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

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Ann Rheum Dis. Published Online First: 5 February 2009.

doi:10.1136/ard.2008.104786

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Extended Report

IL-1 is essential for systemic inflammatory bone loss

Karin Polzer 1, Leo Joosten 2, Jürg Gasser 3, Jörg H Distler 1, Gisela

Ruiz 1, Wolfgang Baum 1, Kurt Redlich 4, Klaus Bobacz 4, f S

Smolen 4, Wim van den Berg 2, Georg Schett 1 and Jochen Zwerina 1*

1 University of Erlangen-Nuremberg, Germany

2 Radboud University Medical Center Nijmegen, Netherlands

3 Novartis Biomedical Research Institutes, Switzerland

4 Medical University of Vienna, Austria

Abstract

Objectives: Chronic inflammation is a major risk factor of systemic

bone loss leading to osteoporotic fracture and substantial morbidity

and mortality. Inflammatory cytokines, particularly TNF and IL-1 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 interleukin-1 (IL-1), we crossed human tumor necrosis factor

alpha (hTNFtg) mice with mice lacking IL-1 and IL-1 (IL-1-/-hTNFtg).

Systemic bone architecture was evaluated using computed tomography

analysis, static and dynamic bone histomorphometry as well as serum

markers of bone metabolism.

Results: hTNFtg mice developed severe bone loss accompanied by a

severe distortion of bone microarchitecture. Bone trabeculae were both

thinner and decreased in numbers resulting in an increased trabecular

separation. Histomorphometric analyses revealed strongly increased

bone resorption in hTNFtg mice as compared to wildtype mice. In

contrast, IL-1-/-hTNFtg mice were fully protected from systemic bone

loss despite still developing inflammation in their joints. Lack of

IL-1 completely reverted increased osteoclast formation and bone

resorption in hTNFtg mice as well as the increased levels of RANKL in

these mice. Both structural parameters as well as osteoclast and

osteoblast numbers were indistinguishable from wildtype mice.

Conclusion: These data indicate that IL-1 is essential for

TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis,

systemic bone is fully protected by the absence of IL-1, which

suggests that IL-1 is an essential mediator of inflammatory

osteopenia.

http://ard.bmj.com/cgi/content/abstract/ard.2008.104786v1?papetoc

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