Cinacalcet Improves Bone Parameters Through Regulation of Osteoclast Endoplasmic Reticulum Stress, Autophagy, and Apoptotic Pathways in Chronic Kidney Disease–Mineral and Bone Disorder

Abstract

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).

Mouse Models of Mineral Bone Disorders Associated with Chronic Kidney Disease

“…Phosphate-enriched diets (HP diet) have been used to enhance the severity of SHPT in many CKD–MBD mouse studies [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 , 56 , 57 , 58 , 64 ], see Table 1 . An increase in vascular disease has been observed in mice with CKD and HP diet [ 18 ], accompanied by a similar increase in bone alterations [ 37 , 38 , 44 ].…”

“…An increase in vascular disease has been observed in mice with CKD and HP diet [ 18 ], accompanied by a similar increase in bone alterations [ 37 , 38 , 44 ]. The recommended minimal standard dietary phosphate content is 0.3% phosphate together with 0.5% calcium [ 70 ], while in CKD–MBD studies, diets usually contained 0.5 to 0.9% phosphate per kg diet [ 20 , 21 , 27 , 28 , 29 , 34 , 35 , 36 , 37 , 38 , 40 , 42 , 44 , 48 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 64 , 65 , 68 ] or even up to 1.2% [ 67 ]. Phosphate-enriched diets contained 0.9 to 2% of phosphate [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 , 56 , 57 , 58 , 64 ].…”

“…The recommended minimal standard dietary phosphate content is 0.3% phosphate together with 0.5% calcium [ 70 ], while in CKD–MBD studies, diets usually contained 0.5 to 0.9% phosphate per kg diet [ 20 , 21 , 27 , 28 , 29 , 34 , 35 , 36 , 37 , 38 , 40 , 42 , 44 , 48 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 64 , 65 , 68 ] or even up to 1.2% [ 67 ]. Phosphate-enriched diets contained 0.9 to 2% of phosphate [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 , 56 , 57 , 58 , 64 ]. These diets were administered over periods ranging from 4 days to 18 weeks [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 ,…”

“…Phosphate-enriched diets contained 0.9 to 2% of phosphate [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 , 56 , 57 , 58 , 64 ]. These diets were administered over periods ranging from 4 days to 18 weeks [ 20 , 27 , 34 , 35 , 36 , 37 , 38 , 44 , 53 , 54 , 55 , 56 , 57 , 58 , 64 ]. Interestingly, an HP diet itself can lead to bone structure changes [ 38 , 44 ] and to HPT, which is amplified by CKD [ 44 ].…”

“…The degree of renal impairment in CKD mice was mostly estimated by the increase in urea (blood urea nitrogen; BUN) [ 19 , 20 , 21 , 28 , 29 , 30 , 31 , 32 , 33 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 46 , 47 , 48 , 49 , 50 , 51 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 61 , 63 , 64 , 65 , 66 , 67 ]. While in some models, BUN levels were similar to control [ 30 , 31 , 43 ], in others, it was 6- to 8-fold increased [ 33 , 58 , 61 , 63 , 64 ].…”