ACY‑1215, a HDAC6 inhibitor, decreases the dexamethasone‑induced suppression of osteogenesis in MC3T3‑E1 cells

Wang,Na; Wang,Hua; Chen,Jianming; Wang,Fubin; Wang,Shuaiyi; Zhou,Qiang; Ying,Jichong; Huang,Shanzhao; Wang,Pu; Yuan,Fangfang

doi:10.3892/mmr.2020.11319

ACY‑1215, a HDAC6 inhibitor, decreases the dexamethasone‑induced suppression of osteogenesis in MC3T3‑E1 cells

Authors:
- Na Wang
- Hua Wang
- Jianming Chen
- Fubin Wang
- Shuaiyi Wang
- Qiang Zhou
- Jichong Ying
- Shanzhao Huang
- Pu Wang
- Fangfang Yuan
View Affiliations

Affiliations: Department of Endocrinology, Ningbo Number 6 Hospital, Ningbo, Zhejiang 315040, P.R. China, Department of Radiology, Ningbo Number 6 Hospital, Ningbo, Zhejiang 315040, P.R. China, Department of Orthopaedics, Ningbo Number 6 Hospital, Ningbo, Zhejiang 315040, P.R. China, Department of Inspection, Ningbo Number 6 Hospital, Ningbo, Zhejiang 315040, P.R. China, Department of Endocrinology, The First Hospital of Jiaxing (The Affiliated Hospital of Jiaxing University), Jiaxing, Zhejiang 314001, P.R. China, Department of Osteopeniology, Ningbo Number 6 Hospital, Ningbo, Zhejiang 315040, P.R. China, Department of Cardiology, Ningbo Number 6 Hospital, Ningbo, Zhejiang 315040, P.R. China, Department of Rheumatology, Ningbo Number 6 Hospital, Ningbo, Zhejiang 315040, P.R. China
Published online on: July 9, 2020 https://doi.org/10.3892/mmr.2020.11319
Pages: 2451-2459

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glucocorticoid‑induced osteoporosis is the commonest form of drug‑induced osteoporosis. Histone deacetylase 6 (HDAC6) is involved in the differentiation from mesenchymal stem cells to osteoblasts. However, the role of ricolinostat (ACY‑1215, HDAC6 inhibitor) in the dexamethasone (Dex)‑induced proliferation and differentiation of preosteoblasts remains to be elucidated. The protein expression and mRNA expression levels of HDAC6, osteopontin (OPN), runt‑related transcription factor 2 (Runx2), osterix (Osx), collagen I (COL1A1) and glucocorticoid receptor (GR) in MC3T3‑E1 cells were analyzed by western blot analysis and reverse transcription‑quantitative PCR analysis. The cell viability was detected by CCK‑8 assay. The alkaline phosphatase (ALP) activity and capacity of mineralization was determined by ALP assay kit and alizarin red staining. HDAC6 expression was increased in patient serum and Dex‑induced MC3T3‑E1 cells at a certain concentration range; 1 µM Dex was selected for further experimentation. Cell viability was decreased after Dex induction and restored following ACY‑1215 treatment. The ALP activity and capability for mineralization was decreased when MC3T3‑E1 cells were induced by 1 µM Dex and was gradually improved by the treatment of ACY‑1215 at 1, 5 and 10 mM. The expression of OPN, Runx2, Osx and COL1A1 was similar, with the changes of capability for mineralization. Furthermore, GR expression was increased in Dex‑induced MC3T3‑E1 cells. ACY‑1215 promoted the GR expression in MC3T3‑E1 cells from 1‑5 mM while GR receptor expression was increased with 10 mM ACY‑1215 treatment. In conclusion, ACY‑1215 reversed the Dex‑induced suppression of proliferation and differentiation of MC3T3‑E1 cells.

View Figures

View References

1	Mirza F and Canalis E: Management of endocrine disease: Secondary osteoporosis: Pathophysiology and management. Eur J Endocrinol. 173:R131–R151. 2015. View Article : Google Scholar : PubMed/NCBI
2	Sheu A and Diamond T: Secondary osteoporosis. Aust Prescr. 39:85–87. 2016.PubMed/NCBI
3	Colangelo L, Biamonte F, Pepe J, Cipriani C and Minisola S: Understanding and managing secondary osteoporosis. Expert Rev Endocrinol Metab. 14:111–122. 2019. View Article : Google Scholar : PubMed/NCBI
4	Rooney M, Bishop N, Davidson J, Beresford MW, Pilkington C, Donagh JM, Wyatt S, Gardner-Medwin J, Satyapal R, Clinch J, et al: The prevention and treatment of glucocorticoid-induced osteopaenia in juvenile rheumatic disease: A randomised double-blind controlled trial. EClinicalMedicine. 12:79–87. 2019. View Article : Google Scholar : PubMed/NCBI
5	Caplan L and Saag KG: Glucocorticoids and the risk of osteoporosis. Expert Opin Drug Saf. 8:33–47. 2009. View Article : Google Scholar : PubMed/NCBI
6	Buckley L, Guyatt G, Fink HA, Cannon M, Grossman J, Hansen KE, Humphrey MB, Lane NE, Magrey M, Miller M, et al: 2017 American college of rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Rheumatol. 69:1521–1537. 2017. View Article : Google Scholar : PubMed/NCBI
7	McGee-Lawrence ME and Westendorf JJ: Histone deacetylases in skeletal development and bone mass maintenance. Gene. 474:1–11. 2011. View Article : Google Scholar : PubMed/NCBI
8	Westendorf JJ: Histone deacetylases in control of skeletogenesis. J Cell Biochem. 102:332–340. 2007. View Article : Google Scholar : PubMed/NCBI
9	Jensen ED, Schroeder TM, Bailey J, Gopalakrishnan R and Westendorf JJ: Histone deacetylase 7 associates with Runx2 and represses its activity during osteoblast maturation in a deacetylation-independent manner. J Bone Miner Res. 23:361–372. 2008. View Article : Google Scholar : PubMed/NCBI
10	Lee HW, Suh JH, Kim AY, Lee YS, Park SY and Kim JB: Histone deacetylase 1-mediated histone modification regulates osteoblast differentiation. Mol Endocrinol. 20:2432–2443. 2006. View Article : Google Scholar : PubMed/NCBI
11	Schroeder TM and Westendorf JJ: Histone deacetylase inhibitors promote osteoblast maturation. J Bone Miner Res. 20:2254–2263. 2005. View Article : Google Scholar : PubMed/NCBI
12	Zhang Y, Kwon S, Yamaguchi T, Cubizolles F, Rousseaux S, Kneissel M, Cao C, Li N, Cheng HL, Chua K, et al: Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol Cell Biol. 28:1688–1701. 2008. View Article : Google Scholar : PubMed/NCBI
13	Dudakovic A, Evans JM, Li Y, Middha S, McGee-Lawrence ME, van Wijnen AJ and Westendorf JJ: Histone deacetylase inhibition promotes osteoblast maturation by altering the histone H4 epigenome and reduces Akt phosphorylation. J Biol Chem. 288:28783–28791. 2013. View Article : Google Scholar : PubMed/NCBI
14	Eslaminejad MB, Fani N and Shahhoseini M: Epigenetic regulation of osteogenic and chondrogenic differentiation of mesenchymal stem cells in culture. Cell J. 15:1–10. 2013.PubMed/NCBI
15	Kretsovali A, Hadjimichael C and Charmpilas N: Histone deacetylase inhibitors in cell pluripotency, differentiation, and reprogramming. Stem Cells Int. 2012:1841542012. View Article : Google Scholar : PubMed/NCBI
16	Menegola E, Di Renzo F, Broccia ML and Giavini E: Inhibition of histone deacetylase as a new mechanism of teratogenesis. Birth Defects Res C Embryo Today. 78:345–353. 2006. View Article : Google Scholar : PubMed/NCBI
17	Rimando MG, Wu HH, Liu YA, Lee CW, Kuo SW, Lo YP, Tseng KF, Liu YS and Lee OK: Glucocorticoid receptor and Histone deacetylase 6 mediate the differential effect of dexamethasone during osteogenesis of mesenchymal stromal cells (MSCs). Sci Rep. 6:373712016. View Article : Google Scholar : PubMed/NCBI
18	Cheng C, Shan W, Huang W, Ding Z, Cui G, Liu F, Lu W, Xu J, He W and Yin Z: ACY-1215 exhibits anti-inflammatory and chondroprotective effects in human osteoarthritis chondrocytes via inhibition of STAT3 and NF-κB signaling pathways. Biomed Pharmacother. 109:2464–2471. 2019. View Article : Google Scholar : PubMed/NCBI
19	Xing L, Zhang X, Feng H, Liu S, Li D, Hasegawa T, Guo J and Li M: Silencing FOXO1 attenuates dexamethasone-induced apoptosis in osteoblastic MC3T3-E1 cells. Biochem Biophys Res Commun. 513:1019–1026. 2019. View Article : Google Scholar : PubMed/NCBI
20	Li S, Jiang H and Gu X: Echinacoside suppresses dexamethasone-induced growth inhibition and apoptosis in osteoblastic MC3T3-E1 cells. Exp Ther Med. 16:643–648. 2018.PubMed/NCBI
21	Han D, Gu X, Gao J, Wang Z, Liu G, Barkema HW and Han B: Chlorogenic acid promotes the Nrf2/HO-1 anti-oxidative pathway by activating p21 Waf1/Cip1 to resist dexamethasone-induced apoptosis in osteoblastic cells. Free Radic Biol Med. 137:1–12. 2019. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
23	Chen HT, Liu H, Mao MJ, Tan Y, Mo XQ, Meng XJ, Cao MT, Zhong CY, Liu Y, Shan H and Jiang GM: Crosstalk between autophagy and epithelial-mesenchymal transition and its application in cancer therapy. Mol Cancer. 18:1012019. View Article : Google Scholar : PubMed/NCBI
24	Li Z, Liu S, Fu T, Peng Y and Zhang J: Microtubule destabilization caused by silicate via HDAC6 activation contributes to autophagic dysfunction in bone mesenchymal stem cells. Stem Cell Res Ther. 10:3512019. View Article : Google Scholar : PubMed/NCBI
25	Wang Y, Shi ZY, Feng J and Cao JK: HDAC6 regulates dental mesenchymal stem cells and osteoclast differentiation. BMC Oral Health. 18:1902018. View Article : Google Scholar : PubMed/NCBI
26	Ota S, Zhou ZQ, Romero MP, Yang G and Hurlin PJ: HDAC6 deficiency or inhibition blocks FGFR3 accumulation and improves bone growth in a model of achondroplasia. Hum Mol Genet. 25:4227–4243. 2016. View Article : Google Scholar : PubMed/NCBI
27	Li L, Liu F, Huang W, Wang J, Wan YP, Li M, Pang YQ and Yin ZS: Ricolinostat (ACY-1215) inhibits VEGF expression via PI3K/AKT pathway and promotes apoptosis in osteoarthritic osteoblasts. Biomed Pharmacother. 118:1093572019. View Article : Google Scholar : PubMed/NCBI
28	Komori T: Regulation of skeletal development by the Runx family transcription factors. J Cell Biochem. 95:445–453. 2005. View Article : Google Scholar : PubMed/NCBI
29	Plotkin L, Manolagas S and Bellido T: Glucocorticoids induce osteocyte apoptosis by blocking focal adhesion kinase-mediated survival. Evidence for inside-out signaling leading to anoikis. J Biol Chem. 282:24120–24130. 2007. View Article : Google Scholar : PubMed/NCBI
30	Rauch A, Seitz S, Baschant U, Schilling AF, Illing A, Stride B, Kirilov M, Mandic V, Takacz A, schmidt-ullrich R, et al: Glucocorticoids suppress bone formation by attenuating osteoblast differentiation via the monomeric glucocorticoid receptor. Cell Metab. 11:517–531. 2010. View Article : Google Scholar : PubMed/NCBI
31	Kim HJ, Zhao H, Kitaura H, Bhattacharyya S, Brewer JA, Muglia LJ, Ross FP and Teitelbaum SL: Glucocorticoids suppress bone formation via the osteoclast. J Clin Invest. 116:2152–2160. 2006. View Article : Google Scholar : PubMed/NCBI
32	Li ZY, Li QZ, Chen L, Chen BD, Zhang C, Wang X and Li WP: HPOB, an HDAC6 inhibitor, attenuates corticosterone-induced injury in rat adrenal pheochromocytoma PC12 cells by inhibiting mitochondrial GR translocation and the intrinsic apoptosis pathway. Neurochem Int. 99:239–251. 2016. View Article : Google Scholar : PubMed/NCBI
33	Li RJ and Liu J: Pharmacogenetics advances of glucocorticoid resistance and polymorphism of glucocorticoid receptor. Chin J New Drugs. 24:1246–1254. 2015.
34	Vandevyver S, Dejager L and Libert C: On the trail of the glucocorticoid receptor: Into the nucleus and back. Traffic. 13:364–374. 2012. View Article : Google Scholar : PubMed/NCBI
35	Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, Yoshida M, Toft DO, Pratt WB and Yao TP: HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Mol Cell. 18:601–607. 2005. View Article : Google Scholar : PubMed/NCBI
36	Espallergues J, Teegarden SL, Veerakumar A, Boulden J, Challis C, Jochems J, Chan M, Petersen T, Deneris E, Matthias P, et al: HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience. J Neurosci. 32:4400–4416. 2012. View Article : Google Scholar : PubMed/NCBI