Interleukin-1 is essential for systemic inflammatory bone loss

Polzer, K; Joosten, Leo A. B.; Gasser, Jürg A.; Distler, Jörg H W; Ruiz, G.; Baum, Wolfgang; Redlich, Kurt; Bobacz, Klaus; Smolen, Josef S.; Berg, W. van den; Schett, Georg; Zwerina, Jochen

doi:10.1136/ard.2008.104786

Cited by 122 publications

(87 citation statements)

References 26 publications

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“…The notion of IL-1-mediated bone loss also is supported by a study where inhibition of IL-1 with soluble IL-1R was shown to significantly reduce inflammation, loss of connective tissue and bone resorption in the periodontium of Macaca fascicularis primates infected with pathogens (23). A different study showed that IL1 -/-hTNFtg mice were completely protected from systemic bone loss mediated through the overexpression of TNF-α (24). A possible pathogenetic role for IL-1β in bone loss is further supported by the fact that IL-1β enables peripheral blood mononuclear cells to differentiate into osteoclasts in the presence of osteoblastic SaOS-2 cells without further stimulation (25).…”

Section: Il-1β Inhibits Human Osteoblast Migrationmentioning

confidence: 57%

IL-1β Inhibits Human Osteoblast Migration

Hengartner

Fiedler

Ignatius

et al. 2013

Mol Med

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Bone has a high capacity for self-renewal and repair. Prolonged local secretion of interleukin 1β (IL-1β), however, is known to be associated with severe bone loss and delayed fracture healing. Since induction of bone resorption by IL-1β may not sufficiently explain these pathologic processes, we investigated, in vitro, if and how IL-1β affects migration of multipotent mesenchymal stromal cells (MSC) or osteoblasts. We found that homogenous exposure to IL-1β significantly diminished both nondirectional migration and site-directed migration toward the chemotactic factors platelet-derived growth factor (PDGF)-BB and insulinlike growth factor 1 (IGF-1) in osteoblasts. Exposure to a concentration gradient of IL-1β induced an even stronger inhibition of migration and completely abolished the migratory response of osteoblasts toward PDGF-BB, IGF-1, vascular endothelial growth factor A (VEGF-A) and the complement factor C5a. IL-1β induced extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinases (JNK) activation and inhibition of these signaling pathways suggested an involvement in the IL-1β effects on osteoblast migration. In contrast, basal migration of MSC and their migratory activity toward PDGF-BB was found to be unaffected by IL-1β. These results indicate that the presence of IL-1β leads to impaired recruitment of osteoblasts which might influence early stages of fracture healing and could have pathological relevance for bone remodeling in inflammatory bone disease.

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Section: Il-1β Inhibits Human Osteoblast Migrationmentioning

confidence: 57%

IL-1β Inhibits Human Osteoblast Migration

Hengartner

Fiedler

Ignatius

et al. 2013

Mol Med

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“…Moreover, IL-17, like IL-1 can elicit cartilage degradation alone or in combination with other cytokines [36,37]. Herein, we show that in the context of TNF-a-driven inflammation, inhibition of IL-17 shared stunning similarities with IL-1 inhibition, as single inhibition of neither IL-1 nor Il-17 effectively inhibits TNF-a-mediated synovial inflammation whereas both strategies are highly effective to protect from local and systemic bone loss as well as cartilage breakdown [6,38]. This observation indicates that inflammatory pathways downstream of TNF-a, such as IL-1 and IL-17, act simultaneously for building up synovial inflammation.…”

Section: Discussionmentioning

confidence: 89%

“…Disease starts at the age of 6 weeks and is accompanied by local and systemic bone loss reflecting inflammatory bone disease of human rheumatoid arthritis. hTNFtg were also intercrossed with IL-1 À/À mice (genetic background C57BL/6 [38,43]). F2 generations were identified by PCR genotyping of the tail using the following primers: hTNF transgene: 5 0 -TACCCC-CTCCTTCAGACACC-3 0 and 5 0 -GCCCTTCATAATATCCCCCA-3 0 ; IL-1a/b primers were as follows: IL-1aF, 5 0 -CTTGGCCATACTG-CAAAGGTCATG-3 0 , IL-1aR, 5 0 -CAGGTCATTTAACCAAGTGGTGC-TG-3 0 ; IL-1a/b KO, 5 0 -GAGGTGCTGTTTCTGGTCTTCACC-3 0 ; IL-1bF, 5 0 -GCGAATGTGTCACTATCTGCCACC-3 0 ; IL-1bR, 5 0 -CCATGCCACAGTCCCTCCAC-3 0 ; In the present study, a total of 45 mice were included and only littermates were used.…”

Section: Animals and Treatmentmentioning

confidence: 99%

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

et al. 2011

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Tumour necrosis factor alpha (TNF-a) is a major inducer for inflammation and bone loss. Here, we investigated whether interleukin (IL)-17 plays a role in TNF-a-mediated inflammation and bone resorption. Human TNF-a transgenic (hTNFtg) mice were treated with a neutralizing anti-IL-17A antibody and assessed for inflammation, cartilage and bone damage. T-cell transcription factors and lymphokine patterns were measured in the LNs. IL-17A inhibition in the absence of IL-1 was also evaluated by treating hTNFtg/IL-1 À/À mice with an IL-17A neutralizing antibody. IL-17A neutralization had only minor effects on TNF-a-induced inflammation but effectively reduced local and systemic bone loss by blocking osteoclast differentiation in vivo. Effects were based on a shift to bone-protective T-cell responses such as enhanced Th2 differentiation, IL-4 and IL-12 expression and Treg cell numbers. Whereas inflammation in hTNFtg/IL-1 À/À mice was highly sensitive to IL-17A blockade, no shift in the T-cell lineages and no additional benefit on bone mass were observed in response to IL-17A neutralization. We thus conclude that IL-17A is a key mediator of TNF-a-induced bone loss by closely interacting with IL-1 in blocking bone protective T-cell responses.Key words: Arthritis . Cytokine . IL-17 . Osteoclast . T cells IntroductionBone is continuously remodelled in life by the interaction between bone resorbing cells, termed osteoclasts, with boneforming cells, termed osteoblasts [1]. Bone resorption and bone formation are usually in physiological balance, maintaining a stable bone mass. An imbalance between bone resorption and bone formation leads to bone loss and several factors such as age, oestrogen deficiency or drug therapy alter this fine balance between osteoclasts and osteoblasts in favour of the former. Immune activation and inflammation is one the pivotal condi-Ã These authors contributed equally to this work. 413tions perturbing this fine balance of bone remodelling ultimately leading to enhanced bone loss [2]. Autoimmune inflammatory diseases, such as chronic arthritis are characterized by activation of the innate and adaptive immune system eliciting profound local and systemic bone loss. Progressive destruction of the joints is associated with pain, functional impairment and low quality of life. In addition, loss of systemic bone mass causes osteoporosis and increased fracture risk in patients with inflammatory arthritis [3]. This tight link between inflammation and bone loss is mediated by inducible expression of factors, such as M-CSF and RANKL, which are essential for osteoclast differentiation [4]. In addition, inflammatory cytokines produced by monocytes and resident mesenchymal cells are of key importance for osteoclast formation, as they regulate expression of RANKL and also sensitize monocytes for osteoclast differentiation. In this context, TNF-a, and IL-1 are of particular key importance for osteoclast formation and bone resorption in inflammatory tissue [5,6].Aside from classical pro-inflammatory mediators like ...

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“…In line with the known effect on growth plate and fracture callus cartilage (16), in our model IL-1β induced (i) enhanced MMP-13-mediated endogenous ECM preprocessing; (ii) enhanced host osteoclastmediated ECM remodeling by increased M-CSF levels and RANKL/OPG ratios; (iii) faster vascularization, despite a minimal reduction in VEGF content (15); and (iv) larger regions of BM, possibly because of an increased synthesis of SDF1, IL-8, M-CSF, and MCP-1. Instead, IL-1β did not induce a reduction of bone mass by increased bone resorption (24), because its administration was temporally confined to the phase preceding bone matrix deposition. Further studies are required to validate the functionality of the engineered bone organ in the context of an immunocompetent model at an orthotopic site, where loading and inflammation would further regulate bone development and homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Engineering of a functional bone organ through endochondral ossification

Scotti

Piccinini

Takizawa

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

273

295

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Embryonic development, lengthening, and repair of most bones proceed by endochondral ossification, namely through formation of a cartilage intermediate. It was previously demonstrated that adult human bone marrow-derived mesenchymal stem/stromal cells (hMSCs) can execute an endochondral program and ectopically generate mature bone. Here we hypothesized that hMSCs pushed through endochondral ossification can engineer a scaled-up ossicle with features of a "bone organ," including physiologically remodeled bone, mature vasculature, and a fully functional hematopoietic compartment. Engineered hypertrophic cartilage required IL-1β to be efficiently remodeled into bone and bone marrow upon subcutaneous implantation. This model allowed distinguishing, by analogy with bone development and repair, an outer, cortical-like perichondral bone, generated mainly by host cells and laid over a premineralized area, and an inner, trabecular-like, endochondral bone, generated mainly by the human cells and formed over the cartilaginous template. Hypertrophic cartilage remodeling was paralleled by ingrowth of blood vessels, displaying sinusoid-like structures and stabilized by pericytic cells. Marrow cavities of the ossicles contained phenotypically defined hematopoietic stem cells and progenitor cells at similar frequencies as native bones, and marrow from ossicles reconstituted multilineage long-term hematopoiesis in lethally irradiated mice. This study, by invoking a "developmental engineering" paradigm, reports the generation by appropriately instructed hMSC of an ectopic "bone organ" with a size, structure, and functionality comparable to native bones. The work thus provides a model useful for fundamental and translational studies of bone morphogenesis and regeneration, as well as for the controlled manipulation of hematopoietic stem cell niches in physiology and pathology.

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Interleukin-1 is essential for systemic inflammatory bone loss

Abstract: These data indicate that IL1 is essential for TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis, systemic bone is fully protected by the absence of IL1, which suggests that IL1 is an essential mediator of inflammatory osteopenia.

Cited by 122 publications

References 26 publications

IL-1β Inhibits Human Osteoblast Migration

IL-1β Inhibits Human Osteoblast Migration

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

Engineering of a functional bone organ through endochondral ossification

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