Lithium chloride attenuates the abnormal osteogenic/adipogenic differentiation of bone marrow-derived mesenchymal stem cells obtained from rats with steroid-related osteonecrosis by activating the β-catenin pathway

Yu,Zefeng; Fan,Lihong; Li,Jia; Ge,Zhaogang; Dang,Xiaoqian; Wang,Kunzheng

doi:10.3892/ijmm.2015.2340

Lithium chloride attenuates the abnormal osteogenic/adipogenic differentiation of bone marrow-derived mesenchymal stem cells obtained from rats with steroid-related osteonecrosis by activating the β-catenin pathway

Authors:
- Zefeng Yu
- Lihong Fan
- Jia Li
- Zhaogang Ge
- Xiaoqian Dang
- Kunzheng Wang
View Affiliations

Affiliations: Department of Orthopedics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
Published online on: September 8, 2015 https://doi.org/10.3892/ijmm.2015.2340
Pages: 1264-1272
Copyright: © Yu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Steroid-related osteonecrosis of the femoral head (ONFH) may be a disease that results from the abnormal osteogenic/adipogenic differentiation of bone marrow-derived mesenchymal stem cells (BMMSCs). In the present study, we examined the possible use of lithium in an aim to reverse the abnormal osteogenic/adipogenic differentiation of BMMSCs isolated from rats with steroid-related ONFH (termed ONFH-BMMSCs). BMMSCs obtained from steroid‑related ONFH rat femurs were cultured with or without lithium chloride (LiCl). BMMSCs obtained from normal rat femurs were cultured as controls. LiCl significantly increased the expression of osteocalcin and Runx2 in the ONFH-BMMSCs during osteogenic induction. The mineralization of ONFH-BMMSCs following osteogenic induction was also enhanced. Furthermore, LiCl exerted anti-adipogenic effects on the ONFH-BMMSCs by inhibiting the expression of peroxisome proliferator-activated receptor γ (PPARγ) and fatty acid binding protein 4 (Fabp4) during adipogenic induction, and decreasing lipid droplet formation at the end of adipogenic induction. These effects of LiCl on the ONFH-BMMSCs were associated with an increased expression of β-catenin and a decreased expression of phosphorylated GSK-3β at Tyr-216, and these effects were abolished by treatment with quercetin, an antagonist of the β-catenin pathway. The normal osteogenic/adipogenic activity of BMMSCs may be impaired in steroid-related ONFH. However, as demonstrated by our findings, LiCl reduces abnormal adipogenic activity and simultaneously increases the osteogenic differentiation of ONFH-BMMSCs by activating the β-catenin pathway.

View Figures

View References

1	Sun Z, Yang S, Ye S, Zhang Y, Xu W, Zhang B, Liu X, Mo F and Hua W: Aberrant CpG islands' hypermethylation of ABCB1 in mesenchymal stem cells of patients with steroid-associated osteonecrosis. J Rheumatol. 40:1913–1920. 2013. View Article : Google Scholar : PubMed/NCBI
2	Lieberman JR, Berry DJ, Mont MA, Aaron RK, Callaghan JJ, Rajadhyaksha AD and Urbaniak JR: Osteonecrosis of the hip: management in the 21st century. Instr Course Lect. 52:337–355. 2003.PubMed/NCBI
3	Webster RA, Blaber SP, Herbert BR, Wilkins MR and Vesey G: The role of mesenchymal stem cells in veterinary therapeutics - a review. N Z Vet J. 60:265–272. 2012. View Article : Google Scholar : PubMed/NCBI
4	Hernigou P and Beaujean F: Abnormalities in the bone marrow of the iliac crest in patients who have osteonecrosis secondary to corticosteroid therapy or alcohol abuse. J Bone Joint Surg Am. 79:1047–1053. 1997.PubMed/NCBI
5	Seamon J, Keller T, Saleh J and Cui Q: The pathogenesis of nontraumatic osteonecrosis. Arthritis (Egypt). 2012:6017632012.
6	Abdallah BM and Kassem M: New factors controlling the balance between osteoblastogenesis and adipogenesis. Bone. 50:540–545. 2012. View Article : Google Scholar
7	Sheng H, Sheng CJ, Cheng XY, Zhang G, Lee KM, Leung KS, Qu S and Qin L: Pathomorphological changes of bone marrow adipocytes in process of steroid-associated osteonecrosis. Int J Clin Exp Pathol. 6:1046–1050. 2013.PubMed/NCBI
8	Taipaleenmäki H, Abdallah BM, AlDahmash A, Säämänen AM and Kassem M: Wnt signalling mediates the cross-talk between bone marrow derived pre-adipocytic and pre-osteoblastic cell populations. Exp Cell Res. 317:745–756. 2011. View Article : Google Scholar : PubMed/NCBI
9	Franceschi RT and Xiao G: Regulation of the osteoblast-specific transcription factor, Runx2: responsiveness to multiple signal transduction pathways. J Cell Biochem. 88:446–454. 2003. View Article : Google Scholar : PubMed/NCBI
10	Liu C, Li Y, Semenov M, Han C, Baeg GH, Tan Y, Zhang Z, Lin X and He X: Control of beta-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell. 108:837–847. 2002. View Article : Google Scholar : PubMed/NCBI
11	Clevers H and Nusse R: Wnt/β-catenin signaling and disease. Cell. 149:1192–1205. 2012. View Article : Google Scholar : PubMed/NCBI
12	Young W: Review of lithium effects on brain and blood. Cell Transplant. 18:951–975. 2009. View Article : Google Scholar : PubMed/NCBI
13	Wexler EM, Geschwind DH and Palmer TD: Lithium regulates adult hippocampal progenitor development through canonical Wnt pathway activation. Mol Psychiatry. 13:285–292. 2008. View Article : Google Scholar
14	Galli C, Piemontese M, Lumetti S, Manfredi E, Macaluso GM and Passeri G: GSK3b-inhibitor lithium chloride enhances activation of Wnt canonical signaling and osteoblast differentiation on hydrophilic titanium surfaces. Clin Oral Implants Res. 24:921–927. 2013. View Article : Google Scholar
15	Itoigawa Y, Kishimoto KN, Sano H, Kaneko K and Itoi E: Molecular mechanism of fatty degeneration in rotator cuff muscle with tendon rupture. J Orthop Res. 29:861–866. 2011. View Article : Google Scholar : PubMed/NCBI
16	Sen B, Xie Z, Case N, Ma M, Rubin C and Rubin J: Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable beta-catenin signal. Endocrinology. 149:6065–6075. 2008. View Article : Google Scholar : PubMed/NCBI
17	Chen S, Li J, Peng H, Zhou J and Fang H: Administration of erythropoietin exerts protective effects against glucocorticoid-induced osteonecrosis of the femoral head in rats. Int J Mol Med. 33:840–848. 2014.PubMed/NCBI
18	Panepucci RA, Siufi JLC, Silva WA Jr, Proto-Siquiera R, Neder L, Orellana M, Rocha V, Covas DT and Zago MA: Comparison of gene expression of umbilical cord vein and bone marrow-derived mesenchymal stem cells. Stem Cells. 22:1263–1278. 2004. View Article : Google Scholar : PubMed/NCBI
19	Boku S, Nakagawa S, Masuda T, Nishikawa H, Kato A, Kitaichi Y, Inoue T and Koyama T: Glucocorticoids and lithium reciprocally regulate the proliferation of adult dentate gyrus-derived neural precursor cells through GSK-3beta and beta-catenin/TCF pathway. Neuropsychopharmacology. 34:805–815. 2009. View Article : Google Scholar
20	Park CH, Chang JY, Hahm ER, Park S, Kim HK and Yang CH: Quercetin, a potent inhibitor against beta-catenin/Tcf signaling in SW480 colon cancer cells. Biochem Biophys Res Commun. 328:227–234. 2005. View Article : Google Scholar : PubMed/NCBI
21	Cui Q, Wang GJ and Balian G: Pluripotential marrow cells produce adipocytes when transplanted into steroid-treated mice. Connect Tissue Res. 41:45–56. 2000. View Article : Google Scholar : PubMed/NCBI
22	Jope RS: Lithium and GSK-3: One inhibitor, two inhibitory actions, multiple outcomes. Trends Pharmacol Sci. 24:441–443. 2003. View Article : Google Scholar : PubMed/NCBI
23	Mai Y, Zhang Z, Yang H, Dong P, Chu G, Yang G and Sun S: BMP and activin membrane-bound inhibitor (BAMBI) inhibits the adipogenesis of porcine preadipocytes through Wnt/beta-catenin signaling pathway. Biochem Cell Biol. 92:172–182. 2014. View Article : Google Scholar : PubMed/NCBI
24	De Boer J, Wang HJ and Van Blitterswijk C: Effects of Wnt signaling on proliferation and differentiation of human mesenchymal stem cells. Tissue Eng. 10:393–401. 2004. View Article : Google Scholar : PubMed/NCBI
25	Gregory CA, Perry AS, Reyes E, Conley A, Gunn WG and Prockop DJ: Dkk-1-derived synthetic peptides and lithium chloride for the control and recovery of adult stem cells from bone marrow. J Biol Chem. 280:2309–2323. 2005. View Article : Google Scholar
26	Makita N, Suzuki M, Asami S, Takahata R, Kohzaki D, Kobayashi S, Hakamazuka T and Hozumi N: Two of four alternatively spliced isoforms of RUNX2 control osteocalcin gene expression in human osteoblast cells. Gene. 413:8–17. 2008. View Article : Google Scholar : PubMed/NCBI
27	Lin GT, Tseng HF, Chang CK, Chuang LY, Liu CS, Yang CH, Tu CJ, Wang EC, Tan HF, Chang CC, et al: SNP combinations in chromosome-wide genes are associated with bone mineral density in Taiwanese women. Chin J Physiol. 51:32–41. 2008.PubMed/NCBI
28	Mackay DL, Tesar PJ, Liang LN and Haynesworth SE: Characterizing medullary and human mesenchymal stem cell-derived adipocytes. J Cell Physiol. 207:722–728. 2006. View Article : Google Scholar : PubMed/NCBI
29	Wang XL, Wang N, Zheng LZ, Xie XH, Yao D, Liu MY, Yao ZH, Dai Y, Zhang G, Yao XS and Qin L: Phytoestrogenic molecule desmethylicaritin suppressed adipogenesis via Wnt/β-catenin 1signaling pathway. Eur J Pharmacol. 714:254–260. 2013. View Article : Google Scholar : PubMed/NCBI
30	Corrado A, Neve A, Macchiarola A, Gaudio A, Marucci A and Cantatore FP: RANKL/OPG ratio and DKK-1 expression in primary osteoblastic cultures from osteoarthritic and osteoporotic subjects. J Rheumatol. 40:684–694. 2013. View Article : Google Scholar : PubMed/NCBI
31	Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL and MacDougald OA: Inhibition of adipogenesis by Wnt signaling. Science. 289:950–953. 2000. View Article : Google Scholar : PubMed/NCBI
32	Liu J and Farmer SR: Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis. A glycogen synthase kinase 3beta phosphorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes. J Biol Chem. 279:45020–45027. 2004. View Article : Google Scholar : PubMed/NCBI
33	Bennett CN, Ross SE, Longo KA, Bajnok L, Hemati N, Johnson KW, Harrison SD and MacDougald OA: Regulation of Wnt signaling during adipogenesis. J Biol Chem. 277:30998–31004. 2002. View Article : Google Scholar : PubMed/NCBI
34	Hughes K, Nikolakaki E, Plyte SE, Totty NF and Woodgett JR: Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 12:803–808. 1993.PubMed/NCBI
35	Garza JC, Guo M, Zhang W and Lu XY: Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3β/β-catenin signaling. Mol Psychiatry. 17:790–808. 2012. View Article : Google Scholar :