Apoptosis Repressor with Caspase Recruitment Domain enhances Survival and Promotes Osteogenic Differentiation of Human Osteoblast Cells Under Zoledronate Treatment

Overview

Journal Mol Med Rep

Specialty Molecular Biology

Date 2016 Aug 31

PMID 27573706

Citations 6

Authors

Longwei Hu

Jing Han

Xi Yang

Yang Wang

Hongya Pan

Liqun Xu

Affiliations

Soon will be listed here.

Abstract

Zoledronate is one of the most potent nitrogen-containing bisphosphonates which has been demonstrated to result in osteoblast apoptosis and impact osteogenic differentiation in vitro. This effect of Zoledronate on osteoblasts may partially explain bisphosphonate‑associated osteonecrosis of the jaw, a serious complication associated with treatment with bisphosphonates. Apoptosis repressor with caspase recruitment domain (ARC) is a multifunctional inhibitor of apoptosis that is physiologically expressed predominantly in post‑mitotic cells such as cardiomyocytes, neurons and skeletal muscle cells. However, its effect on human osteoblasts remains unclear. The current study aimed to investigate the effects of ARC on human osteoblasts under the treatment of high concentrations of Zoledronate. ARC‑overexpressed human osteoblasts were established and were exposed to Zoledronate with different concentrations (0, 1 and 5 µM) in vitro. Cell numbers were detected using the MTT assay, and flow cytometry was used to identity cell apoptosis. Alkaline phosphatase staining, quantitative analysis and ectopic osteogenesis in nude mice were used to evaluate the osteogenic differentiation of ARC‑overexpressed osteoblasts. It was observed that ARC is able to reverse the inhibitory effect of Zoldronate on osteoblasts. ARC is additionally able to promote osteogenic differentiation of osteoblasts and inhibit their apoptosis. These observations suggest a critical role for ARC in the regulation of human osteoblasts under Zoledronate treatment.

Citing Articles

17β-estradiol promotes osteogenic differentiation of BMSCs by regulating mitophagy through ARC.

Shi J, Wen J, Hu L J Orthop Surg Res. 2025; 20(1):35.

PMID: 39794817 PMC: 11724534. DOI: 10.1186/s13018-024-05400-9.

Role of apoptosis repressor with caspase recruitment domain in human health and chronic diseases.

Ao X, Ji G, Zhang B, Ding W, Wang J, Liu Y Ann Med. 2024; 56(1):2409958.

PMID: 39351758 PMC: 11445919. DOI: 10.1080/07853890.2024.2409958.

METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs.

Jin Y, Han X, Wang Y, Fan Z Int J Oral Sci. 2024; 16(1):42.

PMID: 38782892 PMC: 11116408. DOI: 10.1038/s41368-024-00303-1.

In Vitro Cytotoxicity of Antiresorptive and Antiangiogenic Compounds on Oral Tissues Contributing to MRONJ: Systematic Review.

Guirguis R, Tan L, Hicks R, Hasan A, Duong T, Hu X Biomolecules. 2023; 13(6).

PMID: 37371553 PMC: 10296421. DOI: 10.3390/biom13060973.

Apoptosis repressor with caspase recruitment domain (ARC) promotes bone regeneration of bone marrow-derived mesenchymal stem cells by activating Fgf-2/PI3K/Akt signaling.

Hu L, Wang Y, Pan H, Kadir K, Wen J, Li S Stem Cell Res Ther. 2021; 12(1):185.

PMID: 33726822 PMC: 7962397. DOI: 10.1186/s13287-021-02253-5.

References

Tenta R, Sourla A, Lembessis P, Koutsilieris M . Bone-related growth factors and zoledronic acid regulate the PTHrP/PTH.1 receptor bioregulation systems in MG-63 human osteosarcoma cells. Anticancer Res. 2006; 26(1A):283-91. View

Wang M, Qanungo S, Crow M, Watanabe M, Nieminen A . Apoptosis repressor with caspase recruitment domain (ARC) is expressed in cancer cells and localizes to nuclei. FEBS Lett. 2005; 579(11):2411-5. DOI: 10.1016/j.febslet.2005.03.040. View

Manzano-Moreno F, Ramos-Torrecillas J, De Luna-Bertos E, Ruiz C, Garcia-Martinez O . High doses of bisphosphonates reduce osteoblast-like cell proliferation by arresting the cell cycle and inducing apoptosis. J Craniomaxillofac Surg. 2015; 43(3):396-401. DOI: 10.1016/j.jcms.2014.12.008. View

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

Wiemer A, Tong H, Swanson K, Hohl R . Digeranyl bisphosphonate inhibits geranylgeranyl pyrophosphate synthase. Biochem Biophys Res Commun. 2007; 353(4):921-5. DOI: 10.1016/j.bbrc.2006.12.094. View

Wang X, Huang H, Yang F, Xia L, Zhang W, Jiang X . Ectopic study of tissue-engineered bone complex with enamel matrix proteins, bone marrow stromal cells in porous calcium phosphate cement scaffolds, in nude mice. Cell Prolif. 2011; 44(3):274-82. PMC: 6496638. DOI: 10.1111/j.1365-2184.2011.00750.x. View

Chen L, Jiang C, Watts R, Thorne R, Kiejda K, Zhang X . Inhibition of endoplasmic reticulum stress-induced apoptosis of melanoma cells by the ARC protein. Cancer Res. 2008; 68(3):834-42. DOI: 10.1158/0008-5472.CAN-07-5056. View

Aino M, Nishida E, Fujieda Y, Orimoto A, Mitani A, Noguchi T . Isolation and characterization of the human immature osteoblast culture system from the alveolar bones of aged donors for bone regeneration therapy. Expert Opin Biol Ther. 2014; 14(12):1731-44. DOI: 10.1517/14712598.2014.960387. View

Senaratne S, Mansi J, Colston K . The bisphosphonate zoledronic acid impairs Ras membrane [correction of impairs membrane] localisation and induces cytochrome c release in breast cancer cells. Br J Cancer. 2002; 86(9):1479-86. PMC: 2375368. DOI: 10.1038/sj.bjc.6600297. View

10.

Li Y, Liu X, Mei Zhu X, Cai L . ARC contributes to the inhibitory effect of preconditioning on cardiomyocyte apoptosis. Apoptosis. 2007; 12(9):1589-95. DOI: 10.1007/s10495-007-0094-4. View

11.

Jo D, Jun J, Chang J, Hong Y, Song S, Cho D . Calcium binding of ARC mediates regulation of caspase 8 and cell death. Mol Cell Biol. 2004; 24(22):9763-70. PMC: 525473. DOI: 10.1128/MCB.24.22.9763-9770.2004. View

12.

Xing L, Boyce B . Regulation of apoptosis in osteoclasts and osteoblastic cells. Biochem Biophys Res Commun. 2005; 328(3):709-20. DOI: 10.1016/j.bbrc.2004.11.072. View

13.

Daubine F, Le Gall C, Gasser J, Green J, Clezardin P . Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst. 2007; 99(4):322-30. DOI: 10.1093/jnci/djk054. View

14.

Kaiser T, Teufel I, Geiger K, Vater Y, Aicher W, Klein G . Bisphosphonates modulate vital functions of human osteoblasts and affect their interactions with breast cancer cells. Breast Cancer Res Treat. 2013; 140(1):35-48. DOI: 10.1007/s10549-013-2613-z. View

15.

Hong Y, Jo D, Lee J, Chang J, Nam J, Noh J . Down-regulation of ARC contributes to vulnerability of hippocampal neurons to ischemia/hypoxia. FEBS Lett. 2003; 543(1-3):170-3. DOI: 10.1016/s0014-5793(03)00444-7. View

16.

Cheong S, Sun S, Kang B, Bezouglaia O, Elashoff D, McKenna C . Bisphosphonate uptake in areas of tooth extraction or periapical disease. J Oral Maxillofac Surg. 2014; 72(12):2461-8. PMC: 4472335. DOI: 10.1016/j.joms.2014.07.004. View

17.

Li Y, Ge X, Liu X . The cardioprotective effect of postconditioning is mediated by ARC through inhibiting mitochondrial apoptotic pathway. Apoptosis. 2009; 14(2):164-72. DOI: 10.1007/s10495-008-0296-4. View

18.

Mercier I, Vuolo M, Jasmin J, Medina C, Williams M, Mariadason J . ARC (apoptosis repressor with caspase recruitment domain) is a novel marker of human colon cancer. Cell Cycle. 2008; 7(11):1640-7. DOI: 10.4161/cc.7.11.5979. View

19.

Koseki T, Inohara N, Chen S, Nunez G . ARC, an inhibitor of apoptosis expressed in skeletal muscle and heart that interacts selectively with caspases. Proc Natl Acad Sci U S A. 1998; 95(9):5156-60. PMC: 20230. DOI: 10.1073/pnas.95.9.5156. View

20.

Baron R, Ferrari S, Russell R . Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2010; 48(4):677-92. DOI: 10.1016/j.bone.2010.11.020. View