ESPE Yearbook of Paediatric Endocrinology

Abstract: Nature. 2018 Sep;561(7722):195–200.

In brief: This study used various cell-based methods and animal models to investigate the RANK-RANKL signaling pathway in bone homeostasis. The authors show for the first time, that reverse signaling exists from osteoclast to osteoblast and that vesicular RANK, secreted by the osteoclast, relays information to the osteoblast to promote bone formation.

Comment: Bone homeostasis requires coordinated cycles of bone resorption and formation. Signals from osteoclasts to osteoblasts lead to transition from bone resorption to formation. RANKL, a transmembrane protein, has a central role in osteoclastogenesis. Osteoblasts and osteocytes secrete RANKL, which activates the RANK receptor on hematopoietic stem cells, triggering differentiation into osteoclasts. It is less clear how osteoclasts signal to osteoblasts to modify bone formation.

Maturing osteoclasts secrete small extracellular vesicles that contain RANK. Therefore, it is possible that RANKL reverse signaling in osteoblasts is activated by vesicular RANK, secreted from osteoclasts. The authors provide evidence that osteoclasts regulate osteoblasts using the same RANKL–RANK system acting in reverse. They showed that the osteoclastic small extracellular vesicles harbor RANK on their surface. Isolated RANK-bearing vesicles in mouse osteoblast cultures activated the expression of the differentiation-promoting genes Col1a1, Runx2 and Osx in the cells. The presence of RANK-containing vesicles also triggered mineral deposition by osteoblasts. Cellular studies further indicated that stimulation at the early stage promoted osteoblastic mineralization, whereas stimulation at the late stage suppressed osteoblastic mineralization. The timing of vesicular-RANK secretion from osteoclasts and the biphasic properties of RANKL reverse signaling suggest that reverse signaling may contribute to coupling signals.

In light of the bifunctional properties of RANKL, the authors examined the possibility of designing a biological agent to simultaneously activate RANKL reverse signaling in osteoblasts and inhibit RANKL forward signaling to osteoclast precursors. The anti-RANKL antibody denosumab is widely used to treat osteoporosis. By preventing RANKL–RANK forward signaling, denosumab inhibits bone resorption by osteoclasts. However, it transiently also lowers bone formation, because of the tight coupling between osteoclasts and osteoblasts. Here the authors developed a novel anti-RANKL antibody which could potentially uncouple resorption and formation. In a mouse model for post-menopausal osteoporosis, the modified antibody reduced bone resorption but did not suppress bone formation. Based on these findings, we might hopefully in future years expect development of a new osteoporosis drug that combines the benefits of anti-resorptive and bone anabolic therapy.