scholarly journals Conditional deletion of E11/Podoplanin in bone protects against ovariectomy-induced increases in osteoclast formation and activity

2020 ◽  
Vol 40 (1) ◽  
Author(s):  
Katherine A. Staines ◽  
Mark Hopkinson ◽  
Scott Dillon ◽  
Louise A. Stephen ◽  
Robert Fleming ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Remodelling ◽  
Osteoclast Formation ◽  
Conditional Knockout ◽  
Bone Resorption Marker ◽  
Trabecular Microarchitecture ◽  
Dendritic Network ◽  
Osteoclast Number

Abstract E11/Podoplanin (Pdpn) is implicated in early osteocytogenesis and the formation of osteocyte dendrites. This dendritic network is critical for bone modelling/remodelling, through the production of receptor activator of nuclear factor κ B (RANK)-ligand (RANKL). Despite this, the role of Pdpn in the control of bone remodelling is yet to be established in vivo. Here we utilised bone-specific Pdpn conditional knockout mice (cKO) to examine the role of Pdpn in the bone loss associated with ovariectomy (OVX). MicroCT revealed that Pdpn deletion had no significant effect on OVX-induced changes in trabecular microarchitecture. Significant differences between genotypes were observed in the trabecular pattern factor (P<0.01) and structure model index (P<0.01). Phalloidin staining of F-actin revealed OVX to induce alterations in osteocyte morphology in both wild-type (WT) and cKO mice. Histological analysis revealed an expected significant increase in osteoclast number in WT mice (P<0.01, compared with sham). However, cKO mice were protected against such increases in osteoclast number. Consistent with this, serum levels of the bone resorption marker Ctx were significantly increased in WT mice following OVX (P<0.05), but were unmodified by OVX in cKO mice. Gene expression of the bone remodelling markers Rank, Rankl, Opg and Sost were unaffected by Pdpn deletion. Together, our data suggest that an intact osteocyte dendritic network is required for sustaining osteoclast formation and activity in the oestrogen-depleted state, through mechanisms potentially independent of RANKL expression. This work will enable a greater understanding of the role of osteocytes in bone loss induced by oestrogen deprivation.

scholarly journals Alternative regulatory mechanism for the maintenance of bone homeostasis via STAT5-mediated regulation of the differentiation of BMSCs into adipocytes

2021 ◽  
Author(s):  
Semun Seong ◽  
Jung Ha Kim ◽  
Kabsun Kim ◽  
Inyoung Kim ◽  
Jeong-Tae Koh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Loss ◽  
Target Genes ◽  
Osteoclast Differentiation ◽  
Conditional Knockout ◽  
Negative Regulator ◽  
Bone Homeostasis

AbstractSTAT5 is a transcription factor that is activated by various cytokines, hormones, and growth factors. Activated STAT5 is then translocated to the nucleus and regulates the transcription of target genes, affecting several biological processes. Several studies have investigated the role of STAT5 in adipogenesis, but unfortunately, its role in adipogenesis remains controversial. In the present study, we generated adipocyte-specific Stat5 conditional knockout (cKO) (Stat5fl/fl;Apn-cre) mice to investigate the role of STAT5 in the adipogenesis of bone marrow mesenchymal stem cells (BMSCs). BMSC adipogenesis was significantly inhibited upon overexpression of constitutively active STAT5A, while it was enhanced in the absence of Stat5 in vitro. In vivo adipose staining and histological analyses revealed increased adipose volume in the bone marrow of Stat5 cKO mice. ATF3 is the target of STAT5 during STAT5-mediated inhibition of adipogenesis, and its transcription is regulated by the binding of STAT5 to the Atf3 promoter. ATF3 overexpression was sufficient to suppress the enhanced adipogenesis of Stat5-deficient adipocytes, and Atf3 silencing abolished the STAT5-mediated inhibition of adipogenesis. Stat5 cKO mice exhibited reduced bone volume due to an increase in the osteoclast number, and coculture of bone marrow-derived macrophages with Stat5 cKO adipocytes resulted in enhanced osteoclastogenesis, suggesting that an increase in the adipocyte number may contribute to bone loss. In summary, this study shows that STAT5 is a negative regulator of BMSC adipogenesis and contributes to bone homeostasis via direct and indirect regulation of osteoclast differentiation; therefore, it may be a leading target for the treatment of both obesity and bone loss-related diseases.

scholarly journals Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Hua Yang ◽  
Mengjie Zhang ◽  
Jiahao Shi ◽  
Yunhe Zhou ◽  
Zhipeng Wan ◽  
...  
Keyword(s):  
Cerebral Cortex ◽  
Mouse Model ◽  
Glutamate Release ◽  
Critical Role ◽  
Conditional Knockout ◽  
Snare Complex ◽  
Extracellular Glutamate ◽  
Glutamate Level

Several studies have associated reduced expression of synaptosomal-associated protein of 25 kDa (SNAP-25) with schizophrenia, yet little is known about its role in the illness. In this paper, a forebrain glutamatergic neuron-specific SNAP-25 knockout mouse model was constructed and studied to explore the possible pathogenetic role of SNAP-25 in schizophrenia. We showed that SNAP-25 conditional knockout (cKO) mice exhibited typical schizophrenia-like phenotype. A significantly elevated extracellular glutamate level was detected in the cerebral cortex of the mouse model. Compared with Ctrls, SNAP-25 was dramatically reduced by about 60% both in cytoplasm and in membrane fractions of cerebral cortex of cKOs, while the other two core members of SNARE complex: Syntaxin-1 (increased ~80%) and Vamp2 (increased ~96%) were significantly increased in cell membrane part. Riluzole, a glutamate release inhibitor, significantly attenuated the locomotor hyperactivity deficits in cKO mice. Our findings provide in vivo functional evidence showing a critical role of SNAP-25 dysfunction on synaptic transmission, which contributes to the developmental of schizophrenia. It is suggested that a SNAP-25 cKO mouse, a valuable model for schizophrenia, could address questions regarding presynaptic alterations that contribute to the etiopathophysiology of SZ and help to consummate the pre- and postsynaptic glutamatergic pathogenesis of the illness.

scholarly journals Scutellarein inhibits RANKL‐induced osteoclast formation in vitro and prevents LPS‐induced bone loss in vivo

2018 ◽  
Vol 234 (7) ◽  
pp. 11951-11959 ◽  
Author(s):  
Fangsheng Fu ◽  
Siyuan Shao ◽  
Ziyi Wang ◽  
Fangming Song ◽  
Xixi Lin ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Formation

Lung epithelial NOX/DUOX and respiratory virus infections

2014 ◽  
Vol 128 (6) ◽  
pp. 337-347 ◽  
Author(s):  
Nathalie Grandvaux ◽  
Mélissa Mariani ◽  
Karin Fink
Keyword(s):  
Respiratory Virus ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Conditional Knockout ◽  
In Vivo Studies ◽  
Virus Infections ◽  
Lung Epithelial ◽  
Respiratory Virus Infections

Determining the role of NADPH oxidases in the context of virus infection is an emerging area of research and our knowledge is still sparse. The expression of various isoforms of NOX/DUOX (NADPH oxidase/dual oxidase) in the epithelial cells (ECs) lining the respiratory tract renders them primary sites from which to orchestrate the host defence against respiratory viruses. Accumulating evidence reveals distinct facets of the involvement of NOX/DUOX in host antiviral and pro-inflammatory responses and in the control of the epithelial barrier integrity, with individual isoforms mediating co-operative, but surprisingly also opposing, functions. Although in vivo studies in mice are in line with some of these observations, a complete understanding of the specific functions of epithelial NOX/DUOX awaits lung epithelial-specific conditional knockout mice. The goal of the present review is to summarize our current knowledge of the role of individual NOX/DUOX isoforms expressed in the lung epithelium in the context of respiratory virus infections so as to highlight potential opportunities for therapeutic intervention.

scholarly journals Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) Drives Activation of Bone Remodelling and Skeletal Metastasis

2019 ◽  
Vol 17 (6) ◽  
pp. 538-547 ◽  
Author(s):  
Bridie S. Mulholland ◽  
Mark R. Forwood ◽  
Nigel A. Morrison
Keyword(s):  
Breast Cancer Cells ◽  
Bone Remodelling ◽  
Skeletal Metastasis ◽  
Osteoclast Formation ◽  
Intermittent Treatment ◽  
Monocyte Chemoattractant Protein 1 ◽  
Monocyte Chemoattractant ◽  
Monocyte Chemoattractant Protein ◽  
Prostate Cancers

Abstract Purpose of Review The purpose of this review is to explore the role of monocyte chemoattractant protein-1 (MCP-1 or CCL2) in the processes that underpin bone remodelling, particularly the action of osteoblasts and osteoclasts, and its role in the development and metastasis of cancers that target the bone. Recent Findings MCP-1 is a key mediator of osteoclastogenesis, being the highest induced gene during intermittent treatment with parathyroid hormone (iPTH), but also regulates catabolic effects of continuous PTH on bone including monocyte and macrophage recruitment, osteoclast formation and bone resorption. In concert with PTH-related protein (PTHrP), MCP-1 mediates the interaction between tumour-derived factors and host-derived chemokines to promote skeletal metastasis. In breast and prostate cancers, an osteolytic cascade is driven by tumour cell–derived PTHrP that upregulates MCP-1 in osteoblastic cells. This relationship between PTHrP and osteoblastic expression of MCP-1 may drive the colonisation of disseminated breast cancer cells in the bone. Summary There is mounting evidence to suggest a pivotal role of MCP-1 in many diseases and an important role in the establishment of comorbidities. Coupled with its role in bone remodelling and the regulation of bone turnover, there is the potential for pathological relationships between bone disorders and bone-related cancers driven by MCP-1. MCP-1’s role in bone remodelling and bone-related cancers highlights its potential as a novel anti-resorptive and anti-metastatic target.

scholarly journals APC/CCdh1-Rock2 pathway controls dendritic integrity and memory

2017 ◽  
Vol 114 (17) ◽  
pp. 4513-4518 ◽  
Author(s):  
Verónica Bobo-Jiménez ◽  
María Delgado-Esteban ◽  
Julie Angibaud ◽  
Irene Sánchez-Morán ◽  
Antonio de la Fuente ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Memory Loss ◽  
Neuronal Morphology ◽  
Conditional Knockout ◽  
Anaphase Promoting Complex ◽  
Adult Mice ◽  
Dendritic Network ◽  
Rho Protein ◽  
With Memory

Disruption of neuronal morphology contributes to the pathology of neurodegenerative disorders such as Alzheimer’s disease (AD). However, the underlying molecular mechanisms are unknown. Here, we show that postnatal deletion of Cdh1, a cofactor of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase in neurons [Cdh1 conditional knockout (cKO)], disrupts dendrite arborization and causes dendritic spine and synapse loss in the cortex and hippocampus, concomitant with memory impairment and neurodegeneration, in adult mice. We found that the dendrite destabilizer Rho protein kinase 2 (Rock2), which accumulates in the brain of AD patients, is an APC/CCdh1 substrate in vivo and that Rock2 protein and activity increased in the cortex and hippocampus of Cdh1 cKO mice. In these animals, inhibition of Rock activity, using the clinically approved drug fasudil, prevented dendritic network disorganization, memory loss, and neurodegeneration. Thus, APC/CCdh1-mediated degradation of Rock2 maintains the dendritic network, memory formation, and neuronal survival, suggesting that pharmacological inhibition of aberrantly accumulated Rock2 may be a suitable therapeutic strategy against neurodegeneration.

scholarly journals Hedgehog Inhibitors Suppress Osteoclastogenesis in In Vitro Cultures, and Deletion of Smo in Macrophage/Osteoclast Lineage Prevents Age-Related Bone Loss

2020 ◽  
Vol 21 (8) ◽  
pp. 2745
Author(s):  
Yukihiro Kohara ◽  
Ryuma Haraguchi ◽  
Riko Kitazawa ◽  
Yuuki Imai ◽  
Sohei Kitazawa
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Signaling Pathway ◽  
Early Stage ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Age Related ◽  
Hh Signaling

The functional role of the Hedgehog (Hh)-signaling pathway has been widely investigated in bone physiology/development. Previous studies have, however, focused primarily on Hh functions in bone formation, while its roles in bone resorption have not been fully elucidated. Here, we found that cyclopamine (smoothened (Smo) inhibitor), GANT-58 (GLI1 inhibitor), or GANT-61 (GLI1/2 inhibitor) significantly inhibited RANKL-induced osteoclast differentiation of bone marrow-derived macrophages. Although the inhibitory effects were exerted by cyclopamine or GANT-61 treatment during 0–48 h (early stage of osteoclast differentiation) or 48–96 h (late stage of osteoclast differentiation) after RANKL stimulation, GANT-58 suppressed osteoclast formation only during the early stage. These results suggest that the Smo-GLI1/2 axis mediates the whole process of osteoclastogenesis and that GLI1 activation is requisite only during early cellular events of osteoclastogenesis. Additionally, macrophage/osteoclast-specific deletion of Smo in mice was found to attenuate the aging phenotype characterized by trabecular low bone mass, suggesting that blockage of the Hh-signaling pathway in the osteoclast lineage plays a protective role against age-related bone loss. Our findings reveal a specific role of the Hh-signaling pathway in bone resorption and highlight that its inhibitors show potential as therapeutic agents that block osteoclast formation in the treatment of senile osteoporosis.

scholarly journals IL-17A gene transfer induces bone loss and epidermal hyperplasia associated with psoriatic arthritis

2014 ◽  
Vol 74 (6) ◽  
pp. 1284-1292 ◽  
Author(s):  
Iannis E Adamopoulos ◽  
Erika Suzuki ◽  
Cheng-Chi Chao ◽  
Dan Gorman ◽  
Sarvesh Adda ◽  
...  
Keyword(s):  
Psoriatic Arthritis ◽  
Gene Transfer ◽  
Bone Resorption ◽  
Bone Loss ◽  
Bone Destruction ◽  
Chronic Inflammatory Disease ◽  
Epidermal Hyperplasia ◽  
Osteoclast Precursors

BackgroundPsoriatic arthritis (PsA) is a chronic inflammatory disease characterised by clinical features that include bone loss and epidermal hyperplasia. Aberrant cytokine expression has been linked to joint and skin pathology; however, it is unclear which cytokines are critical for disease initiation. Interleukin 17A (IL-17A) participates in many pathological immune responses; however, its role in PsA has not been fully elucidated.ObjectiveTo determine the role of IL-17A in epidermal hyperplasia and bone destruction associated with psoriatic arthritis.DesignAn in vivo gene transfer approach was used to investigate the role of IL-17A in animal models of inflammatory (collagen-induced arthritis) and non-inflammatory (receptor activator of NF-κB ligand (RANKL)-gene transfer) bone loss.ResultsIL-17A gene transfer induced the expansion of IL-17RA+CD11b+Gr1low osteoclast precursors and a concomitant elevation of biomarkers indicative of bone resorption. This occurred at a time preceding noticeable joint inflammation, suggesting that IL-17A is critical for the induction of pathological bone resorption through direct activation of osteoclast precursors. Moreover, IL-17A induced a second myeloid population CD11b+Gr1high neutrophil-like cells, which was associated with cutaneous pathology including epidermal hyperplasia, parakeratosis and Munro's microabscesses formation.ConclusionsCollectively, these data support that IL-17A can play a key role in the pathogenesis of inflammation-associated arthritis and/or skin disease, as observed in PsA.

scholarly journals Suppression Effect of Astaxanthin on Osteoclast Formation In Vitro and Bone Loss In Vivo

2018 ◽  
Vol 19 (3) ◽  
pp. 912 ◽  
Author(s):  
Yun-Ho Hwang ◽  
Kwang-Jin Kim ◽  
Su-Jin Kim ◽  
Seul-Ki Mun ◽  
Seong-Gyeol Hong ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Formation ◽  
Suppression Effect

scholarly journals The Role of IL-1βin the Bone Loss during Rheumatic Diseases

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Piero Ruscitti ◽  
Paola Cipriani ◽  
Francesco Carubbi ◽  
Vasiliki Liakouli ◽  
Francesca Zazzeroni ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Rheumatic Diseases ◽  
Nuclear Factor Kappa B ◽  
Inflammatory Diseases ◽  
Receptor Activator ◽  
Main Factor

Several inflammatory diseases have been associated with increased bone resorption and fracture rates and different studies supported the relation between inflammatory cytokines and osteoclast activity. The main factor required for osteoclast activation is the stimulation by receptor activator of nuclear factor kappa-B ligand (RANKL) expressed on osteoblasts. In this context, interleukin- (IL-) 1β, one of the most powerful proinflammatory cytokines, is a strong stimulator of in vitro and in vivo bone resorption via upregulation of RANKL that stimulates the osteoclastogenesis. The resulting effects lead to an imbalance in bone metabolism favouring bone resorption and osteoporosis. In this paper, we review the available literature on the role of IL-1βin the pathogenesis of bone loss. Furthermore, we analysed the role of IL-1βin bone resorption during rheumatic diseases and, when available, we reported the efficacy of anti-IL-1βtherapy in this field.

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