RGS10-null mutation impairs osteoclast differentiation resulting from the loss of [Ca<sup>2+</sup>]<sub>i</sub> oscillation regulation

Yang, Shuying; Li, Yiping

doi:10.1101/gad.1544107

Cited by 130 publications

(142 citation statements)

References 46 publications

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“…[39][40][41][42] It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To define the role of Rgs12 in vivo, we generated Rgs12 conditional knockout mice.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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Regulators of G protein signaling (Rgs) have pivotal roles in controlling various cellular processes, such as cell differentiation. How Rgs proteins regulate osteoclast (OC) differentiation, function and bone homeostasis is poorly understood. It was previously demonstrated that Rgs12, the largest protein in the Rgs family, is predominantly expressed in OCs and regulates OC differentiation in vitro. To further understand the role and mechanism of Rgs12 in OC differentiation and bone diseases in vivo, we created OC-targeted Rgs12 knockout mice by using inducible Mx1-Cre and CD11b-Cre. Deletion of Rgs12 in hematopoietic cells or specifically in OC precursors resulted in increased bone mass with decreased OC numbers. Loss of Rgs12 impaired OC differentiation and function with impaired Ca 2+ oscillations and reduced nuclear factor of activated T cells (NFAT) 2 expression. The introduction of wild-type osteoblasts did not rescue the defective osteoclastogenesis. Ectopic expression of NFAT2 rescued defective OC differentiation in CD11b;Rgs12 fl/fl cells and promoted normal OC differentiation. Moreover, deletion of Rgs12 significantly inhibited pathological osteoclastogenesis and bone destruction in Rgs12-deficient mice that were subjected to ovariectomy and lipodysaccharide for bone loss. Thus our findings demonstrate that Rgs12 is an important regulator in OC differentiation and function and identify Rgs12 as a potential therapeutic target for osteoporosis and inflammation-induced bone loss. Bone homeostasis is tightly regulated by the balance between osteoblasts (OBs), the bone-forming cells, and osteoclasts (OCs), the bone-resorbing cells. 1 Pathological conditions such as osteoporosis, inflammation, and cancer break this balance in favor of the augmentation of OC activity, resulting in net bone loss. 2-4 As a result, patients with these diseases suffer from pain and risk of bone fracture. Therefore, understanding OC differentiation and function and uncovering potential therapeutic targets are very important and urgent objectives for treatment of these diseases. 5,6 Mature OCs, derived from the monocyte/macrophage hematopoietic lineage, are multinucleated and tartrateresistant acid phosphatase (TRAP) positive. 7 The breakthrough in understanding osteoclastogenesis came from the discovery that receptor activator of NF-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) have essential roles in stimulating monocyte-macrophage lineage cells to differentiate into mature and functional OCs. [8][9][10] Currently, known crucial RANKL downstream transcription factors and genes include active nuclear factor of activated T cells (NFAT) 2, c-Fos, β 3 -integrin, Cathepsin K, and matrix metallopeptidase 9. 11,12 Among these, NFAT2 acts as a master switch for the terminal differentiation of OCs. 13 Robust induction of NFAT2 is dependent on calcium (Ca 2+ ) oscillations. 14 Ca 2+ oscillations lead to calcineurin-mediated activation of NFAT2 and ensure NFAT2 long-lasting transcriptional activation. 13,14 Despite these...

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Section: Discussionmentioning

confidence: 99%

“…55 Nonadherent bone marrow cells were cultured with M-CSF for another 24 h and incubated with viral supernatant for 8 h in the presence of 8 μg/ml polybrene. 40,56,57 After removing the viral-containing medium, the cells were cultured with 20 ng/ml M-CSF and 10 ng/ml RANKL for 3-4 days. OCs were stained with TRAP and analyzed by using qPCR.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2015

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“…RGS10−/− mice exhibit severe osteopetrosis and impaired osteoclast differentiation. (94). These studies indicate that RGS10 specifically regulates RANKL-evoked RGS10/calmodulin-[Ca 2+ ] i oscillationcalcineurin-NFATc1 signaling in osteoclast differentiation and may be a potential therapeutic target for the treatment of bone diseases in which bone resorption is increased.…”

Section: Transcription Factor Activation By Rankl/rank In Osteoclastsmentioning

confidence: 97%

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Boyce

Xing

2008

Archives of Biochemistry and Biophysics

1,392

1,018

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The discovery of the RANKL/RANK/OPG system in the mid 1990s for the regulation of bone resorption has led to major advances in our understanding of how bone modeling and remodeling are regulated. It had been known for many years before this discovery that osteoblastic stromal cells regulated osteoclast formation, but it had not been anticipated that they would do this through expression of members of the TNF superfamily: receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG), or that these cytokines and signaling through receptor activator of NF-κB (RANK) would have extensive functions beyond regulation of bone remodeling. RANKL/RANK signaling regulates osteoclast formation, activation and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL and preventing it from binding to RANK. Thus, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength. Here, we review our current understanding of the role of the RANKL/RANK/ OPG system in bone modeling and remodeling. KeywordsBone resorption; osteoclasts; RANKL; RANK; OPG Normal bone modelingWith the exception of the bones of the calvaria, all bones in the mammalian skeleton are preformed in cartilage moulds from mesenchymal progenitors, which under appropriate stimuli also have the potential to differentiate into a variety of tissue types, including fibrous tissue, fat and muscle. Chondrocytes proliferate near the ends of the cartilage moulds to drive their longitudinal growth, while others in the centers of undergo hypertrophic differentiation. The hypertrophic chondrocytes at the periphery of the centers of these moulds are invaded by blood vessels and undergo apoptosis. Some of this hypertrophic cartilage survives as thin islands of cartilage in the centers of ossification in growing bones. Osteoblasts, which differentiate from progenitors in a collar of connective tissue around the middle of the bones where vascular invasion takes place, follow the endothelial cells and lay down bone matrix on the surfaces of these islands of cartilage to form bone struts or trabeculae (1). Osteoclast precursors (OCPs), derived from progenitors in the spleen and liver are attracted from blood in the invading blood vessels close to newly formed bone trabeculae. These osteoclast precursors fuse with one

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“…Moreover, RGS10-null microglia produced significantly higher levels of proinflammatory cytokines including TNF, IL-1β, and IL-6 than wild-type (WT) microglia upon LPS treatment. Another study showed that RGS10-null mice exhibited impaired osteoclast differentiation due to the absence of RGS10-dependent calcium current oscillations and the loss of nuclear factor of activated T cell c1 (NFATc1) expression (58). This suggests that RGS10 may regulate intracellular calcium oscillations in microglia.…”

Section: Rgs10 In Neuroinflammation and Parkinson's Diseasementioning

confidence: 99%

Regulator of G-protein Signaling (RGS)1 and RGS10 Proteins as Potential Drug Targets for Neuroinflammatory and Neurodegenerative Diseases

Lee

Dagher

2016

AAPS J

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Abstract. Regulator of G-protein signaling (RGS) proteins were originally identified as negative regulators of G-protein-coupled receptor (GPCR) signaling via their GTPase-accelerating protein (GAP) activity. All RGS proteins contain evolutionarily conserved RGS domain; however, they differ in their size and regulatory domains. RGS1 and RGS10 are smaller than other RGS proteins, and their functions involve various inflammatory responses including autoimmune responses in both the periphery and the central nervous system (CNS). Neuroinflammation is the chronic inflammatory response in the CNS. Acute inflammatory response in the CNS is believed to be beneficial by involving the neuroprotective actions of immune cells in the brain, particularly microglia, to limit tissue damage and to aid in neuronal repair. However, chronically elevated levels of cytokines serve to maintain activation of abundant numbers of immune cells potentiating prolonged inflammatory responses and creating an environment of oxidative stress, which further hastens oxidative damage of neurons. In this review, we describe the implications and features of RGS proteins (specifically RGS1 and RGS10) in neuroinflammation and neurodegenerative diseases. We will discuss the experimental and epidemiological evidence on the benefits of anti-inflammatory interventions by targeting RGS1 and/or RGS10 protein function or expression in order to delay or attenuate the progression of neurodegeneration, particularly in multiple sclerosis (MS) and Parkinson's disease (PD).

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RGS10-null mutation impairs osteoclast differentiation resulting from the loss of [Ca²⁺]_i oscillation regulation

Cited by 130 publications

References 46 publications

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

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

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Regulator of G-protein Signaling (RGS)1 and RGS10 Proteins as Potential Drug Targets for Neuroinflammatory and Neurodegenerative Diseases

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RGS10-null mutation impairs osteoclast differentiation resulting from the loss of [Ca2+]i oscillation regulation

Cited by 130 publications

References 46 publications

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

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

Functions of RANKL/RANK/OPG in bone modeling and remodeling

Regulator of G-protein Signaling (RGS)1 and RGS10 Proteins as Potential Drug Targets for Neuroinflammatory and Neurodegenerative Diseases

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RGS10-null mutation impairs osteoclast differentiation resulting from the loss of [Ca²⁺]_i oscillation regulation