Signal transducer and activator of transcription 3 regulates CCAAT-enhancer-binding homologous protein expression in osteoblasts through upregulation of microRNA-205

Zhuang,Jian; Gao,Rufeng; Wu,Haihui; Wu,Xiao; Pan,Fugen

doi:10.3892/etm.2015.2464

Signal transducer and activator of transcription 3 regulates CCAAT-enhancer-binding homologous protein expression in osteoblasts through upregulation of microRNA-205

Authors:
- Jian Zhuang
- Rufeng Gao
- Haihui Wu
- Xiao Wu
- Fugen Pan
View Affiliations

Affiliations: Department of Orthopedics, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, P.R. China
Published online on: April 30, 2015 https://doi.org/10.3892/etm.2015.2464
Pages: 295-299

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

The transcription factor, CCAAT-enhancer-binding protein homologous protein (CHOP), is induced by endoplasmic reticulum-stress and mediates programmed cell death. In osteoblasts, CHOP overexpression increases the rate of apoptosis, leading to osteoblastic dysfunction. However, the regulatory mechanisms underlying CHOP expression remain unclear. In the present study, western blot analysis was used to demonstrate that the activation of signal transducer and activator of transcription 3 (STAT3) inhibited the levels of the CHOP protein, whereas small interfering RNA-mediated the knockdown of STAT3 upregulated CHOP expression. Furthermore, STAT3 was shown to increase the expression level of microRNA (miR)-205. A luciferase reporter assay revealed that miR-205 was able to directly target the 3'-untranslated region of the CHOP gene to inhibit its protein expression. The miR-205 antisense largely abolished the inhibitory effect of STAT3 activation on the levels of CHOP protein. Therefore, the results demonstrated a previously unknown STAT3/miR‑205/CHOP signaling pathway in osteoblasts, which may aid the understanding of the pathogenic mechanisms of associated diseases, including osteoporosis.

View Figures

View References

1	DiGirolamo DJ, Clemens TL and Kousteni S: The skeleton as an endocrine organ. Nat Rev Rheumatol. 8:674–683. 2012. View Article : Google Scholar : PubMed/NCBI
2	Ramji DP and Foka P: CCAAT/enhancer-binding proteins: structure, function and regulation. Biochem J. 365:561–575. 2002.PubMed/NCBI
3	Tabas I and Ron D: Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 13:184–190. 2011. View Article : Google Scholar : PubMed/NCBI
4	Malhi H and Kaufman RJ: Endoplasmic reticulum stress in liver disease. J Hepatol. 54:795–809. 2011. View Article : Google Scholar : PubMed/NCBI
5	Scull CM and Tabas I: Mechanisms of ER stress-induced apoptosis in atherosclerosis. Arterioscler Thromb Vasc Biol. 31:2792–2797. 2011. View Article : Google Scholar : PubMed/NCBI
6	Schönthal AH: Pharmacological targeting of endoplasmic reticulum stress signaling in cancer. Biochem Pharmacol. 85:653–666. 2013. View Article : Google Scholar : PubMed/NCBI
7	Eizirik DL, Miani M and Cardozo AK: Signalling danger: endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation. Diabetologia. 56:234–241. 2013. View Article : Google Scholar : PubMed/NCBI
8	Pereira RC, Stadmeyer LE, Smith DL, Rydziel S and Canalis E: CCAAT/Enhancer-binding protein homologous protein (CHOP) decreases bone formation and causes osteopenia. Bone. 40:619–626. 2007. View Article : Google Scholar : PubMed/NCBI
9	Liu W, Zhu X, Wang Q and Wang L: Hyperglycemia induces endoplasmic reticulum stress-dependent CHOP expression in osteoblasts. Exp Ther Med. 5:1289–1292. 2013.PubMed/NCBI
10	Taub R: Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol. 5:836–847. 2004. View Article : Google Scholar : PubMed/NCBI
11	Yu H, Pardol D and Jove R: STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 9:798–809. 2009. View Article : Google Scholar : PubMed/NCBI
12	Edgar CM, Chakravarthy V, Barnes G, et al: Autogenous regulation of a network of bone morphogenetic proteins (BMPs) mediates the osteogenic differentiation in murine marrow stromal cells. Bone. 40:1389–1398. 2007. View Article : Google Scholar : PubMed/NCBI
13	miRWalk, . The database on predicted and validated microRNA targets. http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/Accessed. March 20–2012
14	Lee H, Herrmann A, Deng JH, et al: Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell. 15:283–293. 2009. View Article : Google Scholar : PubMed/NCBI
15	Ameres SL and Zamore PD: Diversifying microRNA sequence and function. Nat Rev Mol Cell Biol. 14:475–488. 2013. View Article : Google Scholar : PubMed/NCBI
16	Sun K and Lai EC: Adult-specific functions of animal microRNAs. Nat Rev Genet. 14:535–548. 2013. View Article : Google Scholar : PubMed/NCBI
17	Nicolaidou V, Wong MM, Redpath AN, et al: Monocytes induce STAT3 activation in human mesenchymal stem cells to promote osteoblast formation. PLoS One. 7:e398712012. View Article : Google Scholar : PubMed/NCBI
18	Chen JR, Shankar K, Nagarajan S, Badger TM and Ronis MJ: Protective effects of estradiol on ethanol-induced bone loss involve inhibition of reactive oxygen species generation in osteoblasts and downstream activation of the extracellular signal-regulated kinase/signal transducer and activator of transcription 3/receptor activator of nuclear factor-kappaB ligand signaling cascade. J Pharmacol Exp Ther. 324:50–59. 2008. View Article : Google Scholar : PubMed/NCBI
19	Hagman Z, Haflidadóttir BS, et al: miR-205 negatively regulates the androgen receptor and is associated with adverse outcome of prostate cancer patients. Br J Cancer. 108:1668–1676. 2013. View Article : Google Scholar : PubMed/NCBI
20	Su N, Qiu H, Chen Y, Yang T, Yan Q and Wan X: miR-205 promotes tumor proliferation and invasion through targeting ESRRG in endometrial carcinoma. Oncol Rep. 29:2297–2302. 2013.PubMed/NCBI
21	Zhang Y, Xie RL, Croce CM, et al: A program of microRNAs controls osteogenic lineage progression by targeting transcription factor Runx2. Proc Natl Acad Sci USA. 108:9863–9868. 2011. View Article : Google Scholar : PubMed/NCBI
22	Timofeeva OA, Tarasova NI, Zhang X, et al: STAT3 suppresses transcription of proapoptotic genes in cancer cells with the involvement of its N-terminal domain. Proc Natl Acad Sci USA. 110:1267–1272. 2013. View Article : Google Scholar : PubMed/NCBI