Interleukin (IL)-1 is crucially involved in inflammation-induced systemic bone loss, study findings indicate.
Jochen Zwerina (University of Erlangen-Nuremberg, Erlangen, Germany) and co-investigators have shown that loss of trabecular bone mass and cortical thinning can be completely prevented by deleting the IL-1 gene from mice that over-express tumor necrosis factor (TNF).
“Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture, and substantial morbidity and mortality in RA patients,” say Zwerina et al.
“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.”
To establish whether TNF directly triggers bone loss or whether IL-1 is also required, the researchers crossed heterozygous human TNF transgenic (hTNFtg) mice with mice lacking IL-1α and IL-1β (IL-1-/-).
Using micro-computed tomography analysis, bone histomorphometry and serum markers for bone metabolism the researchers compared systemic bone architecture in the four mouse genotypes (wild-type, IL-1-/-, hTNFtg, and IL-1-/-hTNFtg) from the F2 generation.
They found that hTNFtg mice developed severe bone loss accompanied by a severe distortion of bone microarchitecture. Bone trabeculae were both thinner than wild-type mice and decreased in numbers resulting in an increased trabecular separation.
In contrast, bone mineral density was maintained in IL-1-/-hTNFtg mice and no significant change in bone structural parameters was observed when compared with wild-type and IL-1-/- mice.
Histomorphometric analyses revealed strongly increased bone resorption in hTNFtg mice as compared with wild-type mice. IL-1-/-hTNFtg mice, on the other hand, 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 receptor activator of nuclear factor κB ligand in these mice. Both structural parameters as well as osteoclast and osteoblast numbers were indistinguishable from wild-type mice.
“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,” conclude Zwerina and co-authors in the Annals of Rheumatic Diseases.