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

Hui Wen Chiu, Yi Chou Hou, Chien Lin Lu, Kuo Cheng Lu, Wen Chih Liu, Jia Fwu Shyu, Jia Feng Chang, Cai Mei Zheng

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)215-225
Number of pages11
JournalJournal of Bone and Mineral Research
Volume37
Issue number2
DOIs
Publication statusPublished - Feb 2022

Keywords

  • AUTOPHAGY
  • CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER
  • CINACALCET
  • ENDOPLASMIC RETICULUM STRESS
  • OSTEOCLASTS
  • OSTEOCLASTSAPOPTOSIS

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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