Bone Marrow Monocyte/Macrophage Derived Activin A Mediates the Osteoclastogenic Effects of IL-3 in Myeloma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE41992 | GEO | 2014/11/01
SECONDARY ACCESSION(S): PRJNA178719
REPOSITORIES: GEO
Similar Datasets
Project description:Myeloma bone disease is characterized by tremendous bone destruction with suppressed bone formation. IL-3 is a multifunctional cytokine that increases myeloma cell growth and osteoclast proliferation while inhibiting osteoblast differentiation. While IL-3 appears to be an attractive therapeutic target for myeloma, attempts at targeting IL-3 have been unsuccessful due to IL-3M-bM-^@M-^Ys effects on normal hematopoiesis. Thus identification of IL-3M-bM-^@M-^Ys downstream effects in MMBD is important for effective targeting of this cytokine in MM. Here we demonstrated that treatment of myeloma patient CD14+ bone marrow monocyte / macrophages with IL-3 induces high levels of Activin A (ActA), a pluripotent TGF-M-NM-2 superfamily member that, like IL-3, modulates MMBD by enhancing osteoclastogenesis and inhibiting osteoblasts. We show that IL-3 induced osteoclastogenesis is mediated by ActA and is RANKL independent. Additionally, IL-3 induced ActA secretion is greatest early in osteoclastogenesis and ActA acts early in osteoclastogenesis. Therefore we suggest that therapies targeting ActA production should block IL-3M-bM-^@M-^Ys effects in myeloma bone disease. Investigate the mediators of IL-3M-bM-^@M-^Ys effects on bone remodeling in myeloma we performed gene expression profiling using Affymetrix GeneChip analysis of IL-3 treated CD14+ peripheral blood from healthy donor.
2014-11-01 | E-GEOD-41992 | biostudies-arrayexpress
Project description:The myeloma bone marrow microenvironment drives proliferation of malignant plasma cells and promotes resistance to therapy. Interleukin-6 (IL-6) and downstream JAK/STAT signaling are thought to be central components of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells.Here, we validated both in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated murine xenograft models of myeloma, that tofacitinib showed both single-agent and combination therapeutic efficacy in myeloma models. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not rescue ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells drive a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib specifically reverses the growth-promoting effects of the tumor microenvironment through blocking an IL-6-mediated signaling axis. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.
2018-10-24 | PXD006581 | Pride
Project description:This a model from the article:
A mathematical model of bone remodeling dynamics for normal bone cell populations and myeloma bone disease
Bruce P Ayati, Claire M Edwards, Glenn F Webb and John P Wikswo.
Biology Direct2010 Apr 20;5(28).
20406449,
Abstract:
BACKGROUND:
Multiple myeloma is a hematologic malignancy associated with the development of a destructive osteolytic bone disease.
RESULTS:
Mathematical models are developed for normal bone remodeling and for the dysregulated bone remodeling that occurs in myeloma bone disease. The models examine the critical signaling between osteoclasts (bone resorption) and osteoblasts (bone formation). The interactions of osteoclasts and osteoblasts are modeled as a system of differential equations for these cell populations, which exhibit stable oscillations in the normal case and unstable oscillations in the myeloma case. In the case of untreated myeloma, osteoclasts increase and osteoblasts decrease, with net bone loss as the tumor grows. The therapeutic effects of targeting both myeloma cells and cells of the bone marrow microenvironment on these dynamics are examined.
CONCLUSIONS:
The current model accurately reflects myeloma bone disease and illustrates how treatment approaches may be investigated using such computational approaches.
Note:
The paper describes three models 1) Zero-dimensional Bone Model without Tumour, 2) Zero-dimensional Bone Model with Tumour and 3) Zero-dimensional Bone Model with Tumour and Drug Treatment. This model corresponds to the Zero-dimensional Bone Model without Tumour.
Typos in the publication:
Equation (4): The first term should be (β1/α1)^(g12/Γ) and not (β2/α2)^(g12/Γ)
Equation (14): The first term should be (β1/α1)^(((g12/(1+r12))/Γ) and not (β2/α2)^(((g12/(1+r12))/Γ)
Equation (13): The first term should be (β1/α1)^((1-g22+r22)/Γ) and not (β1/α1)^((1-g22-r22)/Γ)
All these corrections has been implemented in the model, with the authors agreement.
Beyond these, there are several mismatches between the equation numbers that are mentioned in for each equation and the reference that has been made to these equations in the figure legend.
2011-12-06 | BIOMD0000000401 | BioModels
Project description:This a model from the article:
A mathematical model of bone remodeling dynamics for normal bone cell populations and myeloma bone disease
Bruce P Ayati, Claire M Edwards, Glenn F Webb and John P Wikswo.
Biology Direct2010 Apr 20;5(28).
20406449,
Abstract:
BACKGROUND:
Multiple myeloma is a hematologic malignancy associated with the development of a destructive osteolytic bone disease.
RESULTS:
Mathematical models are developed for normal bone remodeling and for the dysregulated bone remodeling that occurs in myeloma bone disease. The models examine the critical signaling between osteoclasts (bone resorption) and osteoblasts (bone formation). The interactions of osteoclasts and osteoblasts are modeled as a system of differential equations for these cell populations, which exhibit stable oscillations in the normal case and unstable oscillations in the myeloma case. In the case of untreated myeloma, osteoclasts increase and osteoblasts decrease, with net bone loss as the tumor grows. The therapeutic effects of targeting both myeloma cells and cells of the bone marrow microenvironment on these dynamics are examined.
CONCLUSIONS:
The current model accurately reflects myeloma bone disease and illustrates how treatment approaches may be investigated using such computational approaches.
Note:
The paper describes three models 1) Zero-dimensional Bone Model without Tumour, 2) Zero-dimensional Bone Model with Tumour and 3) Zero-dimensional Bone Model with Tumour and Drug Treatment. This model corresponds to the Zero-dimensional Bone Model with Tumour.
Typos in the publication:
Equation (4): The first term should be (β1/α1)^(g12/Γ) and not (β2/α2)^(g12/Γ)
Equation (14): The first term should be (β1/α1)^(((g12/(1+r12))/Γ) and not (β2/α2)^(((g12/(1+r12))/Γ)
Equation (13): The first term should be (β1/α1)^((1-g22+r22)/Γ) and not (β1/α1)^((1-g22-r22)/Γ)
All these corrections has been implemented in the model, with the authors agreement.
Beyond these, there are several mismatches between the equation numbers that are mentioned in for each equation and the reference that has been made to these equations in the figure legend.
2011-11-25 | BIOMD0000000402 | BioModels
Project description:This a model from the article:
A mathematical model of bone remodeling dynamics for normal bone cell populations and myeloma bone disease
Bruce P Ayati, Claire M Edwards, Glenn F Webb and John P Wikswo.
Biology Direct2010 Apr 20;5(28).
20406449,
Abstract:
BACKGROUND:
Multiple myeloma is a hematologic malignancy associated with the development of a destructive osteolytic bone disease.
RESULTS:
Mathematical models are developed for normal bone remodeling and for the dysregulated bone remodeling that occurs in myeloma bone disease. The models examine the critical signaling between osteoclasts (bone resorption) and osteoblasts (bone formation). The interactions of osteoclasts and osteoblasts are modeled as a system of differential equations for these cell populations, which exhibit stable oscillations in the normal case and unstable oscillations in the myeloma case. In the case of untreated myeloma, osteoclasts increase and osteoblasts decrease, with net bone loss as the tumor grows. The therapeutic effects of targeting both myeloma cells and cells of the bone marrow microenvironment on these dynamics are examined.
CONCLUSIONS:
The current model accurately reflects myeloma bone disease and illustrates how treatment approaches may be investigated using such computational approaches.
Note:
The paper describes three models 1) Zero-dimensional Bone Model without Tumou
r, 2) Zero-dimensional Bone Model with Tumour and 3) Zero-dimensional Bone Model with Tumour and Drug Treatment. This model corresponds to the Zero-dimensional Bo
ne Model with Tumour and Drug Treatment.
Typos in the publication:
Equation (4): The first term should be (β1/α1)^(g12/Γ) and not (β2/α2)^(g12/Γ)
Equation (14): The first term should be (β1/α1)^(((g12/(1+r12))/Γ) and not (β2/α2)^(((g12/(1+r12))/Γ)
Equation (13): The first term should be (β1/α1)^((1-g22+r22)/Γ) and not (β1/α1)^((1-g22-r22)/Γ)
All these corrections has been implemented in the model, with the authors agreement.
Beyond these, there are several mismatches between the equation numbers that are mentioned in for each equation and the reference that has been made to these equations in the figure legend.
2011-11-25 | BIOMD0000000403 | BioModels
Project description:Purpose: Among the diverse cytokines involved in osteoclast differentiation, IL-3 has been shown to inhibit RANKL-induced osteoclastogenesis. However, the mechanism underlying IL-3-mediated inhibition of osteoclast differentiation is not fully understood. In the present study, we demonstrate that IL-3 activation of STAT5 inhibits RANKL-induced osteoclastogenesis through the induction of Id genes. Methods: To investigate the effect of STAT5 on osteoclast differentiation and IL-3-mediated inhibition of osteoclast differentiation, bone marrow derived macrophages isolated from STAT5 wild-type (Stat5fl/fl) or STAT5 cKO (STAT5;MX1-Cre) were differentiated to osteoclast in the presence of M-CSF and RANKL with or without IL-3; and bone marrow derived macrophges from STAT5 wild-type and STAT5 cKO were overexpressed with PMX-FIG (control) or STAT5A1*6 (constitutively active form of STAT5A) and differentiated to osteoclast. To analyze bone phenotype, femurs and tibiae of 16 week-old STAT5 wild-type and STAT5 cKO were subjected to micro CT analysis and histomorphometry, respectively. Results: Overexpression of STAT5 inhibited RANKL-induced osteoclastogenesis. However, RANKL did not regulate either expression or activation of STAT5 during osteoclast differentiation. STAT5 deficiency prevented IL-3-mediated inhibition of osteoclastogenesis, suggesting that STAT5 plays an important role in IL-3-mediated inhibition of osteoclast differentiation. In addition, IL-3-induced STAT5 activation upregulated expression of the Id1 and Id2 genes, which are negative regulators of osteoclastogenesis. Overexpression of ID1 or ID2 in STAT5-deficient cells reversed osteoclast development recovered from IL-3-mediated inhibition. Moreover, micro-computed tomography and histomorphometric analysis revealed that STAT5 conditional knockout mice showed reduced bone mass, with an increased number of osteoclasts. Furthermore, IL-3 inhibited RANKL-induced osteoclast differentiation less effectively in STAT5 conditional knockout mice than in wild-type mice in a RANKL injection model. Conclusion: Taken together, our results suggest that STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis through Id gene expression. Examination of 4 different combination of osteoclast differentiation condition of bone marrow derived macrophages.
2016-08-03 | E-GEOD-76988 | biostudies-arrayexpress
Project description:The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Interleukin-6 (IL-6) and downstream JAK/STAT signaling are thought to be central components of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Here, we validated both in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated murine xenograft models of myeloma, that tofacitinib showed both single-agent and combination therapeutic efficacy in myeloma models. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib specifically reverses the growth-promoting effects of the tumor microenvironment through blocking an IL-6-mediated signaling axis. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.
2017-05-26 | GSE99293 | GEO
Project description:Bone destruction is a hallmark of human myeloma and affects more than 80% of patients. Although it is well established that myeloma cells mediate bone destruction by activating osteoclasts, the mechanism how myeloma cells are regulated to do so is unknown. Here we show that C-reactive protein (CRP), a protein secreted in elevated amounts by hepatocytes in response to myeloma-derived cytokines, may be responsible for activating myeloma cells to promote osteoclastogenesis and inducing bone destruction in vivo. CRP binds to surface CD32A/FcRIIA, activates p38MAPK-twist pathways, and upregulates the secretion of osteolytic cytokines by myeloma cells. Clinical studies examining the relationship between the levels of serum CRP and the numbers of osteolytic bone lesions in newly diagnosed patients support this conclusion.
2017-09-12 | GSE103697 | GEO
Project description:Purpose: Among the diverse cytokines involved in osteoclast differentiation, IL-3 has been shown to inhibit RANKL-induced osteoclastogenesis. However, the mechanism underlying IL-3-mediated inhibition of osteoclast differentiation is not fully understood. In the present study, we demonstrate that IL-3 activation of STAT5 inhibits RANKL-induced osteoclastogenesis through the induction of Id genes. Methods: To investigate the effect of STAT5 on osteoclast differentiation and IL-3-mediated inhibition of osteoclast differentiation, bone marrow derived macrophages isolated from STAT5 wild-type (Stat5fl/fl) or STAT5 cKO (STAT5;MX1-Cre) were differentiated to osteoclast in the presence of M-CSF and RANKL with or without IL-3; and bone marrow derived macrophges from STAT5 wild-type and STAT5 cKO were overexpressed with PMX-FIG (control) or STAT5A1*6 (constitutively active form of STAT5A) and differentiated to osteoclast. To analyze bone phenotype, femurs and tibiae of 16 week-old STAT5 wild-type and STAT5 cKO were subjected to micro CT analysis and histomorphometry, respectively. Results: Overexpression of STAT5 inhibited RANKL-induced osteoclastogenesis. However, RANKL did not regulate either expression or activation of STAT5 during osteoclast differentiation. STAT5 deficiency prevented IL-3-mediated inhibition of osteoclastogenesis, suggesting that STAT5 plays an important role in IL-3-mediated inhibition of osteoclast differentiation. In addition, IL-3-induced STAT5 activation upregulated expression of the Id1 and Id2 genes, which are negative regulators of osteoclastogenesis. Overexpression of ID1 or ID2 in STAT5-deficient cells reversed osteoclast development recovered from IL-3-mediated inhibition. Moreover, micro-computed tomography and histomorphometric analysis revealed that STAT5 conditional knockout mice showed reduced bone mass, with an increased number of osteoclasts. Furthermore, IL-3 inhibited RANKL-induced osteoclast differentiation less effectively in STAT5 conditional knockout mice than in wild-type mice in a RANKL injection model. Conclusion: Taken together, our results suggest that STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis through Id gene expression.
2016-08-03 | GSE76988 | GEO
Project description:Osteolytic destruction is a hallmark of multiple myeloma, resulting from activation of osteoclast mediated bone resorption and reduction of osteoblast-mediated bone formation. However, the molecular mechanism underlying the differentiation and activity of osteoclasts and osteoblasts within a myelomatous microenvironment remains unclear. Here, we demonstrate that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions. CIITA upregulates the secretion of osteolytic cytokines from osteocytes through acetylation at histone 3 lysine 14 in the promoter of TNFSF11 (encoding RANKL) and SOST (encoding sclerostin), leading to enhanced osteoclastogenesis and decreased osteoblastogenesis. In turn, myeloma cell–secreted 2-deoxy-D-ribose, the product of thymidine catalyzed by the function of thymidine phosphorylase, upregulates CIITA expression in osteocytes through the STAT1/IRF1 signaling pathway. Our work thus broadens the understanding of myeloma-induced osteolysis and indicates a potential strategy for disrupting tumor-osteocyte interaction to prevent, or treat patients with, myeloma bone disease.
2022-04-23 | GSE200987 | GEO