Interleukin-4 and Interleukin-13 Stimulate the Osteoclast Inhibitor Osteoprotegerin by Human Endothelial Cells Through the STAT6 Pathway

Stein, Nicola; Kreutzmann, Carmen; Zimmermann, S.P.; Niebergall, Ute; Hellmeyer, L; Goettsch, Claudia; Schoppet, Michael; Hofbauer, Lorenz C.

doi:10.1359/jbmr.080203

Cited by 70 publications

(42 citation statements)

References 43 publications

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“…Although myeloid hyperplasia has been described in combat related HO [4], IL-3 is a potent inhibitor of osteoblastic differentiation [5]. Similarly, IL-13, in addition to inhibiting macrophage activity, has been shown to increase osteoprotegerin expression that serves to inhibit osteoclastogenesis [19]. Its role during the early stages of HO is unknown.…”

Section: Discussionmentioning

confidence: 99%

Do Inflammatory Markers Portend Heterotopic Ossification and Wound Failure in Combat Wounds?

Forsberg

Potter

Polfer

et al. 2014

Clinical Orthopaedics &Amp; Related Research

107

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Background After a decade of war in Iraq and Afghanistan, we have observed an increase in combat-related injury survival and a paradoxical increase in injury severity, mainly because of the effects of blasts. These severe injuries have a devastating effect on each patient's immune system resulting in massive upregulation of the systemic inflammatory response. By examining inflammatory mediators, preliminary data suggest that it may be possible to correlate complications such as wound failure and heterotopic ossification (HO) with distinct systemic and local inflammatory profiles, but this is a relatively new topic. Questions/purposes We asked whether systemic or local markers of inflammation could be used as an objective means, independent of demographic and subjective factors, to estimate the likelihood of (1) HO and/or (2) wound failure (defined as wounds requiring surgical débridement after definitive closure, or wounds that were not closed or covered within 21 days of injury) in patients sustaining combat wounds. Methods Two hundred combat wounded active-duty service members who sustained high-energy extremity The institution of one or more of the authors (JAF) has received, during the study period, funding from a grant from the Orthopaedic Trauma Research Program (OTRP) and the US Navy Bureau of Medicine and Surgery Advance Medical Development Program. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDAapproval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained. This work was performed at the Naval Medical Research Center, Silver Spring, MD, USA, and the National Military Medical Center, Bethesda, MD, USA. The views expressed this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. This study protocol was approved by the Institutional Review Boards at both the National Military Medical Center and Naval Medical Research Center in compliance with all applicable Federal regulations governing the protection of human subjects. One or more of the authors is a military service member (or employee of the U.S. Government). This work was prepared as part of his or her official duties. Title 17 U.S.C §105 provides that 'Copyright protection under this title is not available for any work of the United States Government.' Title 17 U.S.C §101 defines a U.S. Government work as a work prepared by a military service ...

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Section: Discussionmentioning

confidence: 99%

Do Inflammatory Markers Portend Heterotopic Ossification and Wound Failure in Combat Wounds?

Forsberg

Potter

Polfer

et al. 2014

Clinical Orthopaedics &Amp; Related Research

107

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“…In agreement with these findings, we observe the highest IL-13 in the group with the smallest lesions. Interestingly, IL-13 has been shown to induce OPG in endothelial cells and osteoblasts 44 ; however, whether OPG also regulates IL-13 is not known.…”

Section: Discussionmentioning

confidence: 99%

Bone Marrow– or Vessel Wall–Derived Osteoprotegerin Is Sufficient to Reduce Atherosclerotic Lesion Size and Vascular Calcification

Callegari

Coons

Ricks

et al. 2013

ATVB

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Objective— Osteoprotegerin (OPG) is a decoy receptor for the osteoclast differentiation factor receptor activator of NF-κB ligand. OPG regulates bone homeostasis, and its inactivation in mice results in severe osteoporosis. OPG deficiency in apolipoprotein E (ApoE) −/− mice results in increased atherosclerotic lesion size and calcification. Furthermore, receptor activator of NF-κB ligand enhances macrophage-dependent smooth muscle cell calcification in vitro. Here, we hypothesized that reconstitution of ApoE −/− OPG −/− mice with ApoE −/− OPG +/+ bone marrow (BM) would be sufficient to rescue lesion progression and vascular calcification. Conversely, reconstitution of ApoE −/− OPG +/+ mice with ApoE −/− OPG −/− BM may accelerate lesion progression and vascular calcification. Approach and Results— ApoE −/− OPG −/− mice transplanted with ApoE −/− OPG +/+ BM developed smaller atherosclerotic lesions and deposited less calcium in the innominate artery than that of ApoE −/− OPG −/− mice transplanted with ApoE −/− OPG −/− BM. There were no differences in lesion size and calcification in ApoE −/− OPG +/+ mice transplanted with BM from ApoE −/− OPG −/− or ApoE −/− OPG +/+ mice. The large lesions observed in the ApoE −/− OPG −/− mice transplanted with OPG −/− BM were rich in chondrocyte-like cells, collagen, and proteoglycans. Importantly, the ApoE −/− OPG −/− mice transplanted with OPG +/+ BM remained osteoporotic, and the ApoE −/− OPG +/+ mice did not show signs of bone loss regardless of the type of BM received. In coculture experiments, macrophages and mesenchymal stem cells derived from ApoE −/− OPG −/− BM induced more vascular smooth muscle cell calcification than cells derived from ApoE −/− OPG +/+ mice. Conclusions— These results indicate that OPG derived either from the BM or from the vessel wall is sufficient to slow down lesion progression and vascular calcification independent of bone turnover.

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“…Aside IL-1, T-cell-derived lymphokines have been elegantly documented to be instrumental in regulating osteoclast differentiation. Th2 cell-derived IL-4 as well as Th1 cell-derived IFN-g effectively suppress osteoclastogenesis and bone resorption [11,13,24]. Moreover, Treg cells also suppress osteoclast formation by cell-cell contact-dependent mechanisms [14].…”

Section: Discussionmentioning

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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Interleukin-4 and Interleukin-13 Stimulate the Osteoclast Inhibitor Osteoprotegerin by Human Endothelial Cells Through the STAT6 Pathway

Cited by 70 publications

References 43 publications

Do Inflammatory Markers Portend Heterotopic Ossification and Wound Failure in Combat Wounds?

Do Inflammatory Markers Portend Heterotopic Ossification and Wound Failure in Combat Wounds?

Bone Marrow– or Vessel Wall–Derived Osteoprotegerin Is Sufficient to Reduce Atherosclerotic Lesion Size and Vascular Calcification

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

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