Efferent signalling by osteoclasts
The coupling concept of bone resorption and formation was developed at both the whole-body and microscopic levels in the 1960s. At the whole-body level, coupling served to explain a positive correlation observed between whole body rates of bone resorption and formation, as determined by radiocalcium kinetics. At the microscopic level, coupling describes sequential bone remodeling at each basic multicellular unit (BMU), in which bone resorption is followed by an equivalent amount of bone formation. Coupling factors have been defined as osteoclast-derived molecules that facilitate the transition from bone resorption to formation at the BMU level by either recruiting or promoting differentiation and activation of osteoprogenitors and osteoblasts. Factors derived from osteoblasts and osteocytes have generally been excluded from coupling factors to avoid confusion. Coupling factors are either released from the extracellular matrix, such as TGF-beta and IGFs, secreted from osteoclasts, like sphingosine-1-phosphate, or are membrane-bound.
The transmembrane ligand ephrinB2 is one such membrane-bound factor expressed on osteoclasts, while its receptor EphB4 is expressed on osteoprogenitors and osteoblasts. Significantly, ephrinB2/EphB4 signaling is bidirectional. Forward signaling into EphB4-expressing progenitors enhances osteoblast differentiation, while ephrin-expressing osteoclasts receive reverse signaling upon ephrinB2/EphB4 interaction, suppressing osteoclast differentiation and function. It is increasingly clear that osteoclast-derived factors also negatively regulate osteoblasts. Such negative regulators may be GPI-anchored ephrinA2, which is produced by osteoclasts. Our data suggest that its receptor EphA2 expressed on osteoblasts inhibited mineralization. We propose that ephrinA2 and other osteoclast-efferent negative factors should be designated coupling inhibitors.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details are unavailable.