Abstract
Chronic inflammation during many diseases is associated with bone loss. While interferons (IFNs) are often inhibitory to osteoclast formation, the complex role that IFN and interferon-stimulated genes (ISGs) play in osteoimmunology during inflammatory diseases is still poorly understood. We show that mice deficient in IFN signaling components including IFN alpha and beta receptor 1 (IFNAR1), interferon regulatory factor 1 (IRF1), IRF9, and STAT1 each have reduced bone density and increased osteoclastogenesis compared to wild type mice. The IFN-inducible guanylate-binding proteins (GBPs) on mouse chromosome 3 (GBP1, GBP2, GBP3, GBP5, GBP7) are required to negatively regulate age-associated bone loss and osteoclastogenesis. Mechanistically, GBP2 and GBP5 both negatively regulate in vitro osteoclast differentiation, and loss of GBP5, but not GBP2, results in greater age-associated bone loss in mice. Moreover, mice deficient in GBP5 or chromosome 3 GBPs have greater LPS-mediated inflammatory bone loss compared to wild type mice. Overall, we find that GBP5 contributes to restricting age-associated and inflammation-induced bone loss by negatively regulating osteoclastogenesis.
Highlights
Chronic inflammation during many diseases is associated with bone loss
Mice lacking IFN alpha and beta receptor 1 (IFNAR1), IFNβ, IFNγ, or IFNGR1 have reduced bone density compared to wild type (WT) mice, highlighting the importance of IFN signaling in the negative feedback signaling and homeostasis of osteoclasts[14,15,19]
Earlier studies found that Stat1−/− and Irf1−/− mice have increased overall bone density, contrary to what would be expected from increased osteoclastogenesis in vitro[21,22]
Summary
Chronic inflammation during many diseases is associated with bone loss. While interferons (IFNs) are often inhibitory to osteoclast formation, the complex role that IFN and interferonstimulated genes (ISGs) play in osteoimmunology during inflammatory diseases is still poorly understood. In age- and sex-matched mice, the role for type I IFN signaling molecules IFNAR1, IRF9, IRF1, and STAT1 in regulating bone density in femurs of 3-month-old mice by micro-computed tomography (μCT). Because Irf1−/− and Stat1−/− mice were previously shown to have increased bone density, in contrast to our findings (Fig. 1)[21,22], we utilized an additional independent genetic model and examined femurs from Irf1fl/flLysMCre+ mice, and found an osteoclast-specific role for IRF1 in restricting bone loss (Supplementary Fig. 1).
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