Considering its 'static' structure, it's hard to believe that bone is being constantly remodelled by a dynamic equilibrium of deposition and resorption. To prevent matrix-degrading osteoclasts from getting over-zealous, bone-depositing osteoblasts keep them in check, but Taniguchi's group now reports that osteoclasts also exert a considerable amount of self-control.

Osteoclastogenesis — the process by which cells of macrophage/monocyte origin differentiate into functional osteoclasts — requires signalling downstream of RANK (receptor activator of NFκB ligand), which induces expression of the transcription factor c-Fos. Taniguchi and colleagues were looking to see which genes were induced when RANK is activated by its ligand — RANKL — and found that several of them required interferon (IFN)-α/β signalling. As mice with a defective IFN-α/β receptor system show enhanced signs of osteoporosis, the authors suspected that IFN-α/β signalling negatively regulates osteoclast activity.

Further analysis showed that IFN-β — not IFN-α — was responsible for this negative regulation. But how does IFN-β inhibit c-Fos? As c-Fos transcripts weren't downregulated, the authors carried out pulse-chase experiments to establish that protein synthesis was inhibited, and proposed that the double-stranded-RNA-activated protein kinase PKR was involved. This was not a wild guess — it is well known that PKR is induced by IFN-β through the heterotrimeric transcription factor complex ISGF3 (IFN-stimulated gene factor 3), and the authors showed that the inhibitory action of IFN-β was indeed mediated by ISGF3. Furthermore, PKR inhibits protein synthesis by phosphorylating eIF2α — a protein that has an important function in messenger RNA translation. As IFN-β could not fully inhibit osteoclast differentiation in PKR−/− mice, the authors propose that PKR is a target, probably among several others, that prevents osteoclastogenesis by inhibiting c-Fos.

Digging slightly deeper, Taniguchi and colleagues found that c-Fos itself was responsible for the RANKL-mediated induction of IFN-β, probably by directly binding to the IFN-β promoter. So, RANKL induces c-Fos, which induces IFN-β and then, in turn, IFN-β inhibits c-Fos expression. c-Fos, therefore, signals its own inhibition. The authors also showed that applying IFN-β to the site of bone destruction in an in vivo model inhibited bone resorption, causing excitement among clinicians, too.