Credit: Springer Nature Limited

New research by Hiroshi Suzuki and colleagues shows that reverse signalling of receptor activator of nuclear factor-κB (RANK; also known as TNFRSF11A) ligand (RANKL; also known as TNFSF11) in osteoblasts has a role in linking bone resorption and formation.

RANKL belongs to the tumour necrosis factor family, which is a group of proteins that act as bidirectional signalling molecules and produce intracellular reverse signalling. Previously, osteoblasts were thought to be the main producers of RANKL; however, mounting evidence suggests that osteocytes are the main source during bone remodelling. “Because of this finding, we hypothesized that osteoblastic RANKL might have a different physiological role than that of osteocytic RANKL,” explains corresponding author Masashi Honma.

In this study, the researchers showed that maturing osteoclasts secreted vesicular RANK (vRANK), which binds to osteoblastic RANKL and activates reverse signalling through Runx2. The stimulation also increased the mineralization of osteoblasts.

…activation of RANKL reverse signalling inhibited reduced bone formation

Next, the authors created a mouse model (RanklP29A) to suppress reverse signalling of RANKL but not forward signalling, which triggers osteoclastogenesis. When recombinant RANKL was administered, osteoclast maturation in both RanklP29A and wild-type mice was increased; however, bone formation was disrupted in RanklP29A mice compared with wild-type mice. The results suggest that osteoblastic RANKL reverse signalling is involved in linking bone resorption and formation.

Finally, Suzuki and colleagues targeted RANKL reverse signalling in an ovariectomized mouse model to test whether it is a possible pharmacological target for the treatment of osteoporosis. They found that activation of RANKL reverse signalling inhibited reduced bone formation. “Our findings indicate that the role of RANKL is the accelerator of bone turnover rather than the stimulator of bone resorption,” concludes Honma.

This article is modified from the original in Nat. Rev. Endo. (