Differential outcomes of Erythropoietin and its non-erythropoietic analogue cibinetide on bone density

Erythropoietin (Epo), the master regulator of erythropoiesis, has also been implicated in a wide range of non-erythroid activities, including tissue protection. These functions are mediated via two receptors: hematopoiesis via the Epo receptor (EpoR) homodimer and tissue protection via a heteromer composed of EpoR and CD131. Cibinetide (ARA290) is a non-erythropoietic analogue of Epo, acting selectively on the heteromer complex. Our published findings that Epo stimulates osteoclast precursors and entrains a decrease in bone density, raise questions regarding the underlying molecular mechanisms.

Unexpectedly, we found that cibinetide injections in 12-week-old female mice (120 µg/kg thrice weekly for one month) resulted in a significant increase in tissue mineral density in cortical bone by 5.8% (1416.4±39.27 vs 1338.74±16.56 mgHA/cm³) and in trabecular bone by 5.2% (1056.52±30.94 vs 1004.13±16.91 mg HA/cm³) (p<0.05), as measured using microCT.

In vitro, Epo administration to bone marrow derived macrophages (BMDM) enhanced osteoclastogenesis, whereas cibinetide administration had the opposite effect in a dose dependent manner. Combined cibinetide and Epo treatment inhibited osteoclastogenesis in BMDM, suggesting that cibinetide overrides the pro-osteoclastogenic effect of Epo.

Our findings demonstrate the increasing complexity of EpoR signaling in bone, and pave the way for clinical translation through potential combination therapy of Epo and cibinetide in anemic patients in an attempt to preserve the erythropoietic actions of Epo, while preventing/attenuating the associated bone loss.