Abstract: SA-PO211
Etelcalcetide Improves Bone Turnover in Renal Osteodystrophy Possibly Through Regulation of Bone Immunity and Inflammation
Session Information
- Vascular Calcification, Nephrolithiasis, Bone
November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
Abstract Time: 10:00 AM - 12:00 PM
Category: Bone and Mineral Metabolism
- 401 Bone and Mineral Metabolism: Basic
Authors
- Cai-Mei, Zheng, Taipei Medical University College of Medicine, Taipei, Taiwan
- Lu, Kuo-Cheng, Fu-Jen Catholic University, Taipei, Taiwan
- Hou, Yi-Chou, Fu-Jen Catholic University, Taipei, Taiwan
- Lu, Chien-Lin, Fu-Jen Catholic University, Taipei, Taiwan
- Chiu, Hui-Wen, Taipei Medical University College of Medicine, Taipei, Taiwan
Background
Etelcalcetide, a new calcimimetic agent, allosterically binds the extracellular N terminal domain of calcium-sensing receptor (CaSR) and consequently decreases PTH secretion. As such, it is approved to use in chronic kidney disease-mineral and bone disorder (CKD-MBD) among dialysis patients. We hypothesized that the direct protective effects of etelcalcetide on bone exist in these patients and might be explained by direct anti-oxidant and/or anti-inflammatory effects on bone cells other than lowering PTH levels.
Methods
Osteoclasts (OC) and osteoblasts (OB) were differentiated by the mice macrophage cell line RAW264.7 and mouse muscle myoblast C2C12, respectively. OC differentiation was analyzed by tartrate resistant acid phosphatase (TRAP). OB proliferation was evaluated by ALP activity. Furthermore, RNA-Sequencing (RNA-seq) was determined by next-generation sequencing (NGS). Genes with a 1.5-Fold change threshold are uploaded to the Ingenuity Pathway Analysis (IPA) in RAW264.7 cells. In addition, PCR analysis on RAW264.7 cells confirm these IPA-based molecular mechanisms underlying etelcalcetide on osteoclast differentiation.
Results
Etelcalcetide dose-dependently inhibited OC differentiation as indicated by decreased TRAP levels. On the other hand, etelcalcetide dose-dependently increases OB proliferation as indicated by increased ALP activity. It also affects several pathways in RANKL-induced differentiation of macrophages to osteoclasts. Possible molecular mechanisms as expressed by IPA analysis include: etelcalcetide induced activation of interferon regulatory factor IRF-7/IFN-alpha/beta dependent inhibition of NF-kB related RANK-L induced osteoclastogenesis. On the other hand, it possibly inhibited the TRIM24/IRF3-STAT signaling pathways to inhibit osteoclastogenesis. PCR analysis revealed an increase in IRF7 expression but had no significant effect on TRIM24.
Conclusion
We found the beneficial roles of etelcalcetide in improving bone anabolism by a dual mechanism on bone cells, inhibiting osteoclast differentiation and increasing osteoblast maturation and differentiation. The underlying novel pathways might be through regulation of the cellular energy metabolism, immunity and inflammatory pathways in CKD-MBD-related bone loss.