RANK-L and RANK: T Cells, Bone Loss, and Mammalian Evolution

Theill, Lars E.; Boyle, William J.; Penninger, Josef

doi:10.1146/annurev.immunol.20.100301.064753

Cited by 733 publications

(683 citation statements)

References 132 publications

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“…We observed an increment of transduction signals (RANK and RANK-L) associated both to osteoclast activation, bone remodelling, and inflammatory cell communications [20]. However, since induction of an angiogenic phenotype has been reported to be associated with the up-regulation of RANK/RANK-L signalling [21,22], conceivably this latter event might be related to a functional recovery of injured cells.…”

Section: Discussionmentioning

confidence: 67%

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Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

Morbidelli

Monici²,

Marziliano

et al. 2005

Biochemical and Biophysical Research Communications

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Health hazards in astronauts are represented by cardiovascular problems and impaired bone healing. These disturbances are characterized by a common event, the loss of function by vascular endothelium, leading to impaired angiogenesis. We investigated whether the exposure of cultured endothelial cells to hypogravity condition could affect their behaviour in terms of functional activity, biochemical responses, morphology, and gene expression. Simulated hypogravity conditions for 72 h produced a reduction of cell number. Genomic analysis of endothelial cells exposed to hypogravity revealed that proapoptotic signals increased, while antiapoptotic and proliferation/survival genes were down-regulated by modelled low gravity. Activation of apoptosis was accompanied by morphological changes with mitochondrial disassembly and organelles/cytoplasmic NAD(P)H redistribution, as evidenced by autofluorescence analysis. In this condition cells were not able to respond to angiogenic stimuli in terms of migration and proliferation. Our study documents functional, morphological, and transcription alterations in vascular endothelium exposed to simulated low gravity conditions, thus providing insights on the occurrence of vascular tissue dysregulation in crewmen during prolonged space flights. Moreover, the alteration of vascular endothelium can intervene as a concause in other systemic effects, like bone remodelling, observed in weightlessness. Ó 2005 Elsevier Inc. All rights reserved.Keywords: Endothelial cell; Hypogravity; Gene expression; Autofluorescence; Apoptosis; Angiogenesis; Migration; Proliferation Angiogenesis, a process which leads to formation of new vessels, has a relevant physiological role during development and in the adult life [1,2]. Endothelial cells are the true player of the angiogenesis process. Several cardiovascular pathologies are caused by endothelial dysfunction (myocardial ischemia, atherosclerosis), thus growth factors and strategies able to restore the integrity of the endothelium and to promote angiogenesis can be viewed as innovative therapeutic approaches [3,4].Indications that mechanical stimulation of cells, and endothelium in particular, is able to change some of their functions at biochemical and molecular level are reported in the literature [5]. In spite of the evidence that cells are sensitive to mechanical stimuli, the molecular mechanisms by which individual cells recognize and respond to external forces are not well understood. Our interest on hypogravity originates from the recognition that several disturbances associated to endothelium-0006-291X/$ -see front matter Ó

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Section: Discussionmentioning

confidence: 67%

“…1). RANK (receptor activator of NK-kB) and RANK-L, biochemical markers of bone remodelling and inflammatory reactions [20], were overexpressed in hypogravity condition (Fig. 1).…”

Section: Simulated Hypogravity Alters Gene Expression Pattern In Endomentioning

confidence: 97%

Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

Morbidelli

Monici²,

Marziliano

et al. 2005

Biochemical and Biophysical Research Communications

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“…3 OCs are multinucleated cells that are derived from hematopoietic precursors of the monocyte/macrophage lineage in the presence of macrophage colony-stimulating factor (M-CSF) and RANKL. [4][5][6][7] Many other cytokines have been shown to affect bone metabolism and OC activity, including interleukin (IL)-1, IL-4, IL-7, IL-10, IL-13 and TNF. [8][9][10] A previous study by our lab showed that both transforming growth factor-beta 1 (TGF-b1) and IL-10 suppress osteoclastogenesis and bone resorption in a dosage-dependent manner and exhibit synergistic effects.…”

Section: Introductionmentioning

confidence: 99%

Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro

et al. 2010

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Cross-talk has been shown to occur between the immune system and bone metabolism pathways. In the present study, we investigated the impact of CD4 1 CD25 1 Foxp3 1 regulatory T (Treg) cells on osteoclastogenesis and bone resorption. Treg cells that were isolated and purified from peripheral blood mononuclear cells (PBMCs) of healthy adults inhibited both the differentiation of osteoclasts (OCs) from human embryo bone marrow cells (BMCs) and the pit formation in a dose-dependent manner. In cell cocultures, the production levels of both interleukin-10 (IL-10) and transforming growth factor-beta 1 (TGF-b1) were proportionally upregulated as the ratio of Treg cells to BMCs was increased, and the inhibition of OC differentiation and bone resorption by Treg cells was completely reversed by anti-IL-10 and anti-TGF-b1 antibodies. Treatment of BMC and Treg cell cocultures with 17b-estradiol (E2) at concentrations between 10 27 and 10 29 mol/l suppressed OC differentiation and bone resorption more efficiently than it did in cultures of BMCs alone; this enhanced suppression occurred via the stimulation of Treg cell IL-10 and TGF-b1 expression. These data suggest that Treg cells suppress OC differentiation and bone resorption by secreting IL-10 and TGF-b1. E2 enhances the suppressive effects of Treg cells on OC differentiation and bone resorption by stimulating IL-10 and TGF-b1 secretion from these cells. Therefore, Treg cell-derived IL-10 and TGF-b1 are likely involved in the regulation of E2 on bone metabolism and represent potential therapeutic targets for the treatment of postmenopausal osteoporosis (PMO).

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“…(1,2) The imbalance between osteoblast and osteoclast activity underlies various bone and joint diseases, such as osteoporosis and rheumatoid arthritis. (3)(4)(5)(6) Osteoclasts are multinucleated giant cells that are polarized and resorb bone through specialized machinery so as to attach to mineralized matrix and degrade it. The differentiation of monocyte/ macrophage-lineage precursor cells into mature osteoclasts is induced by the tumor necrosis factor (TNF) family cytokine receptor activator of NF-kB ligand (RANKL) together with colonystimulating factor (M-CSF), and provides an activating signal as well as survival signals to osteoclasts.…”

Section: Introductionmentioning

confidence: 99%

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Shirakawa

Nakamura

Masuda

et al. 2012

Journal of Bone and Mineral Research

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Class IA phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptors and regulate a wide range of cellular processes. In osteoclasts, they are activated downstream of a v b 3 integrin and colony-stimulating factor-1 receptor (c-Fms), which are involved in the regulation of bone-resorbing activity. The physiological relevance of the in vitro studies using PI3K inhibitors has been of limited value, because they inhibit all classes of PI3K. Here, we show that the osteoclast-specific deletion of the p85 genes encoding the regulatory subunit of the class IA PI3K results in an osteopetrotic phenotype caused by a defect in the bone-resorbing activity of osteoclasts. Class IA PI3K is required for the ruffled border formation and vesicular transport, but not for the formation of the sealing zone. p85a/b doubly deficient osteoclasts had a defect in macrophage colony-stimulating factor (M-CSF)-induced protein kinase B (Akt) activation and the introduction of constitutively active Akt recovered the bone-resorbing activity. Thus, the class IA PI3K-Akt pathway regulates the cellular machinery crucial for osteoclastic bone resorption, and may provide a molecular basis for therapeutic strategies against bone diseases. ß

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RANK-L and RANK: T Cells, Bone Loss, and Mammalian Evolution

Cited by 733 publications

References 132 publications

Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals

Estrogen enhances the functions of CD4+CD25+Foxp3+ regulatory T cells that suppress osteoclast differentiation and bone resorption in vitro

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

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