scholarly journals Pivotal Role of OCL-Derived IGF1 in Drug Resistance and Bone Destruction in MM

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4336-4336
Author(s):  
Jumpei Teramachi ◽  
Kazuaki Miyagawa ◽  
Delgado-Calle Jesus ◽  
Jolene Windle ◽  
Noriyoshi Kurihara ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Bone Resorption ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
Bone Destruction ◽  
Bone Marrow Microenvironment ◽  
Rank Ligand ◽  
Marrow Cells

Multiple myeloma (MM) is largely incurable, and is characterized by devastating bone destruction caused by increased osteoclast (OCL) differentiation and bone resorption in more than 85% of MM patients. OCLs in MM not only promote bone resorption but also increase MM cell growth and drug resistance. Despite recent advances in anti-myeloma treatment, development of anti-MM drug resistance is a major limitation of MM therapy. Therefore, new treatment modalities are urgently needed to overcome drug resistance and decrease bone resorption. IGF1 is a crucial factor for tumor cell growth and survival of malignant cells, especially in MM. IGFI also contributes to development of drug resistance of MM cells to anti-MM agents, including proteasome inhibitors and immunomodulatory agents, but how OCLs contribute to drug resistance is still not clearly delineated. We found that IGF1 was highly expressed in OCLs attached to bone and bone marrow myeloid cells in vivo, and the expression levels of IGF1 in OCLs from MM bearing mice is higher than in normal OCLs. Intriguingly, OCLs produced more IGF1 (0.8 ng/ml/protein) than MM cells (not detected) and bone marrow stromal cells (BMSCs) (0.4 ng/ml/protein) in vitro. In addition, IGF1 protein expression in OCLs was upregulated (1.8 fold) by treatment with conditioned media (CM) from 5TGM1 murine MM cells, TNF-α or IL-6, major paracrine factors that are increased in the bone marrow microenvironment in MM. These results suggest that OCLs are a major source of local IGF1 in the MM bone marrow microenvironment. To further characterize the role of OCL-derived IGF1, we generated a novel mouse with targeted deletion of Igf1 in OCLs (IGF1-/--OCL), and assessed the role of OCL-derived IGF1 in drug resistance of MM cells and bone destruction. Treatment of 5TGM1 cells with bortezomib (BTZ) (3 nM, 48 hours) decreased the viability of 5TGM1 cells by 50%. Importantly, the cytotoxic effects of BTZ on MM cells were decreased (by 5%) when MM cells were cocultured with OCLs from wild type (WT) mice. In contrast, coculture of MM cells with IGF1-/--OCLs or WT-OCLs treated with IGF1 neutralizing antibody (IGF1-ab) did not block BTZ's effects on MM cell death. Consistent with these results, coculture of MM cells with IGF1-/--OCLs or WT-OCLs treated with IGF1-ab resulted in BTZ-induced caspase-dependent apoptosis in MM cells. We next examined the effects of OCLs on the signaling pathways responsible for MM cell survival. WT-OCL-CM promptly induced the phosphorylation of Akt and activation of p38, ERK and NF-κB in MM cells. However, these pathways were not activated by MM cells treated with IGF1-/--OCL-CM or IGF1-ab-treated WT-OCL-CM. Since adhesion of MM cells to BMSCs via interaction of VLA-4 and VCAM-1 plays a critical role in cell adhesion-mediated drug resistance (CAMDR) in MM, we tested if treatment of human BMSCs with human OCL-CM upregulated VCAM-1 expression. We found that OCL-CM upregulated VCAM-1 expression on BMSCs (x fold). In contrast, treatment of BMSCs with OCLs treated with IGF1-ab blocked VCAM-1 induction. These data suggest that OCL-derived IGF1 can contribute to MM cell drug resistance in the bone marrow microenvironment. We then examined the role of IGF1 inhibition on osteoclastogenesis and the bone resorption capacity of OCLs. RANK ligand induced the expression of cathepsin K and NFATc1 in CD11b+ bone marrow cells from WT mice, differentiation markers of OCLs, and the formation of TRAP-positive multinucleated OCLs. However, OCLs formed by RANK ligand treatment of CD11b+ bone marrow cells from IGF1-/- mice had markedly decreased cathepsin K and NFATc1 expression and OCL formation. Next, we tested the bone resorption capacity of OCLs formed by CD11b+ bone marrow cells from IGF1-/- mice vs. WT mice. Similar numbers of OCLs were cultured with RANK ligand on bone slices for 72 hours. The bone resorption activity of Igf1-/--OCLs was significantly decreased (70%) compared with WT-OCLs. These results suggest that OCL-derived IGF1 plays a critical role in MM drug resistance and bone destruction, and that inhibition of the effect of IGF1 in OCLs should decrease MM drug resistance and bone destruction. Disclosures Roodman: Amgen trial of Denosumab versus Zoledronate: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Critical role of nitric oxide for proliferation and apoptosis of bone-marrow cells under septic conditions

2000 ◽  
Vol 79 (5) ◽  
pp. 249-254 ◽  
Author(s):  
W. Barthlen ◽  
C. Klemens ◽  
S. Rogenhofer ◽  
J. Stadler ◽  
N. Unbehaun ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
Proliferation And Apoptosis ◽  
Marrow Cells

A Critical Role of the Rho Family GTPase Cdc42 in Hematopoietic Stem Cell Mobilization, Homing, Engraftment and Differentiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 269-269
Author(s):  
Linda Yang ◽  
Lei Wang ◽  
Jose A. Cancelas ◽  
David A. Williams ◽  
Yi Zheng
Keyword(s):  
Bone Marrow ◽  
B Cell ◽  
Bone Marrow Cells ◽  
Critical Role ◽  
Hematopoietic Cell ◽  
B Cell Differentiation ◽  
Hematopoietic Stem ◽  
Rho Family ◽  
Marrow Cells

Abstract The Rho family GTPase Cdc42 has emerged as a key signaling molecule with unique roles in multiple hematopoietic cell lineages. To investigate the physiologic role of Cdc42 in hematopoietic stem cells/progenitors (HSC/Ps), we bred conditional cdc42flox/floxmice with Mx-Cre mice that allowed interferon-inducible cdc42 deletion in hematopoietic cells in vivo following polyI:C induction. Loss of Cdc42 expression in the bone marrow caused significant leukocytosis with neutrophilia in peripheral blood (PB) (Table). Concurrently, deletion of cdc42 in the bone marrow led to a massive efflux of HSC/Ps from bone marrow to PB, liver and spleen (Table) and increased proliferative activity of HSC/Ps. Consequently, flow analysis further revealed that the number of Lin-Sca-1+c-Kit+ (LSK) HSCs in BM, PB, spleen and liver increased significantly following cdc42 deletion (Table). Transplantation of the cdc42−/− bone marrow cells into NOD/SCID recipient mice or competitive transplantation into BoyJ recipient mice showed that cdc42 deficiency in the bone marrow caused the impaired engraftment (Table) and the failure of hematopoiesis after a transient increase of cell cycle rate of HSCs. The engraftment defect is associated with a homing deficiency (Table). The cdc42−/− (Lin−c-Kit+) HSC/Ps showed defects in cortical F-actin assembly, adhesion to fibronectin and directional migration in response to SDF-1α (Table). These data suggest that defective actin structure and adhesion of the cdc42−/− HSC/Ps may contribute to the loss of retention of the cells in the BM niche and to the mobilization phenotype. Moreover, deletion of cdc42 resulted in significantly reduced thymus cellularity, T cell, B cell population, and decreased Ter119+ cell number associated with markedly decreased CFU-E activity of the bone marrow cells (Table). Two additional complimentary approaches, BM-reconstitution by cdc42−/− HSCs and reciprocal (rescue) transplantation by WT HSCs, further demonstrated that the Cdc42 loss-of-function phenotypes are hematopoietic cell intrinsic. Taken together these results implicate Cdc42 as a critical regulator of HSC mobilization, homing and engraftment, and indicate that Cdc42 is involved in erythropoiesis and in T- and B-cell differentiation and homeostasis. WT Cdc42−/− *p<0.05**p<0.005†p<0.001 White blood cell count, × 109 /L 11.0±2.5 40.8±3.9† Neutrophil count, × 109 /L 4.6±0.8 34.1±4.7† CFU-C per 105 liver cells 0.13±0.12 169±132* CFU-C per 104 spleen cells 1.36±1.05 68.4±55.6** CFU-C per 100μl PB 3.67±2 58.8±47.3** LSK HSCs in BM 0.52%±0.22% 0.94%±0.45%* LSK HSCs in PB 0.13%±0.08% 0.31%±0.15%* LSK HSCs in spleen 0.37%±0.20% 0.63%±0.23%* LSK HSCs in liver 0.23%±0.10% 0.70%±0.18%* Engraftment in NOD/SCID mice 35.0%±4.9% 23.0%±7.1%* Competitive transplantation 61.5%±6.7% 22.2%±2.9%** CFU-C Homing to BM (% injected) 0.85%± 0.11% 0.28%± 0.12%** Adhesion to fibronectin (%plating) 50.8%±2.5% 28.8%±4.0%** Migration to SDF (%input) 26.2%±5.3% 5.4%±0.9%† CD3+ T cells in BM 5.4%±0.22% 2.7%±0.45%** B220+ B cells in BM 8.4%±4.6% 1.5%±2.0%† Ter119+ cells in BM 15.2%±9.3% 6.0%±4.2%* CFU-E per 105 BM cells 87.8±9.7 25.6±4.2†

scholarly journals The Role of the Bone Marrow Microenvironment in the Response to Infection

2020 ◽  
Vol 11 ◽  
Author(s):  
Courtney B. Johnson ◽  
Jizhou Zhang ◽  
Daniel Lucas
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Immune Cells ◽  
Critical Role ◽  
Primary Source ◽  
Bone Marrow Microenvironment ◽  
Future Research ◽  
Multipotent Stem Cells ◽  
Hematopoietic Stem

Hematopoiesis in the bone marrow (BM) is the primary source of immune cells. Hematopoiesis is regulated by a diverse cellular microenvironment that supports stepwise differentiation of multipotent stem cells and progenitors into mature blood cells. Blood cell production is not static and the bone marrow has evolved to sense and respond to infection by rapidly generating immune cells that are quickly released into the circulation to replenish those that are consumed in the periphery. Unfortunately, infection also has deleterious effects injuring hematopoietic stem cells (HSC), inefficient hematopoiesis, and remodeling and destruction of the microenvironment. Despite its central role in immunity, the role of the microenvironment in the response to infection has not been systematically investigated. Here we summarize the key experimental evidence demonstrating a critical role of the bone marrow microenvironment in orchestrating the bone marrow response to infection and discuss areas of future research.

scholarly journals THE ROLE OF THYMUS AND BONE MARROW CELLS IN DELAYED HYPERSENSITIVITY

1971 ◽  
Vol 134 (5) ◽  
pp. 1144-1154 ◽  
Author(s):  
David G. Tubergen ◽  
Joseph D. Feldman
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Specific Antigen ◽  
Delayed Hypersensitivity ◽  
Cell Type ◽  
Skin Reactions ◽  
Lymph Node Cells ◽  
Thymus Cells ◽  
Marrow Cells

Adoptive transfer experiments were performed to define the immunological role of thymus and bone marrow cells in the induction of delayed hypersensitivity (DH). The results indicated the following, (a) Bone marrow from immune donors contained cells capable of being stimulated by antigen to initiate the expression of DH. (b) Bone marrow from nonimmune or tolerant donors contained cells that were needed to complete the expression of DH after the infusion of immune lymph node cells. (c) Normal bone marrow and thymus cells cooperated in the irradiated recipient to induce the most vigorous skin reactions to specific antigen; these reactions were seen only when the recipients were stimulated by antigen. Either cell type alone was ineffective. (d) In the presence of tolerant bone marrow cells, thymus cells from immune donors gave a more vigorous response than did thymus cells from normal or tolerant donors. (e) There was suggestive evidence that thymus cells were the source of trigger elements that initiated DH. (f) Antigen in the irradiated recipient was necessary to induce DH after infusion of bone marrow cells alone, or bone marrow and thymus cells together.

scholarly journals Nox2 Activity Is Required in Obesity-Mediated Alteration of Bone Remodeling

2018 ◽  
Vol 2018 ◽  
pp. 1-10
Author(s):  
Md Mizanur Rahman ◽  
Amina El Jamali ◽  
Ganesh V. Halade ◽  
Allal Ouhtit ◽  
Haissam Abou-Saleh ◽  
...  
Keyword(s):  
Bone Mineral Density ◽  
Bone Marrow ◽  
Bone Remodeling ◽  
Bone Mineral ◽  
Bone Marrow Cells ◽  
Bone Marrow Microenvironment ◽  
Ros Generation ◽  
Chow Diet ◽  
Mineral Density ◽  
Marrow Cells

Despite increasing evidence suggesting a role for NADPH oxidases (Nox) in bone pathophysiology, whether Nox enzymes contribute to obesity-mediated bone remodeling remains to be clearly elucidated. Nox2 is one of the predominant Nox enzymes expressed in the bone marrow microenvironment and is a major source of ROS generation during inflammatory processes. It is also well recognized that a high-fat diet (HFD) induces obesity, which negatively impacts bone remodeling. In this work, we investigated the effect of Nox2 loss of function on obesity-mediated alteration of bone remodeling using wild-type (WT) and Nox2-knockout (KO) mice fed with a standard lab chow diet (SD) as a control or a HFD as an obesity model. Bone mineral density (BMD) of mice was assessed at the beginning and after 3 months of feeding with SD or HFD. Our results show that HFD increased bone mineral density to a greater extent in KO mice than in WT mice without affecting the total body weight and fat mass. HFD also significantly increased the number of adipocytes in the bone marrow microenvironment of WT mice as compared to KO mice. The bone levels of proinflammatory cytokines and proosteoclastogenic factors were also significantly elevated in WT-HFD mice as compared to KO-HFD mice. Furthermore, the in vitro differentiation of bone marrow cells into osteoclasts was significantly increased when using bone marrow cells from WT-HFD mice as compared to KO-HFD mice. Our data collectively suggest that Nox2 is implicated in HFD-induced deleterious bone remodeling by enhancing bone marrow adipogenesis and osteoclastogenesis.

Sign in / Sign up

Export Citation Format

Share Document