Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA404075 | ENA |
REPOSITORIES: ENA
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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: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
Project description:This series represents samples of multiple myeloma patients with bone lytic lesion by MRI. Keywords = multiple myeloma Keywords = osteolytic lesions Keywords = MRI Keywords = osteoblast Keywords = mesenchymal stem cell Keywords = Wnt signaling Keywords = DKK1 Keywords: other
2004-01-01 | GSE754 | GEO
Project description:This series represents samples of multiple myeloma patients without bone lytic lesion by MRI. Keywords = multiple myeloma Keywords = osteolytic lesions Keywords = MRI Keywords = osteoblast Keywords = mesenchymal stem cell Keywords = Wnt signaling Keywords = DKK1 Keywords: other
2004-01-01 | GSE753 | GEO
Project description:This series represents samples of multiple myeloma patients with and without bone lytic lesion by MRI. Keywords = multiple myeloma Keywords = osteolytic lesions Keywords = MRI Keywords = osteoblast Keywords = mesenchymal stem cell Keywords = Wnt signaling Keywords = DKK1 Keywords: other
2004-01-01 | GSE755 | GEO
Project description:This study provides a novel mechanism that RAS activation of breast cancer cells induces osteolytic bone metastasis by stimulating the exosome-mediated transfer of osteoclastogenic miRNAs including miR-494-3p to bone cells
2023-07-12 | GSE235802 | GEO
Project description:Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. Genomic profiling of distinct HSPC subsets revealed a consistent deregulation of signaling cascades, including TGF beta signaling, p38MAPK signaling and pathways involved in cytoskeletal organization, migration, adhesion and cell cycle regulation in MM patients. CD34+ subsets of 7 patients with Multiple Myeloma and 5 healthy volunteers were analysed by means of gene expression profiling with the Affymetrix HU-133A 2.0 array
2010-10-27 | E-GEOD-24870 | biostudies-arrayexpress
Project description:Osteocyte CIITA Aggravates Osteolytic Bone Lesions in Myeloma
| PRJNA827810 | ENA
Project description:Multiple myeloma (MM) bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 (MMP-13) as a novel MM-derived fusogen that, in turn, induces osteoclast activation independent of its proteolytic activity. While the mechanism by which the metalloprotease signals osteoclasts has remained the subject of conjecture, we now identify the checkpoint protein, programmed death-1 homolog (PD-1H/VISTA), as the bona fide MMP-13 receptor expressed on both pre- and mature osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-induced upregulation of ERK1/2-NFATc1-DC-STAMP signaling, the induction of osteoclast fusion and the increase in bone-resorptive activity. Further studies revealed that the intracellular domain of PD-1H interacts with the actin cytoskeleton of OCLs and plays a necessary role in supporting c-Src activation as well as sealing zone formation. The critical role of PD-1H in the development of lytic bone lesions in MM was confirmed using a Pd-1h-/- myeloma bone disease mouse model wherein MM cells injected into Pd-1h-/-Rag2-/- results in attenuated bone destruction relative to Pd-1hwtRag2-/- mice. Our findings identify a novel role for PD-1H in bone biology outside of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a novel approach for the treatment of MM-associated osteolysis.
2022-03-24 | MSV000089119 | MassIVE
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