scholarly journals Osteopetrosis and Its Relevance for the Discovery of New Functions Associated with the Skeleton

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Amélie E. Coudert ◽  
Marie-Christine de Vernejoul ◽  
Maurizio Muraca ◽  
Andrea Del Fattore
Keyword(s):  
Bone Marrow ◽  
Immune System ◽  
Bone Mass ◽  
Male Fertility ◽  
Genetic Disorder ◽  
Whole Body ◽  
Insulin Metabolism ◽  
Facial Nerves ◽  
Osteoclast Function

Osteopetrosis is a rare genetic disorder characterized by an increase of bone mass due to defective osteoclast function. Patients typically displayed spontaneous fractures, anemia, and in the most severe forms hepatosplenomegaly and compression of cranial facial nerves leading to deafness and blindness. Osteopetrosis comprises a heterogeneous group of diseases as several forms are known with different models of inheritance and severity from asymptomatic to lethal. This review summarizes the genetic and clinical features of osteopetrosis, emphasizing how recent studies of this disease have contributed to understanding the central role of the skeleton in the whole body physiology. In particular, the interplay of bone with the stomach, insulin metabolism, male fertility, the immune system, bone marrow, and fat is described.

scholarly journals The Interplay between Immunosenescence and Microbiota in the Efficacy of Vaccines

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 636 ◽  
Author(s):  
Rossella Cianci ◽  
Laura Franza ◽  
Maria Grazia Massaro ◽  
Raffaele Borriello ◽  
Francesco De Vito ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Elderly People ◽  
Whole Body ◽  
Current Evidence ◽  
Medical Procedures ◽  
Inflammatory Microenvironment

Vaccinations are among the most effective medical procedures and have had an incredible impact on almost everyone’s life. One of the populations that can benefit the most from them are elderly people. Unfortunately, in this group, vaccines are less effective than in other groups, due to immunosenescence. The immune system ages like the whole body and becomes less effective in responding to infections and vaccinations. At the same time, immunosenescence also favors an inflammatory microenvironment, which is linked to many conditions typical of the geriatrics population. The microbiota is one of the key actors in modulating the immune response and, in this review, we discuss the current evidence on the role of microbiota in regulating the immune response to vaccines, particularly in elderly people.

A Critical Role for Innate Immunity In Allogeneic Hematopoietic Cell Rejection Via the TLR4/TRIF Pathway

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 77-77
Author(s):  
Hong Xu ◽  
Jun Yan ◽  
Ziqiang Zhu ◽  
Yiming Huang ◽  
Yujie Wen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Immunity ◽  
T Cells ◽  
Immune System ◽  
T Cell ◽  
Innate Immune System ◽  
Critical Role ◽  
Innate Immune ◽  
Wild Type

Abstract Abstract 77 Adaptive immunity, especially T cells, has long been believed to be the dominant immune barrier in allogeneic transplantation. Targeting host T cells significantly reduces conditioning for bone marrow cell (BMC) engraftment. Innate immunity has been recently shown to pose a significant barrier in solid organ transplantation, but has not been addressed in bone marrow transplantation (BMT). Using T cell deficient (TCR-β/δ−/−) or T and B cell deficient (Rag−/−) mice, we found that allogeneic BMC rejection occurred early before the time required for T cell activation and was T- and B-cell independent, suggesting an effector role for innate immune cells in BMC rejection. Therefore, we hypothesized that by controlling both innate and adaptive immunity, the donor BMC would have a window of advantage to engraft. Survival of BMC in vivo was significantly improved by depleting recipient macrophages and/or NK cells, but not neutrophils. Moreover, depletion of macrophages and NK cells in combination with co-stimulatory blockade with anti-CD154 and rapamycin as a novel form of conditioning resulted in 100% allogeneic engraftment without any irradiation and T cell depletion. Donor chimerism remained stable and durable up to 6 months. Moreover, specific Vβ5½ and Vβ11 clonal deletion was detected in host CD4+ T cells in chimeras, indicating central tolerance to donor alloantigens. Whether and how the innate immune system recognizes or responds to allogeneic BMCs remains unknown. Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. The signaling function of TLR depends on intracellular adaptors. The adaptor MyD88 transmits signals emanating from all TLR, except TLR3 while TRIF specifically mediates TLR3 and TLR4 signaling via type 1 IFN. To further determine the innate signaling pathways in allogeneic BMC rejection, B6 background (H2b) MyD88−/− and TRIF−/− mice were conditioned with anti-CD154/rapamycin plus 100 cGy total body irradiation and transplanted with 15 × 106 BALB/c (H2d) BMC. Only 33.3% of MyD88−/− recipients engrafted at 1 month, resembling outcomes for wild-type B6 mice. In contrast, 100% of TRIF−/− mice engrafted. The level of donor chimerism in TRIF−/− mice was 5.1 ± 0.6% at one month, significantly higher than in MyD88−/− and wild-type B6 controls (P < 0.005). To determine the mechanism of innate signaling in BMC rejection, we examined whether TRIF linked TLR3 or TLR4 is the key pattern recognition receptor involved in BMC recognition. To this end, TLR3−/− and TLR4−/− mice were transplanted with BALB/c BMC with same conditioning. None of the TLR3−/− mice engrafted. In contrast, engraftment was achieved in 100% of TLR4−/− mice up to 6 months follow up. Taken together, these results suggest that rejection of allogeneic BMC is uniquely dependent on the TLR4/TRIF signaling pathway. Thus, our results clearly demonstrate a previously unappreciated role for innate immunity in allogeneic BMC rejection. Our current findings are distinct from prior reports demonstrating a critical role of MyD88 in rejection of allogeneic skin grafts and lung, and may reflect unique features related to BMC. The findings of the role of innate immunity in BMC rejection would lead to revolutionary changes in our understanding and management of BMT. This would be informative in design of more specific innate immune targeted conditioning proposals in BMT to avoid the toxicity. Disclosures: Bozulic: Regenerex LLC: Employment. Ildstad:Regenerex LLC: Equity Ownership.

scholarly journals Daily leptin blunts marrow fat but does not impact bone mass in calorie-restricted mice

2016 ◽  
Vol 229 (3) ◽  
pp. 295-306 ◽  
Author(s):  
M J Devlin ◽  
D J Brooks ◽  
C Conlon ◽  
M van Vliet ◽  
L Louis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Mass ◽  
Body Mass ◽  
Body Fat ◽  
Whole Body ◽  
Body Fat Percentage ◽  
Fat Percentage ◽  
Marrow Fat ◽  
Bone Marrow Fat ◽  
Skeletal Acquisition

Starvation induces low bone mass and high bone marrow adiposity in humans, but the underlying mechanisms are poorly understood. The adipokine leptin falls in starvation, suggesting that hypoleptinemia may be a link between negative energy balance, bone marrow fat accumulation, and impaired skeletal acquisition. In that case, treating mice with leptin during caloric restriction (CR) should reduce marrow adipose tissue (MAT) and improve bone mass. To test this hypothesis, female C57Bl/6J mice were fed a 30% CR or normal (N) diet from 5 to 10 weeks of age, with daily injections of vehicle (VEH), 1mg/kg leptin (LEP1), or 2mg/kg leptin (LEP2) (N=6–8/group). Outcomes included body mass, body fat percentage, and whole-body bone mineral density (BMD) via peripheral dual-energy X-ray absorptiometry, cortical and trabecular microarchitecture via microcomputed tomography (μCT), and MAT volume via μCT of osmium tetroxide-stained bones. Overall, CR mice had lower body mass, body fat percentage, BMD, and cortical bone area fraction, but more connected trabeculae, vs N mice (P<0.05 for all). Most significantly, although MAT was elevated in CR vs N overall, leptin treatment blunted MAT formation in CR mice by 50% vs VEH (P<0.05 for both leptin doses). CR LEP2 mice weighed less vs CR VEH mice at 9–10 weeks of age (P<0.05), but leptin treatment did not affect body fat percentage, BMD, or bone microarchitecture within either diet. These data demonstrate that once daily leptin bolus during CR inhibits bone marrow adipose expansion without affecting bone mass acquisition, suggesting that leptin has distinct effects on starvation-induced bone marrow fat formation and skeletal acquisition.

scholarly journals p53-dependent induction of P2X7 on hematopoietic stem and progenitor cells regulates hematopoietic response to genotoxic stress

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Lin Tze Tung ◽  
HanChen Wang ◽  
Jad I. Belle ◽  
Jessica C. Petrov ◽  
David Langlais ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Transcriptional Response ◽  
Genotoxic Stress ◽  
Whole Body ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Stem And Progenitor Cells ◽  
Hematopoietic Response

AbstractStem and progenitor cells are the main mediators of tissue renewal and repair, both under homeostatic conditions and in response to physiological stress and injury. Hematopoietic system is responsible for the regeneration of blood and immune cells and is maintained by bone marrow-resident hematopoietic stem and progenitor cells (HSPCs). Hematopoietic system is particularly susceptible to injury in response to genotoxic stress, resulting in the risk of bone marrow failure and secondary malignancies in cancer patients undergoing radiotherapy. Here we analyze the in vivo transcriptional response of HSPCs to genotoxic stress in a mouse whole-body irradiation model and, together with p53 ChIP-Seq and studies in p53-knockout (p53KO) mice, characterize the p53-dependent and p53-independent branches of this transcriptional response. Our work demonstrates the p53-independent induction of inflammatory transcriptional signatures in HSPCs in response to genotoxic stress and identifies multiple novel p53-target genes induced in HSPCs in response to whole-body irradiation. In particular, we establish the direct p53-mediated induction of P2X7 expression on HSCs and HSPCs in response to genotoxic stress. We further demonstrate the role of P2X7 in hematopoietic response to acute genotoxic stress, with P2X7 deficiency significantly extending mouse survival in irradiation-induced hematopoietic failure. We also demonstrate the role of P2X7 in the context of long-term HSC regenerative fitness following sublethal irradiation. Overall our studies provide important insights into the mechanisms of HSC response to genotoxic stress and further suggest P2X7 as a target for pharmacological modulation of HSC fitness and hematopoietic response to genotoxic injury.

scholarly journals Hem1 promotes osteoclast fusion and bone resorption in mice

2021 ◽  
Author(s):  
Xiaoyan Wang ◽  
Lijian Shao ◽  
Aaron Warren ◽  
Kimberly Krager ◽  
Nukhet Aykin-Burns ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Resorption ◽  
Bone Mass ◽  
Fetal Liver ◽  
Adaptor Proteins ◽  
Bone Cell ◽  
Hematopoietic Stem ◽  
Bone Cell Differentiation ◽  
Stem And Progenitor Cells

Abstract Hem1 (Hematopoietic protein 1), a hematopoietic cell-specific member of the Hem family of cytoplasmic adaptor proteins, is essential for lymphopoiesis and innate immunity and for the transition of hematopoiesis from the fetal liver to the bone marrow. However, the role of Hem1 in bone cell differentiation and bone remodeling is unknown. Here, we show that deletion of Hem1 resulted in a markedly increase in bone mass due to defective bone resorption in mice of both sexes. Hem1-deficient osteoclast progenitors were able to differentiate into osteoclasts, but the osteoclasts exhibited impaired osteoclast fusion and decreased bone-resorption activity, potentially due to cytoskeletal disorganization and decreased mitochondrial respiration. Transplantation of bone marrow hematopoietic stem and progenitor cells from wild-type into Hem1 KO mice increased bone resorption and normalized bone mass. These findings indicate that Hem1 plays a pivotal role in the maintenance of normal bone mass.

scholarly journals The Role of TOX in the Development of Innate Lymphoid Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-7 ◽  
Author(s):  
Corey R. Seehus ◽  
Jonathan Kaye
Keyword(s):  
Bone Marrow ◽  
Immune System ◽  
Natural Killer ◽  
Cell Fate ◽  
Lymphoid Cell ◽  
Adaptive Immune System ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Innate Lymphoid Cell

TOX, an evolutionarily conserved member of the HMG-box family of proteins, is essential for the development of various cells of both the innate and adaptive immune system. TOX is required for the development of CD4+T lineage cells in the thymus, including natural killer T and T regulatory cells, as well as development of natural killer cells and fetal lymphoid tissue inducer cells, the latter required for lymph node organogenesis. Recently, we have identified a broader role for TOX in the innate immune system, demonstrating that this nuclear protein is required for generation of bone marrow progenitors that have potential to give rise to all innate lymphoid cells. Innate lymphoid cells, classified according to transcription factor expression and cytokine secretion profiles, derive from common lymphoid progenitors in the bone marrow and require Notch signals for their development. We discuss here the role of TOX in specifying CLP toward an innate lymphoid cell fate and hypothesize a possible role for TOX in regulating Notch gene targets during innate lymphoid cell development.

Gender-related differences in the oxidant state of cells in Fanconi anemia heterozygotes

2011 ◽  
Vol 392 (7) ◽  
Author(s):  
Sandra Petrovic ◽  
Andreja Leskovac ◽  
Jelena Kotur-Stevuljevic ◽  
Jelena Joksic ◽  
Marija Guc-Scekic ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Fanconi Anemia ◽  
Bone Marrow Failure ◽  
Genetic Disorder ◽  
Significant Difference ◽  
Heterozygous Carriers ◽  
Male Carriers ◽  
Female Carriers

Abstract Fanconi anemia (FA) is a rare cancer-prone genetic disorder characterized by progressive bone marrow failure, chromosomal instability and redox abnormalities. There is much biochemical and genetic data, which strongly suggest that FA cells experience increased oxidative stress. The present study was designed to elucidate if differences in oxidant state exist between control, idiopathic bone marrow failure (idBMF) and FA cells, and to analyze oxidant state of cells in FA heterozygous carriers as well. The results of the present study confirm an in vivo prooxidant state of FA cells and clearly indicate that FA patients can be distinguished from idBMF patients based on the oxidant state of cells. Female carriers of FA mutation also exhibited hallmarks of an in vivo prooxidant state behaving in a similar manner as FA patients. On the other hand, the oxidant state of cells in FA male carriers and idBMF families failed to show any significant difference vs. controls. We demonstrate that the altered oxidant state influences susceptibility of cells to apoptosis in both FA patients and female carriers. The results highlight the need for further research of the possible role of mitochondrial inheritance in the pathogenesis of FA.

scholarly journals The “birth of death”: MRI step-by-step reveals the early appearance of a bone marrow infarct

2019 ◽  
Vol 8 (3) ◽  
pp. 205846011983469 ◽  
Author(s):  
Elie Barakat ◽  
Nathalie Guischer ◽  
Frédéric Houssiau ◽  
Frederic E. Lecouvet
Keyword(s):  
Bone Marrow ◽  
De Novo ◽  
Whole Body ◽  
High Signal ◽  
Systemic Steroid ◽  
High Dose ◽  
Mr Images ◽  
Whole Body Mri ◽  
Skeletal Involvement

The magnetic resonance imaging (MRI) appearance of an “established” bone marrow infarct is well-known, consisting of an area of preserved bone marrow signal surrounded by a serpiginous line. We report the uncommon observation of the very early phases of appearance of a bone marrow infarct, showing its progressive de novo appearance on MR images paralleling clinical symptoms and high-dose systemic steroid administration in a young female patient, presenting with acute knee pain. The initial knee MR examination performed one week after pain onset showed no abnormality. One week later, a second examination showed subtle ill-defined dotted signal abnormalities of the bone marrow of uncertain significance, of high signal on PDFS sequences. A third MR study obtained again one week later showed more evident findings with confluence of the high signal “dots” into a serpiginous line with a geographical appearance of the lesion, corresponding to the typical MRI presentation of bone marrow infarcts. Follow-up MRI at seven weeks showed definitive stability of this bone marrow infarct. A whole-body MRI performed for whole skeleton screening revealed multiple bone marrow infarcts typical for systemic avascular necrosis. This case represents a novel observation of the “birth” of a bone marrow infarct, from early intriguing changes to its typical ring-shaped appearance on MR images. It also reminds of the key role of MRI for early diagnosis of bone marrow infarcts and illustrates the emerging role of whole-body MRI for the detection of multifocal, asymptomatic skeletal involvement by ischemic lesions in systemic osteonecrosis.

Role of host immune system in BB/Wor rat. Predisposition to diabetes resides in bone marrow

Diabetes ◽  
1988 ◽  
Vol 37 (5) ◽  
pp. 520-525 ◽  
Author(s):  
K. Nakano ◽  
J. P. Mordes ◽  
E. S. Handler ◽  
D. L. Greiner ◽  
A. A. Rossini
Keyword(s):  
Bone Marrow ◽  
Immune System ◽  
Host Immune System

scholarly journals The Endocrine Function of Osteocalcin Regulated by Bone Resorption: A Lesson from Reduced and Increased Bone Mass Diseases

2019 ◽  
Vol 20 (18) ◽  
pp. 4502 ◽  
Author(s):  
Rossi ◽  
Battafarano ◽  
Pepe ◽  
Minisola ◽  
Del Fattore
Keyword(s):  
Bone Resorption ◽  
Bone Mass ◽  
Hormonal Regulation ◽  
Male Fertility ◽  
Continuous Process ◽  
Bone Diseases ◽  
Endocrine Function ◽  
Whole Body ◽  
Great Role ◽  
Self Renewal

Bone is a peculiar tissue subjected to a continuous process of self-renewal essential to assure the integrity of the skeleton and to explicate the endocrine functions. The study of bone diseases characterized by increased or reduced bone mass due to osteoclast alterations has been essential to understand the great role played by osteocalcin in the endocrine functions of the skeleton. The ability of osteoclasts to regulate the decarboxylation of osteocalcin and to control glucose metabolism, male fertility, and cognitive functions was demonstrated by the use of animal models. In this review we described how diseases characterized by defective and increased bone resorption activity, as osteopetrosis and osteoporosis, were essential to understand the involvement of bone tissue in whole body physiology. To translate this knowledge into humans, recently published reports on patients were described, but further studies should be performed to confirm this complex hormonal regulation in humans.

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