Cinacalcet Hydrochloride Improves Bone Disorder in Renal Osteodystrophy by Regulating Endoplasmic Reticulum Stress and Autophagy

Chronic kidney disease (CKD) patients experience bone loss and fracture because of a specific CKD related systemic disorder known as CKD- mineral bone disorder (CKD-MBD). Abnormal bone metabolism (renal osteodystrophy, ROD) is a part of CKD-MBD and is a disorder of bone remodeling. Hormonal dysregulation including abnormal vitamin D metabolism, parathyroid hormone (PTH) resistance and decreased calcium-sensing receptor (CaR) expression, etc. specifically occur among these patients. Accumulated findings revealed that chronic inflammation and endoplasmic reticulum (ER) stress plays important role in CKD progression among these patients. One of the inflammatory pathway, TGF-β signaling found to play an important role in the pathogenesis of high-turnover ROD independent of serum PTH level. ER stress activates unfolded protein response (UPR) pathway, which leads to various organ dysfunction. Recent studies have shown that autophagy plays an important role for the maintenance of bone homeostasis through degradation of unnecessary proteins related with UPR pathway. Dysregulated autophagy and ER stress in bone cells relates the process of bone loss and subsequent osteoporosis. However, their role in ROD is still unclear. In our first part of the study, we will evaluate the role of ER stress and autophagy in ROD using CKD mice. Cinacalcet is a calcimimetic agent used clinically to control PTH and mineral disorder in CKD patients. Though clinical trials found that cinacalcet improve bone mieral density, its effect was thought to be secondarily to improvement in systemic PTH levels. In our recent study, we found that cinacalcet improves the bone strength and bone mineral density through increasing cortical bone thickness and decreasing cortical bone porosity among CKD mice. In molecular level, we proved that cinacalcet inhibits osteoclast function and survival revaled by decreased tartrate-resistant acid phosphatase (TRAP) stain. When the cinacalcet-treated serum is co-cultured with osteoblasts, improve mineralization was seen by increased alizarin red stain. Thus, we believe that cinacalcet plays a direct role in bone anabolism. In our second part of the study, we will create a new model of CKD mice, CKD-thyroparathyroidectomy mice to evaluate the cinacalcet’s direct effects on bone. Further, we will evaluate the effect of cinacalcet on TGF-β signaling, ER stress and autophagy of bone cells and bone parameters among CKD-TPTX mice.