RESEARCH - IL-1 is essential for systemic inflammatory bone loss

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Ann Rheum Dis 2010;69:284-290 doi:10.1136/ard.2008.104786

Basic and translational research

Extended report

Interleukin-1 is essential for systemic inflammatory bone loss

K Polzer1,4, L Joosten2, J Gasser3, J H Distler1, G Ruiz1, W Baum1, K

Redlich4, K Bobacz4, J S Smolen4, W van den Berg2, G Schett1,4, J

Zwerina1,4

+ Author Affiliations

1Department of Internal Medicine 3 and Institute for Clinical

Immunology, University of Erlangen, Germany

2Rheumatology Research and Advanced Therapeutics and Department of

Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen,

The Netherlands

3Novartis Institutes for Biomedical Research, Basel, Switzerland

4Department of Internal Medicine 3, Medical University of Vienna, Austria

Abstract

Objectives: Chronic inflammation is a major risk factor for systemic

bone loss leading to osteoporotic fracture and substantial morbidity

and mortality. Inflammatory cytokines, particularly tumour necrosis

factor (TNF) and interleukin-1 (IL1), are thought to play a key role

in the pathogenesis of inflammation-induced bone loss, but their exact

roles are yet to be determined.

Methods: To determine whether TNF directly triggers bone loss or

requires IL1, human TNFα mice (hTNFtg) were crossed with mice lacking

IL1α and IL1β (IL1−/−hTNFtg). Systemic bone architecture was evaluated

using CT scanning, static and dynamic bone histomorphometry and serum

markers of bone metabolism.

Results: hTNFtg mice developed severe bone loss accompanied by a

severe distortion of bone microarchitecture. Bone trabeculae were

thinner and decreased in numbers, resulting in increased trabecular

separation. Histomorphometric analyses revealed strongly increased

bone resorption in hTNFtg mice compared with wild-type mice. In

contrast, IL1−/−hTNFtg mice were fully protected from systemic bone

loss despite still developing inflammation in their joints. Lack of

IL1 completely reversed increased osteoclast formation and bone

resorption in hTNFtg mice and the increased levels of RANKL in these

mice. Structural parameters and osteoclast and osteoblast numbers were

indistinguishable from wild-type mice.

Conclusions: 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.

http://ard.bmj.com/content/69/01/284.abstract?etoc

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