An in vivo genome wide gene expression study of circulating monocytes suggested GBP1, STAT1 and CXCL10 as novel risk genes for the differentiation of peak bone mass

Lei, Shu‐Feng; Wu, Shan; Li, Liming; Deng, Fei‐Yan; Xiao, Su-Mei; Jiang, Cheng; Chen, Yuan; Jiang, Hui; Yang, Fang; Tan, Lijun; Sun, Xiao; Zhu, Xinyao; Liu, Man-Yuan; Liu, Yaozhong; Chen, Xiang-Ding; Deng, Hong‐Wen

doi:10.1016/j.bone.2008.05.016

Cited by 42 publications

(60 citation statements)

References 40 publications

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“…By applying the weighted gene coexpression network analysis (WGCNA) on the gene expression data of PBMs from high versus low BMD individuals [110], Farber [108] reconstructed the PBMs transcriptional network and identified a coexpression module (referred to as module 9) whose overall expression level was significantly higher in the low BMD group. Using two BMD GWAS datasets, Farber [108] demonstrated that the highly connected hub genes of module 9 were more likely, relative to less connected genes, to be genetically associated with BMD, providing strong independent validation of the biological importance of module 9 and specifically its hub genes in the regulation of BMD.…”

Section: Using Pbms As a Working Cell Model To Study For Bone Diseasesmentioning

confidence: 99%

Circulating monocytes: an appropriate model for bone-related study

2015

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Peripheral blood monocytes (PBMs) are an important source of precursors of osteoclasts, the bone-resorbing cells and the cytokines produced by PBMs that have profound effects on osteoclast differentiation, activation, and apoptosis. So PBMs represent a highly valuable and unique working cell model for bone-related study. Finding an appropriate working cell model for clinical and (epi-)genomic studies of human skeletal disorders is a challenge. Peripheral blood monocytes (PBMs) can give rise to osteoclasts, the bone-resorbing cells. Particularly, PBMs provide the sole source of osteoclast precursors for adult peripheral skeleton where the bone marrow is normally hematopoietically inactive. PBMs can secrete potent pro- and anti-inflammatory cytokines, which are important for osteoclast differentiation, activation, and apoptosis. Reduced production of PBM cytokines represents a major mechanism for the inhibitory effects of sex hormones on osteoclastogenesis and bone resorption. Abnormalities in PBMs have been linked to various skeletal disorders/traits, strongly supporting for the biological relevance of PBMs with bone metabolism and disorders. Here, we briefly review the origin and further differentiation of PBMs. In particular, we discuss the close relationship between PBMs and osteoclasts, and highlight the utility of PBMs in study the pathophysiological mechanisms underlying various skeletal disorders.

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Section: Using Pbms As a Working Cell Model To Study For Bone Diseasesmentioning

confidence: 99%

Circulating monocytes: an appropriate model for bone-related study

2015

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“…Osteoblasts produce and secrete osteoprotegerin, a decoy receptor that binds to RANKL and blocks RANKL/RANK interactions and hence suppresses the ability of RANK to increase bone resorption (9). Previous studies have shown that blood monocytes also produce a wide variety of inflammatory factors and transcription factors involved in bone metabolism, including interleukin-1 (10), tumor necrosis factor-α (TNF-α) (11), interleukin-6 (12), platelet-derived growth factor (13), transforming growth factor-β (14), resolvinE1 (15), runt-related transcription factor 2 (Runx2; 16), guanylate binding protein 1 (GBP1), signal transducer and activator of transcription 1 (STAT1), CXC chemokine ligand 10 (CXCL10) (17), chemokine receptor 3, histidine decarboxylase and glucocorticoid receptor genes (18).…”

Section: Introductionmentioning

confidence: 99%

Detection of significant pathways in osteoporosis based on graph clustering

Xiao

Shan

Zhu

et al. 2012

Molecular Medicine Reports

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Abstract. Osteoporosis is the most common and serious skeletal disorder among the elderly, characterized by a low bone mineral density (BMD). Low bone mass in the elderly is highly dependent on their peak bone mass (PBM) as young adults. Circulating monocytes serve as early progenitors of osteoclasts and produce significant molecules for bone metabolism. An improved understanding of the biology and genetics of osteoclast differentiation at the pathway level is likely to be beneficial for the development of novel targeted approaches for osteoporosis. The objective of this study was to explore gene expression profiles comprehensively by grouping individual differentially expressed genes (DEGs) into gene sets and pathways using the graph clustering approach and Gene Ontology (GO) term enrichment analysis. The results indicated that the DEGs between high and low PBM samples were grouped into nine gene sets. The genes in clusters 1 and 8 (including GBP1, STAT1, CXCL10 and EIF2AK2) may be associated with osteoclast differentiation by the immune system response. The genes in clusters 2, 7 and 9 (including SOCS3, SOD2, ATF3, ADM EGR2 and BCL2A1) may be associated with osteoclast differentiation by responses to various stimuli. This study provides a number of candidate genes that warrant further investigation, including DDX60, HERC5, RSAD2, SIGLEC1, CMPK2, MX1, SEPING1, EPSTI1, C9orf72, PHLDA2, PFKFB3, PLEKHG2, ANKRD28, IL1RN and RNF19B.

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“…RANKL promotes IP-10 expression in preosteoclasts, and IP-10 mediates RANKL expression in CD4 + T cells in the synovium. It was proposed that this positive cross-talk between IP-10 and RANKL, or other cytokines, such as TNF-a, is responsible for inflammation and bone erosion, whereby CD4 + T cells and macrophages are recruited into the synovium (39). In human circulating monocytes serving as early progenitors of osteoclasts, STAT1 and IP-10 were identified as candidate genes whose expression is responsible for the increase in the differentiation of peak bone mass at the monocyte stage (39).…”

Section: Discussionmentioning

confidence: 99%

“…It was proposed that this positive cross-talk between IP-10 and RANKL, or other cytokines, such as TNF-a, is responsible for inflammation and bone erosion, whereby CD4 + T cells and macrophages are recruited into the synovium (39). In human circulating monocytes serving as early progenitors of osteoclasts, STAT1 and IP-10 were identified as candidate genes whose expression is responsible for the increase in the differentiation of peak bone mass at the monocyte stage (39). In addition to increased expression during RANKL-mediated osteoclastogenesis, serum levels of IP-10 were abnormally high (over 7-fold) in Usp18-knockout mice compared with normal littermates.…”

Section: Discussionmentioning

confidence: 99%

Elevated Response to Type I IFN Enhances RANKL-Mediated Osteoclastogenesis in Usp18-Knockout Mice

Yim

Park

Lee

et al. 2016

The Journal of Immunology

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A balance between bone formation and bone resorption is critical for the maintenance of bone mass. In many pathological conditions, including chronic inflammation, uncontrolled activation of osteoclast differentiation often causes excessive bone resorption that results in osteoporosis. In this study, we identified the osteopenia phenotype of mice lacking Usp18 (also called Ubp43), which is a deISGylating enzyme and is known as a negative regulator of type I IFN signaling. The expression of Usp18 was induced in preosteoclasts upon receptor activator of NF-κB ligand (RANKL) treatment. In an in vitro osteoclast-differentiation assay, bone marrow macrophages from Usp18-deficient mice exhibited an enhanced differentiation to multinucleated cells, elevated activation of NFATc1, and an increased expression of osteoclast marker genes upon RANKL treatment. Furthermore, in vitro quantification of bone resorption revealed a great increase in osteoclastic activities in Usp18-deficient cells. Interestingly, proinflammatory cytokine genes, such as IP-10 (CXCL10), were highly expressed in Usp18-deficient bone marrow macrophages upon RANKL treatment compared with wild-type cells. In addition, serum cytokine levels, especially IP-10, were significantly high in Usp18-knockout mice. In sum, we suggest that, although type I IFN is known to restrict osteoclast differentiation, the exaggerated activation of the type I IFN response in Usp18-knockout mice causes an osteopenia phenotype in mice.

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An in vivo genome wide gene expression study of circulating monocytes suggested GBP1, STAT1 and CXCL10 as novel risk genes for the differentiation of peak bone mass

Cited by 42 publications

References 40 publications

Circulating monocytes: an appropriate model for bone-related study

Circulating monocytes: an appropriate model for bone-related study

Detection of significant pathways in osteoporosis based on graph clustering

Elevated Response to Type I IFN Enhances RANKL-Mediated Osteoclastogenesis in Usp18-Knockout Mice

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