Gαi to ameliorate the inhibition of cAMP formation and thus facilitates muscle relaxation. In addition, Willard et al 21 found that RGS12 serves as a scaffold and organizes Abstract-Cardiac hypertrophy is a major predictor of heart failure and is regulated by diverse signaling pathways. As a typical multi-domain member of the regulator of G-protein signaling (RGS) family, RGS12 plays a regulatory role in various signaling pathways. However, the precise effect of RGS12 on cardiac hypertrophy remains largely unknown.In this study, we observed increased expression of RGS12 in the development of pathological cardiac hypertrophy and heart failure. We then generated genetically engineered mice and neonatal rat cardiomyocytes to investigate the effects of RGS12 during this pathological process. P<0.05). RGS12 also contri...

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Regulators of G protein signaling 12 promotes osteoclastogenesis in bone remodeling and pathological bone loss

Cited by 37 publications

References 61 publications

The impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity

The impact of RGS and other G-protein regulatory proteins on Gαi-mediated signaling in immunity

Regulator of G Protein Signaling Protein 12 (Rgs12) Controls Mouse Osteoblast Differentiation via Calcium Channel/Oscillation and Gαi-ERK Signaling

Pivotal Role of Regulator of G-protein Signaling 12 in Pathological Cardiac Hypertrophy

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