Ephrin signalling modifies the bone-building action of parathyroid hormone (#127)
Parathyroid hormone (PTH) is the only current anabolic therapy available for patients with a high risk of bone fracture (osteoporosis). Although effective, its mechanism of action remains unclear, particularly since continual high levels of circulating PTH lead to bone destruction. We have reported that EphrinB2 expression by osteoblasts (bone forming cells) is stimulated rapidly by parathyroid hormone (PTH) and inhibition of the interaction of ephrinB2 with one of its receptors EphB4 impaired late stages of osteoblast differentiation in vitro.
To study ephrinB2/EphB4 signaling in PTH anabolic action, we treated mice with PTH in the presence and absence of soluble EphB4 (sEphB4) to inhibit ephrinB2/EphB4 signaling. This treatment, with or without PTH, increased osteoblast formation, but production of osteoid and formation of mineralized bone was not increased, suggesting a functional impairment. Strikingly, sEphB4 treatment converted PTH anabolic effect to a resorptive response because formation of osteoclasts (bone destroying cells) was increased and trabecular number reduced. This influence of sEphB4 was confirmed in vitro; osteoclast formation, and RANKL production by osteoblasts, in response to PTH , 1,25-dihydroxyvitaminD3 or oncostatin M was increased with addition of sEphB4.
In addition genetically altered mice lacking the ephrinB2 reverse signalling domain showed increased osteoblast formation, but the level of bone formation was not increased, as observed with sEphB4 treatment. In contrast to the effects of systemic ephrinB2/EphB4 inhibition, osteoclast numbers were reduced.
These results indicate that ephrinB2/EphB4 signaling enhances late stages of osteoblast differentiation, and communicates with the hemopoietic lineage to restrict osteoclast formation, and that this is required for the effective anabolic action of PTH.