Reduction of particle-induced osteolysis by interleukin-6 involves anti-inflammatory effect and inhibition of early osteoclast precursor differentiation.
The goal of this study was to define the anti-osteoclastogenic and/or anti-inflammatory role of IL-6 in inflammatory bone resorption using in vivo and in vitro methods. To this end, titanium particles were placed on murine calvaria, and bone resorption and osteoclast formation quantified in wild-type and IL-6(-/-) mice. In this model, calvarial bone loss and osteoclast formation were increased in titanium-treated IL-6(-/-) mice. Although basal numbers of splenic osteoclast precursors (OCP) were similar, IL-6(-/-) mice treated with particles in vivo had increased splenic OCP suggesting an enhanced systemic inflammatory response. In vitro osteoclastogenesis was measured using splenic (OCP) at various stages of maturation, including splenocytes from WT, IL-6(-/-) and TNFalpha transgenic mice. ELISA was used to measure TNFalpha production. IL-6 inhibited osteoclastogenesis in early OCP obtained from wild-type and IL-6(-/-) spleens. Pre-treatment of OCP with M-CSF for three days increased the CD11b(high)/c-Fms+ cell population, resulting in an intermediate staged OCP. Osteoclastogenesis was unaffected by IL-6 in M-CSF pre-treated and TNFalpha transgenic derived OCP. IL-6(-/-) splenocytes secreted greater concentrations of TNFalpha in response to titanium particles than WT; addition of exogenous IL-6 to these cultures decreased TNFalpha expression while anti-IL-6 antibody increased TNFalpha. While IL-6 lacks effects on intermediate staged precursors, the dominant in vivo effects of IL-6 appear to be related to strong suppression of early OCP differentiation and an anti-inflammatory effect targeting TNFalpha. Thus, the absence of IL-6 results in increased inflammatory bone loss.
Darowish
Michael
M
Center for Musculoskeletal Research, University of Rochester, School of Medicine and Dentistry, Rochester, NY 14642, USA.
Rahman
Ra'Kerry
R
Li
Ping
P
Bukata
Susan V
SV
Gelinas
Jill
J
Huang
Willis
W
Flick
Lisa M
LM
Schwarz
Edward M
EM
O'Keefe
Regis J
RJ
D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D007249:Inflammation / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000172:deficiency / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010014:Osteolysis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D013154:Spleen / Q000166:cytology; D013234:Stem Cells / Q000166:cytology*; D014025:Titanium / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D039481:CD11b Antigen; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D014025:Titanium