Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin
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ABSTRACT:
PROVIDER: PRJNA634512 | ENA |
REPOSITORIES: ENA
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Project description:It is generally believed that bone micro-fractures, associated with osteocyte death, lead to osteoclast recruitment and thereupon to removal and replacement of damaged bone. However, the underlying mechanism is still incompletely defined. In this study we hypothesized that the pattern recognition receptor macrophage-inducible C-type lectin (Mincle) is expressed in osteoclasts and is responsible for the recognition of osteocyte death. To understand the mechanistic role of Mincle in osteoclasts, we performed in-depth analysis of the effect of Mincle deficiency on the genomic transcriptional network of osteoclasts. Whole transcriptome RNA sequencing (RNAseq) was performed on osteoclasts stimulated with necrotic osteocyte supernatant compared to control osteoclasts (stimulated with viable osteocyte supernatant), derived from either wildtype or Mincle knockout mice.
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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.
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Project description:The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast formation and the occurrence of bone lesions are still unknown. Osteocytes regulate bone remodeling at least in part through the cell death and apoptosis triggering osteoclast recruitment and formation. In this study, firstly we shown that MM cells increased osteocyte death and affect their transcriptional profile evaluated by microarray analysis up-regulating osteoclastogenic cytokines as interleukin (IL)-11. Consistently we show that the conditioned media of human pre-osteocytes co-cultured with MM cells significantly increased osteoclastogenesis. To translate into a clinical perspective such in vitro evidences, we then performed histological analysis on bone biopsies obtained from MM patients, MGUS and healthy controls. We found a significant reduction in the number of viable osteocytes in MM patients as compared to controls. A significant negative correlation between the number of viable osteocytes and that of osteoclasts was also demonstrated. Moreover, as regards the skeletal involvement, we found that MM patients with bone lesions have a significant lower number of viable osteocyte than those without. Overall, our data suggest a role of osteocytic cell death in MM-induced osteoclast formation in vitro and MM bone disease in vivo in MM patients. This series of microarray experiments contains the gene expression profiles of HOB-01 osteocytes cultured alone and co-cultured with the JJN3 human myeloma cell line. 5 micrograms of total RNA was processed, and in accordance with the manufacturer's protocols, the fragmented biotin-labelled cRNA were hybridized on GeneChip Human Genome U133 Plus 2.0 Arrays (Affymetrix Inc.). The arrays were scanned using the Agilent GeneChip Scanner 3000 7G. The images were acquired using Affymetrix GeneChip Operating System (GCOS) 1.1 software and the probe level data converted to expression values using default GCOS1.1 scaling. Natural-scaled data are provided.
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Project description:The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast formation and the occurrence of bone lesions are still unknown. Osteocytes regulate bone remodeling at least in part through the cell death and apoptosis triggering osteoclast recruitment and formation. In this study, firstly we shown that MM cells increased osteocyte death and affect their transcriptional profile evaluated by microarray analysis up-regulating osteoclastogenic cytokines as interleukin (IL)-11. Consistently we show that the conditioned media of human pre-osteocytes co-cultured with MM cells significantly increased osteoclastogenesis. To translate into a clinical perspective such in vitro evidences, we then performed histological analysis on bone biopsies obtained from MM patients, MGUS and healthy controls. We found a significant reduction in the number of viable osteocytes in MM patients as compared to controls. A significant negative correlation between the number of viable osteocytes and that of osteoclasts was also demonstrated. Moreover, as regards the skeletal involvement, we found that MM patients with bone lesions have a significant lower number of viable osteocyte than those without. Overall, our data suggest a role of osteocytic cell death in MM-induced osteoclast formation in vitro and MM bone disease in vivo in MM patients.
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Project description:Type of Experiment: 1) Profiles of Osteoblast vs. osteocyte in vitro; 2) Profiles of osteoblast low density vs. confluency in vitro; 3) Profiles of osteocyte with gap junction vs. without gap junction. Experimental factors: 1) 2T3 osteoblast cells at low density expressed extensive filopodia, reminiscent of early osteoblast precursors and similar to MLO-Y4 dendritic processes. 2) MLO-Y4 osteocytes at low vs. high density represent the genes that are changed in a highly connected network vs. low connected network. The number of hybridizations performed: Triplicate hybridizations for each status. Keywords = Osteoblast Keywords = Osteocyte
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Project description:Type of Experiment: 1) Profiles of Osteoblast vs. osteocyte in vitro; 2) Profiles of osteoblast low density vs. confluency in vitro; 3) Profiles of osteocyte with gap junction vs. without gap junction. Experimental factors: 1) 2T3 osteoblast cells at low density expressed extensive filopodia, reminiscent of early osteoblast precursors and similar to MLO-Y4 dendritic processes. 2) MLO-Y4 osteocytes at low vs. high density represent the genes that are changed in a highly connected network vs. low connected network. The number of hybridizations performed: Triplicate hybridizations for each status. Keywords = Osteoblast Keywords = Osteocyte Keywords: parallel sample
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