The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures.

Romas, E.; Udagawa, Nobuyuki; Zhou, Hong; Tamura, Tatsuya; Saito, Masashi; Taga, Tetsuya; Hilton, Douglas J.; Suda, Toshio; Ng, KW; Martin, T. J.

doi:10.1084/jem.183.6.2581

Cited by 194 publications

(123 citation statements)

References 45 publications

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“…Similarly, we have previously reported that IL-11 is upregulated by both bone marrow stromal and endothelial cells in the presence of MM cells, 36 and other authors have found that MM cells stimulate OB IL-11 production. 37 IL-11 is a cytokine that is known to be critical for OCL formation under physiological conditions, 38,39 and to be involved in the development of osteolytic bone metastases in breast cancer patients. 40 --42 Interestingly, like other gp130 cytokines, it can induce OCL formation independently of RANKL.…”

Section: Discussionmentioning

confidence: 99%

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

et al. 2012

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The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast (OCL) formation and bone lesions is still unknown. Osteocytes regulate bone remodelling at least partially, as a result of their cell death triggering OCL recruitment. In this study, we found that the number of viable osteocytes was significantly smaller in MM patients than in healthy controls, and negatively correlated with the number of OCLs. Moreover, the MM patients with bone lesions had a significantly smaller number of viable osteocytes than those without, partly because of increased apoptosis. These findings were further confirmed by ultrastructural in vitro analyses of human preosteocyte cells cocultured with MM cells, which showed that MM cells increased preosteocyte death and apoptosis. A micro-array analysis showed that MM cells affect the transcriptional profiles of preosteocytes by upregulating the production of osteoclastogenic cytokines such as interleukin (IL)-11, and increasing their pro-osteoclastogenic properties. Finally, the osteocyte expression of IL-11 was higher in the MM patients with than in those without bone lesions. Our data suggest that MM patients are characterized by a reduced number of viable osteocytes related to the presence of bone lesions, and that this is involved in MM-induced OCL formation.Leukemia ( Keywords: multiple myeloma; osteocytes; bone disease; osteoclasts INTRODUCTIONThe presence of osteolytic bone lesions or osteoporosis is the hallmark of multiple myeloma (MM), and leads to bone fragility and fractures in MM patients. The bone lesions are characterized by severely unbalanced and uncoupled bone remodelling in the area of plasma cell infiltration due to increased osteoclast (OCL) formation and activity, and osteoblast (OB) suppression. 1 --3 Local factors produced by MM cells and the bone marrow microenvironment are involved in the MM-induced increase in osteoclastogenesis, and include an imbalance in the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio that favours RANKL, 2,4 and the MM cell production of osteoclastogenic factors such as Chemokine (C --C motif) ligand 3 (CCL3)/macrophage inflammatory proteins (MIP)-1a. 5 --7 OB exhaustion is mainly due to a reduction in OB differentiation and formation, from mesenchymal stem cells and OB progenitors, that is induced by MM cells as a result of cell-to-cell contacts and the release of soluble factors. 3,8 --11 Osteocytes are differentiated cells of osteogenic lineage 12 located in the lacuno-canalicular system of the bone (see the review by Bonewald). 13 There is increasing evidence that they regulate physiological local bone remodelling, 13 --16 partly as a result of the cell death and apoptosis that triggers OCL formation and bone resorption, 15 --19 and partly by secreting sclerostin, a molecule that is specifically produced by osteocytes that inhibits bone formation. 20,21 Interestingly, an apoptosis-related reduction in osteocyte viability has recently been demonstrated in

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Section: Discussionmentioning

confidence: 99%

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

et al. 2012

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“…In contrast, gp130 cytokine expression by cells within the bone remodelling unit are high throughout life (Table 1). Furthermore, the expression of gp130 cytokines by osteoblasts in particular, is strongly influenced by bone-active hormones and inflammatory cytokines including PTH, 1,25-dihydroxyvitamin D3, IL-1, estradiol and testosterone (22)(23)(24)(25). This indicates that gp130 cytokines, like RANKL, may play important paracrine roles to regulate bone formation and resorption within the bone remodelling unit during normal bone development, growth and remodelling.…”

Section: Gp130 Actions On the Skeletonmentioning

confidence: 99%

“…The pro-osteoclastic gp130 cytokines generally stimulate osteoclast formation by acting on osteoblast lineage cells to enhance expression of the key osteoclastogenic factor RANKL, and by reducing osteoblastic expression of its inhibitor OPG (29)(30)(31). Furthermore, studies using the gp130 knockout mouse, and a gp130 neutralising antibody have demonstrated that a gp130-dependent pathway is involved in the stimulation of osteoclast formation by other factors, including 1,25-dihydroxyvitamin D3, parathyroid hormone (PTH), and inflammatory cytokines such as IL-1, (22,32). Neutralising antibody studies also indicated that PTH-stimulated osteoclast formation requires at least IL-6R (24) and IL-11 (33).…”

Section: Gp130 Cytokine Action On Osteoclastsmentioning

confidence: 99%

GP130 cytokines and bone remodelling in health and disease

Sims¹,

Walsh²

2010

BMB Reports

108

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Gp130 cytokinesGlycoprotein 130 (gp130) is a receptor subunit capable of intracellular signalling that is required for the cellular action of a wide range of cytokines. The most well known of these are interleukin (IL-) 6 and IL-11, leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), oncostatin M (OSM) and ciliary neurotrophic factor (CNTF). Every cytokine that binds to gp130 generates specific intracellular signalling events by forming specific receptor:ligand complexes, each with distinct components and/or architecture (Fig.

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“…The murine IL-11R␣ 1 gene is expressed at relatively low abundance in a broad spectrum of tissues including bone marrow, spleen, thymus, lung, bladder, heart, brain, kidney, muscle, salivary gland, small and large intestine, ovary, testis and uterus as well as a number of primary cell types such as macrophages, osteoblasts and osteoclasts. 4,20,21 Expression of the IL-11R␣ 2 gene is restricted to the testis, lymph node and thymus. 19 The human IL-11R␣ chain shares 85% nucleotide identity and 84% amino acid identity with the murine genes.…”

Section: Il-11 Receptormentioning

confidence: 99%

True

1999

Leukemia

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Interleukin 11 (IL-11) is a pleiotropic cytokine with biological activities on many different cell types. Recombinant human IL-11 (rhIL-11) is produced by recombinant DNA technology in Escherichia coli. Both in vitro and in vivo, rhIL-11 has shown effects on multiple hematopoietic cell types. Its predominant in vivo hematopoietic activity is the stimulation of peripheral platelet counts in both normal and myelosuppressed animals. This activity is mediated through effects on both early and late progenitor cells to stimulate megakaryocyte differentiation and maturation. rhIL-11 has been approved for the treatment of chemotherapy-induced thrombocytopenia. The hematopoietic effects of rhIL-11 are most likely direct effects on progenitor cells and megakaryocytes in combination with other cytokines or growth factors. rhIL-11 also induces secretion of acute phase proteins (ferritin, haptoglobin, C-reactive protein, and fibrinogen) from the liver. The induction of heme oxidase and inhibition of several P450 oxidases have been reported from in vitro studies. In vivo, rhIL-11 treatment decreases sodium excretion by the kidney by an unknown mechanism and induces hemodilution. rhIL-11 also exhibits anti-inflammatory effects in a variety of animal models of acute and chronic inflammation, including inflammatory bowel disease, inflammatory skin disease, autoimmune joint disease, and various infection-endotoxemia syndromes. rhIL-11 has trophic effects on non-transformed intestinal epithelium under conditions of mucosal damage. The mechanism of the anti-inflammatory activity of rhIL-11 has been extensively studied. rhIL-11 directly affects macrophage and T cell effector function. rhIL-11 inhibits tumor necrosis factor-alpha (TNF␣), interleukin 1␤ (IL-1␤), interleukin 12 (IL-12), interleukin 6 (IL-6), and nitric oxide (NO) production from activated macrophages in vitro. The inhibition of cytokine production was associated with inhibition of nuclear translocation of the transcription factor, nuclear factor kappa B (NF-B). The block to NF-B nuclear translocation correlates with the ability of rhIL-11 to maintain or enhance production of the inhibitors of NF-B, IB-␣ and IB-␤. In addition to effects on macrophages, rhIL-11 also reduces CD4 ؉ T cell production of Th1 cytokines, such as IFN␥ induced by IL-12, while enhancing Th2 cytokine production. rhIL-11 also blocks IFN␥ production in vivo. The molecular effects of rhIL-11 have also been studied in a clinical trial. Molecular analysis of skin biopsies of patients with psoriasis before and during rhIL-11 treatment demonstrates a decrease in mRNA levels of TNF␣, IFN␥ and iNOS. These activities suggest that in addition to its thrombopoietic clinical use, rhIL-11 may also be valuable in the treatment of inflammatory diseases. The clinical utility of the anti-inflammatory properties of rhIL-11 is being investigated in patients with Crohn's disease, psoriasis and rheumatoid arthritis. These diseases are believed to be initiated and maintained by activated CD4 ؉ Th1 cells in conjunction w...

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The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures.

Cited by 194 publications

References 45 publications

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation

GP130 cytokines and bone remodelling in health and disease

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