The possible mechanisms underlying the quantitative and qualitative effects of
cinacalcet on bone were explored in a
chronic kidney disease-mineral and bone disorder (
CKD-MBD) mouse model in relation to the influence of the interactions among the osteoclast (OC) endoplasmic reticulum (ER) stress, autophagy and apoptosis pathways on OC differentiation.
Body weight and biochemical parameters improved significantly in the CKD + cinacalcet groups compared to the CKD group. Micro-computed tomography (μCT) revealed both cortical and trabecular parameters deteriorated significantly in the CKD group and were reversed by
cinacalcet in a dose-dependent manner. Nanoindentation analysis of bone quality proved that both cortical hardness and elastic modulus improved significantly with high dose
cinacalcet treatment. In vitro studies revealed that
cinacalcet inhibited receptor activator of NF-κB
ligand (RANKL)/receptor activator of NF-κB (RANK)-induced OC differentiation in a concentration-dependent manner through a close interaction between activation of
caspase-related apoptosis, reversal of OC autophagy through the
protein kinase B (Akt)/
mammalian target of rapamycin (mTOR) and
adenosine monophosphate-activated
protein kinase (AMPK) pathways, and attenuation of the OC ER stress/CREBH/NFATc1 signaling pathway.
Cinacalcet improves both bone quantity and bone quality in CKD mouse model and inhibits OC differentiation through regulation of the interactions among the apoptosis, ER stress, and autophagy pathways within OCs. © 2021 American Society for Bone and
Mineral Research (ASBMR).