Targeted expression of Cre recombinase in macrophages and osteoclasts in transgenic mice

Ferron, Mathieu; Vacher, Jean

doi:10.1002/gene.20108

Cited by 100 publications

(96 citation statements)

References 21 publications

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“…To assess the role of Rgs12 in OC differentiation and function in vivo, we crossed Rgs12 fl/fl mice 25 with either CD11b-Cre 22 or Mx1-Cre 23 transgenic lines to generate Rgs12 conditional knockout mice (CD11b;Rgs12 fl/fl and Mx1;Rgs12 fl/fl , respectively). In Mx1;Rgs12 fl/fl mice, Rgs12 was deleted in hematopoietic cells, including OCs, by injecting poly I:C at postnatal days 10, 12, and 14.…”

Section: Resultsmentioning

confidence: 99%

“…25 Mx1-Cre targets not only OC precursor cells but also multiple hematopoietic cell types, including megakaryocytes, lymphocytes, mast cells, and monocytemacrophages. To specifically understand the role of Rgs12 in OC lineage in vivo, we also generated a specific conditional knockout model with CD11b-Cre for deleting Rgs12 more exclusively in the OC lineage cells at a relatively early and developmental stage 22 to facilitate understanding of Rgs12 in OC differentiation and function. CD11b;Rgs12 fl/fl and Mx1;Rgs12 fl/fl mice all displayed skeletal defects such as a marked increase in cancellous bone mass and decreased OC numbers.…”

Section: Discussionmentioning

confidence: 99%

“…Methodology for generation of Rgs12 fl/fl , Mx1-Cre, and CD11b-Cre mice have been previously described. 22,23,25 To generate Rgs12 fl/+ ;CD11b-Cre mice, Rgs12 fl/fl mice were crossed with CD11b-Cre transgenic mice. To generate Rgs12 fl/fl ;CD11b-Cre mice (referred to as CD11b;Rgs12 fl/fl ), female Rgs12 fl/fl mice were crossed with male Rgs12 fl/+ ;CD11b-Cre mice.…”

Section: Methodsmentioning

confidence: 99%

“…All experimental mice (CD11b;Rgs12 fl/fl and CD11b;Rgs12 fl/+ ) were male because transgene integration of CD11b-Cre is on the Y chromosome. 22 All animal studies were approved by University at Buffalo Institutional Animal Care and Use Committee.…”

Section: Methodsmentioning

confidence: 99%

“…This strain is a useful tool for the study of gene function during OC and macrophage differentiation from embryonic stage. 22 Mx1-Cre mice express Cre recombinase in hematopoietic lineage cells, including early stage OC progenitor cells, and is induced by polyinosinic-polycytidylic acid (poly I:C). 23,24 This strain makes it possible to study gene function at various postnatal bone development and remodeling stages.…”

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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: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%