Obesity is characterized by low-grade inflammation, which is accompanied by increased accumulation of immune cells in peripheral tissues including adipose tissue (AT), skeletal muscle, liver and pancreas, thereby impairing their primary metabolic functions in the regulation of glucose homeostasis. Obesity has also shown to have a detrimental effect on bone homeostasis by altering bone marrow and hematopoietic stem cell differentiation and thus impairing bone integrity and immune cell properties. The origin of immune cells arises in the bone marrow, which has been shown to be affected with the obesogenic condition via increased cellularity and shifting differentiation and function of hematopoietic and bone marrow mesenchymal stem cells in favor of myeloid progenitors and increased bone marrow adiposity. These obesity-induced changes in the bone marrow microenvironment lead to dramatic bone marrow remodeling and compromising immune cell functions, which in turn affect systemic inflammatory conditions and regulation of whole-body metabolism. However, there is limited information on the inflammatory secretory factors creating the bone marrow microenvironment and how these factors changed during metabolic complications. This review summarizes recent findings on inflammatory and cellular changes in the bone marrow in relation to obesity and further discuss whether dietary intervention or physical activity may have beneficial effects on the bone marrow microenvironment and whole-body metabolism.

• Klíčová slova
• bone marrow mesenchymal stem cells, bone marrow microenvironment, hematopoietic stem cells, immune responses, life-style interventions, obesity,
• MeSH
• buněčné mikroprostředí imunologie   MeSH
• hematopoetické kmenové buňky imunologie   patologie   MeSH
• hematopoéza * MeSH
• kostní dřeň imunologie   patologie   MeSH
• lidé MeSH
• obezita patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Multiple myeloma (MM) is a heterogeneous hematological malignancy characterized by the uncontrolled clonal proliferation of bone marrow (BM) plasma cells. The poor prognosis of patients is associated with the presence of extramedullary disease (EMD). Previously, different mechanisms involved in the colonization of BM niches by MM cells and their escape during EMD have been described. Thus, we aimed to investigate the expression of selected cytokines in the BM plasma of MM patients as well as EMD patients to reveal novel molecules involved in EMD pathogenesis. Expression of 120 different cytokines was measured in BM plasma of 13 MM and 11 EMD patients using Proteome Profiler Antibody Arrays. The correlation between statistically significant cytokines and clinicopathological parameters of patients was determined using the Spearman correlation analysis. Finally, protein-protein interactions were analyzed, and GO and KEGG pathways enrichment analysis was performed. In total, 27 cytokines were found to be differently expressed between MM and EMD patients. After the Benjamini-Hochberg correction for multiple testing, the statistical significance of two cytokines downregulated in EMD (EGF, BDNF) and six cytokines upregulated in EMD (NAP-2, ADIPOQ, CRP, MIG, BAFF, and THBS1) was maintained. Correlation analysis proved a significant association between the expression of these molecules and selected clinical-pathological features of MM/EMD patients. Protein association network analysis revealed important protein-protein interactions between THBS1/EGF, MIG/NAP-2, THBS1/NAP-2, EGF/NAP-2, and ADIPOQ/CRP. Finally, identified cytokines were proved to be significantly involved in focal adhesion, PI3K/AKT, and MAPK signaling pathways, and regulation of cell development, localization, proliferation, migration, differentiation, immune system processes, and stress response. Obtained results confirm the key function of the BM microenvironment in the pathogenesis of MM and indicate the essential role of numerous cytokines in disease progression and EMD development. However, the exact mechanisms need to be further clarified.

• MeSH
• kostní dřeň MeSH
• lidé MeSH
• mnohočetný myelom * patologie   MeSH
• nádorové mikroprostředí MeSH
• progrese nemoci MeSH
• proteom * MeSH
• proteomika MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• proteom * MeSH

Reciprocal interactions between a tumor and its microenvironment control expansion of tumor cells. Here we show a specific type of interaction in which blasts of experimental leukemia destroy the bone marrow (BM) structures and kill stromal cells. The in vitro experiments showed that the cytotoxic agent released by leukemic cells is the fragmented DNA derived from their genome and occurring in nucleosome-like complexes. This DNA entered nuclei of BM or other cells and induced H2A.X phosphorylation at serine 139, similar to double-strand break-inducing agents. There was a correlation between large amounts of acquired DNA and death of recipient cells. Moreover, the DNA integrated into chromosomal DNA of recipient cells. Primary human acute myeloid leukemia cells also released fragmented DNA that penetrated the nuclei of other cells both in vitro and in vivo. We suggest that DNA fragments released from leukemic and also perhaps other types of tumor cells can activate DNA repair mechanisms or death in recipient cells of a tumor microenvironment, depending on the amount of the acquired DNA. This can impair DNA stability and viability of tumor stromal cells, undermine homeostatic capacity of tumor microenvironment and facilitate tumor progression.

• MeSH
• akutní myeloidní leukemie patologie   MeSH
• apoptóza MeSH
• buněčné jádro metabolismus   MeSH
• buňky stromatu fyziologie   MeSH
• DNA metabolismus   MeSH
• histony metabolismus   MeSH
• kostní dřeň patologie   MeSH
• kur domácí MeSH
• kuřecí embryo MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádorové mikroprostředí * MeSH
• nádory kostní dřeně patologie   MeSH
• nukleozomy metabolismus   MeSH
• oprava DNA MeSH
• poškození DNA MeSH
• progrese nemoci MeSH
• transplantace nádorů MeSH
• zvířata MeSH
• Check Tag
• kuřecí embryo MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• DNA MeSH
• histony MeSH
• nukleozomy MeSH

PURPOSE OF REVIEW: The goal of this review is to discuss the role of insulin signaling in bone marrow adipocyte formation, metabolic function, and its contribution to cellular senescence in relation to metabolic bone diseases. RECENT FINDINGS: Insulin signaling is an evolutionally conserved signaling pathway that plays a critical role in the regulation of metabolism and longevity. Bone is an insulin-responsive organ that plays a role in whole body energy metabolism. Metabolic disturbances associated with obesity and type 2 diabetes increase a risk of fragility fractures along with increased bone marrow adiposity. In obesity, there is impaired insulin signaling in peripheral tissues leading to insulin resistance. However, insulin signaling is maintained in bone marrow microenvironment leading to hypermetabolic state of bone marrow stromal (skeletal) stem cells associated with accelerated senescence and accumulation of bone marrow adipocytes in obesity. This review summarizes current findings on insulin signaling in bone marrow adipocytes and bone marrow stromal (skeletal) stem cells and its importance for bone and fat metabolism. Moreover, it points out to the existence of differences between bone marrow and peripheral fat metabolism which may be relevant for developing therapeutic strategies for treatment of metabolic bone diseases.

• Klíčová slova
• Bone marrow adipose tissue, Bone marrow mesenchymal stem cells, Insulin signaling, Marrow adiposity,
• MeSH
• adipogeneze MeSH
• buněčná diferenciace MeSH
• buňky kostní dřeně metabolismus   MeSH
• glukagonu podobný peptid 1 metabolismus   MeSH
• glukosa metabolismus   MeSH
• insulinu podobný růstový faktor I metabolismus   MeSH
• inzulin metabolismus   MeSH
• inzulinová rezistence MeSH
• kosti a kostní tkáň metabolismus   MeSH
• kostní dřeň metabolismus   MeSH
• lidé MeSH
• metabolické nemoci kostí metabolismus   MeSH
• mezenchymální kmenové buňky metabolismus   MeSH
• obezita metabolismus   MeSH
• parathormon metabolismus   MeSH
• protein 4 vázající insulinu podobné růstové faktory metabolismus   MeSH
• proteiny insulinového receptorového substrátu metabolismus   MeSH
• receptor inzulinu metabolismus   MeSH
• receptor pro konečné produkty pokročilé glykace metabolismus   MeSH
• stárnutí buněk * MeSH
• tuková tkáň metabolismus   MeSH
• tukové buňky metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• glukagonu podobný peptid 1 MeSH
• glukosa MeSH
• insulinu podobný růstový faktor I MeSH
• inzulin MeSH
• parathormon MeSH
• protein 4 vázající insulinu podobné růstové faktory MeSH
• proteiny insulinového receptorového substrátu MeSH
• receptor inzulinu MeSH
• receptor pro konečné produkty pokročilé glykace MeSH

Erythropoiesis was studied in mice repeatedly subjected to individual doses of 3 Gy of 60Co gamma-rays at 4-day intervals up to a total dose of 24 Gy on the basis of total bone marrow and spleen cellularity follow-up and analysis of myelograms and splenograms. Half of the mice received 10(6) nuclear cells of syngeneic bone marrow after each fractional radiation dose. It was mainly the spleen which was involved in the adaptation and regeneration of erythropoiesis, its contribution to total erythropoiesis in bone marrow recipients having been as much as 73.9% (day 20 of experiment, total dose 15 Gy). In mice only irradiated, the number of nuclear cells of erythroid lineage decreased to zero values sooner in the spleen (day 16 of experiment, total dose 12 Gy) when compared to the bone marrow (day 24 of experiment, total dose 18 Gy). Analysis of the results of collections made on day 9 after the last irradiation, however, revealed that the haemopoietic microenvironment of the spleen and haemopoietic cells capable of differentiation in the erythroid direction are so resistant to irradiation in only irradiated mice that erythropoiesis in their spleens exhibits signs of regeneration even after the highest total dose of 24 Gy.

• MeSH
• buňky kostní dřeně MeSH
• erytropoéza * MeSH
• kinetika MeSH
• kostní dřeň účinky záření   MeSH
• myši inbrední C57BL MeSH
• myši inbrední CBA MeSH
• myši MeSH
• počet erytrocytů MeSH
• radioizotopy kobaltu MeSH
• slezina cytologie   účinky záření   MeSH
• transplantace kostní dřeně * MeSH
• záření gama MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• radioizotopy kobaltu MeSH

Marrow cavities in all bones of newborn mammals contain haematopoietic tissue and stromal microenvironment that support haematopoiesis (haematopoietic microenvironment), known as red bone marrow (BM). From the early postnatal period onwards, the haematopoietic microenvironment, mainly in tubular bones of the extremities, is replaced by mesenchymal cells that accumulate lipid drops, known as yellow BM, whereas haematopoietic tissue gradually disappears. We analysed the ability of mesenchymal cell progenitors in red and yellow BM to produce bone and haematopoietic microenvironment in vivo after transplantation into normal or haematopoietically deficient (irradiated and old) recipients. We found that (1) normal substitution of red with yellow BM results from a gradual loss of mesenchymal stem cells (MSCs) capable of developing bone and haematopoietic microenvironment; (2) the mesenchymal cell population in tubular bones still containing active haematopoietic tissue gradually becomes depleted of MSCs, starting from a young age; (3) haematopoietic microenvironment is incapable of self-maintenance and its renewal depends on the presence of precursor cells; (4) the mesenchymal cell population remaining in areas with yellow BM contains cells able to develop functionally active haematopoietic microenvironment in conditions of haematopoietic insufficiency. Our data also indicate the possible existence of bi-potential stromal precursor cells producing either bone in normal, or bone together with active haematopoietic microenvironment in irradiated or old recipients. This study opens a spectrum of opportunities for the extension of haematopoietic territories by substituting the fat contents of BM cavities with haematopoietic tissue, thereby improving haematopoiesis compromised by cytotoxic treatments, irradiation, ageing, etc.

• MeSH
• buňky kostní dřeně cytologie   metabolismus   fyziologie   MeSH
• hematopoetické kmenové buňky cytologie   metabolismus   fyziologie   MeSH
• kostní dřeň metabolismus   fyziologie   MeSH
• krysa rodu Rattus MeSH
• mezenchymální kmenové buňky cytologie   metabolismus   fyziologie   MeSH
• transplantace mezenchymálních kmenových buněk MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Obesity adversely affects bone and fat metabolism in mice and humans. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been shown to improve glucose metabolism and bone homeostasis in obesity. However, the impact of omega-3 PUFAs on bone marrow adipose tissue (BMAT) and bone marrow stromal cell (BMSC) metabolism has not been intensively studied yet. In the present study we demonstrated that omega-3 PUFA supplementation in high fat diet (HFD + F) improved bone parameters, mechanical properties along with decreased BMAT in obese mice when compared to the HFD group. Primary BMSCs isolated from HFD + F mice showed decreased adipocyte and higher osteoblast differentiation with lower senescent phenotype along with decreased osteoclast formation suggesting improved bone marrow microenvironment promoting bone formation in mice. Thus, our study highlights the beneficial effects of omega-3 PUFA-enriched diet on bone and cellular metabolism and its potential use in the treatment of metabolic bone diseases.

• MeSH
• adipozita MeSH
• kosti a kostní tkáň metabolismus   MeSH
• kostní dřeň * metabolismus   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• obezita komplikace   prevence a kontrola   metabolismus   MeSH
• omega-3 mastné kyseliny * farmakologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• omega-3 mastné kyseliny * MeSH

OBJECTIVES: Our aim was to correlate serum levels of selected markers of bone metabolism and bone marrow microenvironment to cytogenetic changes in patients with multiple myeloma (MM). METHODS: We assed cytogenetic changes in 308 patients and correlated them with the following levels of bone marrow metabolism: thymidine kinase (TK), β2-microglobulin (b-2-m), Dickkopf-1 protein (DKK-1), C-terminal telopeptide collagen-I (ICTP), N-terminal propeptide of type I procollagen (PINP), receptor for interleukin 6 (rIL-6), vascular cell adhesive molecule-1 (VCAM), soluble intercellular adhesion molecule-1, osteoprotegerin (OPG), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), syndecan-1 (SYN-1) and Fas antigen. RESULT: Individuals with delRB1 had lower levels of OPG (M = 7.39 vs. 5.46 pmol/L, p = .025) and VEGF (M = 304 vs. 196 pg/ml; p = .036). t(14;16) was associated with higher β2m levels (M = 7.59 vs. 4.13 mg/L; p = .022) and lower DKK-1 levels (M = 4465 ng/L vs. 12,593). The presence of 1q21 gain was associated with higher levels of TK (M = 100.0 vs. 11.0 IU/L, p = .026) and lower levels of PINP (M = 49.3 vs. 67.4 mg/L, p = .030). CONCLUSIONS: Our analysis has shown, some cytogenetic changes, especially delRB1, t(14;16) and 1q21gain, which affect the components of the cytokine network in multiple myeloma.

• Klíčová slova
• bone marrow microenvironment, cytogenetics, myeloma, myeloma bone disease,
• MeSH
• biologické markery MeSH
• cytogenetické vyšetření MeSH
• kostní dřeň metabolismus   MeSH
• lidé MeSH
• mnohočetný myelom * diagnóza   genetika   MeSH
• nádorové mikroprostředí MeSH
• vaskulární endoteliální růstový faktor A MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery MeSH
• vaskulární endoteliální růstový faktor A MeSH

Multiple myeloma is a hematooncological disease characterized by malignant proliferation of plasma cells. These cells accumulate in the bone marrow where they suppress physiological hematopoiesis; at the same time, these cells interact with a wide variety of cytokines, growth factors and adhesion molecules. It is obvious that the bone marrow microenvironment plays an important role in disease pathogenesis as well as treatment resistance.

• MeSH
• cytokiny fyziologie   MeSH
• kostní dřeň patofyziologie   MeSH
• lidé MeSH
• mezibuněčné signální peptidy a proteiny fyziologie   MeSH
• mnohočetný myelom patofyziologie   MeSH
• molekuly buněčné adheze fyziologie   MeSH
• plazmatické buňky fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cytokiny MeSH
• mezibuněčné signální peptidy a proteiny MeSH
• molekuly buněčné adheze MeSH

Mice received doses of 3 Gy of 60Co-gamma rays total body irradiation at four-day intervals up to a total dose of 24 Gy. After each dose per fraction half of the animals were injected with 10(6) bone marrow cells. At four- and nine-day intervals evaluations were made of the blood count, bone marrow and spleen cellularities, and spleen mass. In animals subjected only to irradiation the damage of hemopoietic organs was becoming deeper until the end of observation; the majority of these mice died by nine days after the irradiation with the last dose per fraction (by 37 days of the experiment). The authors consider anemia as the main cause of their death. All of the mice that were given bone marrow injections survived; nine days after the last dose of irradiation the mean cellularities of their bone marrows and spleens were 76.8% and 112.3% of the unirradiated controls respectively. In general, regeneration of erythropoiesis was quite successful, the number of thrombocytes was positively influenced, and the number of leukocytes nearly unchanged in bone marrow recipients when compared with the only irradiated mice. We observed two periods of maximum and one of minimum bone marrow and spleen regeneration, which were not synchronized. These results deny an unrepairable damage to the hemopoietic microenvironment in conditions of our experiment. This paper follows up with our preceding work [10] describing results of an experiment which ended on day 24.

• MeSH
• celotělové ozáření MeSH
• dávka záření MeSH
• experimentální radiační poranění mortalita   patofyziologie   terapie   MeSH
• hematopoéza * MeSH
• kostní dřeň fyziologie   MeSH
• myši inbrední C57BL MeSH
• myši inbrední CBA MeSH
• myši MeSH
• počet erytrocytů MeSH
• počet leukocytů MeSH
• počet trombocytů MeSH
• regenerace MeSH
• slezina fyziologie   MeSH
• transplantace kostní dřeně * MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH