Osteoclasts: New Insights

Xu, Feng; Teitelbaum, Steven L.

doi:10.4248/br201301003

Cited by 387 publications

(242 citation statements)

References 189 publications

(98 reference statements)

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“…Additionally, although no changes in total osteoclast number were detected, alterations in LDS osteoclast activity may also contribute to the overall skeletal phenotype. 32 In contrast to the decreased TGF-b1-induced pSmad2 levels in osteoblasts in vitro, we observed increased levels of pSmad2/3 immunoreactivity in cortical bone of LDS mice in vivo. This result is consistent with previous findings in vascular smooth muscle cells of the aortic wall from LDS mice.…”

Section: Discussioncontrasting

confidence: 70%

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Dysregulated TGF‐β signaling alters bone microstructure in a mouse model of Loeys‐Dietz syndrome

Dewan

Tomlinson

Mitchell

et al. 2015

Journal Orthopaedic Research

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Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular and skeletal abnormalities resembling Marfan syndrome, including a predisposition for pathologic fracture. LDS is caused by heterozygous mutations in the genes encoding transforming growth factor-b (TGF-b) type 1 and type 2 receptors. In this study, we characterized the skeletal phenotype of mice carrying a mutation in the TGF-b type 2 receptor associated with severe LDS in humans. Cortical bone in LDS mice showed significantly reduced tissue area, bone area, and cortical thickness with increased eccentricity. However, no significant differences in trabecular bone volume were observed. Dynamic histomorphometry performed in calcein-labeled mice showed decreased mineral apposition rates in cortical and trabecular bone with normal numbers of osteoblasts and osteoclasts. Mechanical testing of femurs by three-point bending revealed reduced femoral strength and fracture resistance. In vitro, osteoblasts from LDS mice demonstrated increased mineralization with enhanced expression of osteoblast differentiation markers compared with control cells. These changes were associated with impaired TGF-b1-induced Smad2 and Erk1/2 phosphorylation and upregulated TGF-b1 ligand mRNA expression, compatible with G357W as a loss-of-function mutation in the TGF-b type 2 receptor. Paradoxically, phosphorylated Smad2/3 in cortical osteocytes measured by immunohistochemistry was increased relative to controls, possibly suggesting the cross-activation of TGF-brelated receptors. The skeletal phenotype observed in the LDS mouse closely resembles the principal structural features of bone in humans with LDS and establishes this mouse as a valid in vivo model for further investigation of TGF-b receptor signaling in bone.

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Section: Discussioncontrasting

confidence: 70%

“…In total, these results indicate that the ultimate impact of the LDS mutation in bone is complex and not completely modeled in vitro. Additionally, although no changes in total osteoclast number were detected, alterations in LDS osteoclast activity may also contribute to the overall skeletal phenotype …”

Section: Discussionmentioning

confidence: 88%

Dysregulated TGF‐β signaling alters bone microstructure in a mouse model of Loeys‐Dietz syndrome

Dewan

Tomlinson

Mitchell

et al. 2015

Journal Orthopaedic Research

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“…This indicates that Aβ enhances OC function via an NFATc1-mediated pathway. Since NF-κB and NFATc1 coodinate to promote expression of most osteoclast marker genes [30], Aβ is able to promote the transcription of osteoclast-specific genes such as TRAP and cathepsin K, contributing to the enhancement effect of Aβ on OC function. Consistent with a study showing high extracellular calcium affected osteoclastogenesis in mouse BMM cell culture [31], our results further demonstrate that Aβ enhances RANKL-induced calcium oscilations in BMMs, indicating that Aβ upregulates NFATc1 in response to RANKL stimulation by increasing calcium signaling-dependent NFAT activation.…”

Section: Discussionmentioning

confidence: 99%

Amyloid β Peptide Enhances RANKL-Induced Osteoclast Activation through NF-κB, ERK, and Calcium Oscillation Signaling

Yang

Teguh

et al. 2016

IJMS

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Osteoporosis and Alzheimer’s disease (AD) are common chronic degenerative disorders which are strongly associated with advanced age. We have previously demonstrated that amyloid beta peptide (Aβ), one of the pathological hallmarks of AD, accumulated abnormally in osteoporotic bone specimens in addition to having an activation effect on osteoclast (Bone 2014,61:164-75). However, the underlying molecular mechanisms remain unclear. Activation of NF-κB, extracellular signal-regulated kinase (ERK) phosphorylates, and calcium oscillation signaling pathways by receptor activator NF-κB ligand (RANKL) plays a pivotal role in osteoclast activation. Targeting this signaling to modulate osteoclast function has been a promising strategy for osteoclast-related diseases. In this study, we investigated the effects of Aβ on RANKL-induced osteoclast signaling pathways in vitro. In mouse bone marrow monocytes (BMMs), Aβ exerted no effect on RANKL-induced osteoclastogenesis but promoted osteoclastic bone resorption. In molecular levels, Aβ enhanced NF-κB activity and IκB-α degradation, activated ERK phosphorylation and stimulated calcium oscillation, thus leading to upregulation of NFAT-c1 expression during osteoclast activation. Taken together, our data demonstrate that Aβ enhances RANKL-induced osteoclast activation through IκB-α degradation, ERK phosphorylation, and calcium oscillation signaling pathways and that Aβ may be a promising agent in the treatment of osteoclast-related disease such as osteoporosis.

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“…Actin ring structures reflect the establishment of sealing zones between osteoclasts and bone that are necessary for resorption (53). Signals provided by α v β 3 integrins are required for inducing actin reorganization and attachment of osteoclasts to the bone matrix (54, 55). Mice lacking the β3 integrin have dysfunctional osteoclasts and show protection from bone loss induced by ovariectomy (56, 57).…”

Section: Discussionmentioning

confidence: 99%

Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption

Shashkova

Trivedi

Cline-Smith

et al. 2016

The Journal of Immunology

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Osteoimmunology arose from the recognition that cytokines produced by lymphocytes can affect bone homeostasis. We have previously shown that osteoclasts, cells that resorb bone, act as antigen-presenting cells. Cross-presentation of antigens by osteoclasts leads to expression of CD25 and FoxP3, markers of regulatory T-cells in the CD8 T-cells. Osteoclast-induced FoxP3+ CD8 T-cells (OC-iTcREG) suppress priming of CD4 and CD8 T-cells by dendritic cells. OC-iTcREG also limit bone resorption by osteoclasts, forming a negative feedback loop. Here we show that OC-iTcREG express concurrently T-bet and Eomesodermin (Eomes) and IFN-γ. Pharmacological inhibition of IκK blocked IFN-γ, T-bet and Eomes production by TcREG. Furthermore, we show using chromatin immunoprecipitation, NF-κB enrichment in the T-bet and Eomes promoter. We demonstrate that IFN-γ produced by TcREG is required for suppression of osteoclastogenesis and for degradation of tumor necrosis factor receptor-associated factor 6 (TRAF6) in osteoclast precursors. The latter prevents signaling by receptor activator of NF-κB ligand (RANKL) needed for osteoclastogenesis. Knockout of IFN-γ rendered TcREG inefficient in preventing actin ring formation in osteoclasts, a process required for bone resorption. TcREG generated in vivo using IFN-γ−/− T-cells had impaired ability to protect mice from bone resorption and bone loss in response to high-dose RANKL. The results of this study demonstrate a novel link between NF-κB signaling and induction of IFN-γ in TcREG and establish important role for IFN-γ in TcREG-mediated protection from bone loss.

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Osteoclasts: New Insights

Cited by 387 publications

References 189 publications

Dysregulated TGF‐β signaling alters bone microstructure in a mouse model of Loeys‐Dietz syndrome

Dysregulated TGF‐β signaling alters bone microstructure in a mouse model of Loeys‐Dietz syndrome

Amyloid β Peptide Enhances RANKL-Induced Osteoclast Activation through NF-κB, ERK, and Calcium Oscillation Signaling

Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-γ To Regulate Bone Resorption

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