Transgenic mice that express Cre recombinase in osteoclasts

Chiu, W.S. Maria; McManus, J. F.; Notini, Amanda J.; Cassady, A. I.; Zajac, Jeffrey D; Davey, Rachel A

doi:10.1002/gene.20041

Cited by 93 publications

(120 citation statements)

References 21 publications

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“…S4). To exclude that this reduction in bone erosions was the result of the ubiquitous deletion of FcγRIV on monocytes, macrophages, and neutrophils in FcγRIV knockout mice, we generated a mouse with an osteoclast-specific deletion of FcγRIV by crossing FcγRIV-floxed mice with cathepsin K-cre animals (CtskCreR4flox) (35). As shown in Fig.…”

Section: Role Of Fcγri and Fcγriv For Osteoclast Development And Bonementioning

confidence: 99%

Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice

Seeling

Hillenhoff

David

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

153

175

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Destruction of bone tissue by osteoclasts represents a severe pathological phenotype during inflammatory arthritis and results in joint pain and bone malformations. Previous studies have established the essential role of cytokines including TNFα and receptor–ligand interactions, such as the receptor activator of nuclear factor-kappa B–receptor activator of nuclear factor-kappa B ligand interaction for osteoclast formation during joint inflammation. Moreover, autoantibodies contribute to joint inflammation in inflammatory arthritis by triggering cellular fragment crystallizable (Fc)γ receptors (FcγR), resulting in the release of proinflammatory cytokines and chemokines essential for recruitment and activation of innate immune effector cells. In contrast, little is known about the expression pattern and function of different FcγRs during osteoclast differentiation. This would allow osteoclasts to directly interact with autoantibody immune complexes, rather than being influenced indirectly via proinflammatory cytokines released upon immune complex binding to other FcγR-expressing innate immune cells. To address this question, we studied FcγR expression and function on osteoclasts during the steady state and during acute joint inflammation in a model of inflammatory arthritis. Our results suggest that osteoclastogenesis is directly influenced by IgG autoantibody binding to select activating FcγRs on immature osteoclasts, resulting in enhanced osteoclast generation and, ultimately, bone destruction.

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Section: Role Of Fcγri and Fcγriv For Osteoclast Development And Bonementioning

confidence: 99%

Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice

Seeling

Hillenhoff

David

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

153

175

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“…Conditional inactivation in osteoblasts was performed using the Col1a1-Cre transgenic mice expressing Cre under the control of the osteoblast-specific 2.3-kb sequence of the rat collagen type 1A1 promoter. These mice have been used to direct strong osteoblast-or osteoclast-specific expression of various genes in transgenic mice (54)(55)(56)(57). The promoter is active in osteoblast precursors, osteoblasts, and osteocytes (58).…”

Section: Discussionmentioning

confidence: 99%

FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin

Kode¹,

Mosialou²,

Silva³

et al. 2012

J. Clin. Invest.

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Serotonin is a critical regulator of bone mass, fulfilling different functions depending on its site of synthesis. Brain-derived serotonin promotes osteoblast proliferation, whereas duodenal-derived serotonin suppresses it. To understand the molecular mechanisms of duodenal-derived serotonin action on osteoblasts, we explored its transcriptional mediation in mice. We found that the transcription factor FOXO1 is a crucial determinant of the effects of duodenum-derived serotonin on bone formation We identified two key FOXO1 complexes in osteoblasts, one with the transcription factor cAMP-responsive element-binding protein 1 (CREB) and another with activating transcription factor 4 (ATF4). Under normal levels of circulating serotonin, the proliferative activity of FOXO1 was promoted by a balance between its interaction with CREB and ATF4. However, high circulating serotonin levels prevented the association of FOXO1 with CREB, resulting in suppressed osteoblast proliferation. These observations identify FOXO1 as the molecular node of an intricate transcriptional machinery that confers the signal of duodenal-derived serotonin to inhibit bone formation.

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“…For example, CD11b or lysozyme drivers are useful to target macrophage precursors because they are upregulated only upon macrophage differentiation (12,19,25). In addition, Ctsk or TRAP drivers are useful to target preosteoclasts and mature osteoclasts because they are upregulated only upon osteoclast differentiation (11,34). Therefore, the PPAR␥-tTAbased models represent a novel osteoclast progenitor-targeting strategy that is complementary to other existing models for the comprehensive investigation of osteoclast lineage specification and differentiation.…”

Section: Discussionmentioning

confidence: 99%

Osteoclast Progenitors Reside in the Peroxisome Proliferator-Activated Receptor γ-Expressing Bone Marrow Cell Population

Wei

Zeve

Wang

et al. 2011

Molecular and Cellular Biology

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Osteoclasts are bone-resorbing cells essential for skeletal development, homeostasis, and regeneration. They derive from hematopoietic progenitors in the monocyte/macrophage lineage and differentiate in response to RANKL. However, the precise nature of osteoclast progenitors is a longstanding and important question. Using inducible peroxisome proliferator-activated receptor ␥ (PPAR␥)-tTA TRE-GFP (green fluorescent protein) reporter mice, we show that osteoclast progenitors reside specifically in the PPAR␥-expressing hematopoietic bone marrow population and identify the quiescent PPAR␥ ؉ cells as osteoclast progenitors. Importantly, two PPAR␥-tTA TRE-Cre-controlled genetic models provide compelling functional evidence. First, Notch activation in PPAR␥ ؉ cells causes high bone mass due to impaired osteoclast precursor proliferation. Second, selective ablation of PPAR␥ ؉ cells by diphtheria toxin also causes high bone mass due to decreased osteoclast numbers. Furthermore, PPAR␥ ؉ cells respond to both pathological and pharmacological resorption-enhancing stimuli. Mechanistically, PPAR␥ promotes osteoclast progenitors by activating GATA2 transcription. These findings not only identify the long-sought-after osteoclast progenitors but also establish unprecedented tools for their visualization, isolation, characterization, and genetic manipulation.Bone is a dynamic tissue that constantly remodels itself by balancing osteoclast-mediated bone resorption and osteoblastmediated bone formation. Osteoclasts derive from hematopoietic progenitors (5) in the monocyte/macrophage lineage (41, 47); in contrast, osteoblasts are of mesenchymal lineage (38). Physiological osteoclast functions are essential for skeletal development, homeostasis, and regeneration in response to injury. However, pathological increases in osteoclast activities are associated with several diseases, including osteoporosis, arthritis, and bone metastasis of cancers (35).Osteoclast lineage specification is a multistep process that requires osteoclast progenitor commitment (41, 47), macrophage colony-stimulating factor (M-CSF)-mediated osteoclast precursor proliferation (57), and RANKL (receptor activator of NF-B ligand)-mediated osteoclast differentiation (8,29,56). Although the discovery of RANKL has revolutionized research in osteoclast biology, RANKL mainly acts at later stages of osteoclastogenesis. The cellular identity and the precise nature of the bona fide osteoclast progenitors are underexplored. Previous studies have elegantly characterized the cell surface markers that enrich osteoclast progenitors using flow cytometry (25); however, tools are lacking to label osteoclast progenitors in vivo for visualization, isolation, and lineage tracing, as well as to genetically manipulate osteoclast progenitors for functional characterization.Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a member of the nuclear receptor family of transcription factors that can be activated by lipophilic ligands, including the diabetic drug rosiglitazone (BRL, or Ava...

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Transgenic mice that express Cre recombinase in osteoclasts

Cited by 93 publications

References 21 publications

Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice

Inflammatory monocytes and Fcγ receptor IV on osteoclasts are critical for bone destruction during inflammatory arthritis in mice

FOXO1 orchestrates the bone-suppressing function of gut-derived serotonin

Osteoclast Progenitors Reside in the Peroxisome Proliferator-Activated Receptor γ-Expressing Bone Marrow Cell Population

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