Top

Published in:

01-05-2016 | Original Article

Lithium prevents rat steroid-related osteonecrosis of the femoral head by β-catenin activation

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

Published in: Endocrine | Issue 2/2016

Abstract

This study explored the use of lithium to prevent rat steroid-related osteonecrosis of the femoral head (ONFH) through the modulation of the β-catenin pathway. ONFH was induced by methylprednisolone combined with lipopolysaccharide, and serum lipids were analyzed. ONFH was detected by hematoxylin–eosin staining. Micro-CT-based angiography and bone scanning were performed to analyze vessels and bone structure, respectively. Immunohistochemical staining for peroxisome proliferator-activated receptor gamma (PPARγ), bone morphogenetic protein-2 (BMP-2), and vascular endothelial growth factor (VEGF) was analyzed. Protein levels of phospho-glycogen synthase kinase-3β at Tyr-216 (p-Tyr²¹⁶ GSK-3β), total glycogen synthase kinase-3β (GSK-3β) and β-catenin, as well as mRNA levels of GSK-3β and β-catenin in femoral heads, were assessed. The rate of empty bone lacunae in the femoral heads was lower in the lithium and control groups than in the model group. The lithium group showed preventive effects against steroid-related vessel loss by micro-CT-based angiography and VEGF staining. Lithium treatment improved hyperlipidemia and reduced PPARγ expression. Moreover, lithium improved steroid-related bone loss in micro-CT bone scans and BMP-2 staining analyses. Furthermore, local β-catenin was reduced in steroid-related ONFH, and lithium treatment increased β-catenin expression while reducing p-Tyr²¹⁶ GSK-3β levels. The local β-catenin pathway was inhibited during steroid-related ONFH. Lithium may enhance angiogenesis and stabilize osteogenic/adipogenic homeostasis during steroid-related ONFH in rats by activating the β-catenin pathway.

J. Gagala, M. Buraczynska, T. Mazurkiewicz, A. Ksiazek, Endothelial nitric oxide synthase gene intron 4 polymorphism in non-traumatic osteonecrosis of the femoral head. Int. Orthop. 37(7), 1381–1385 (2013). doi:10.1007/s00264-013-1892-7 CrossRefPubMedPubMedCentral

Y.J. Lee, J.S. Lee, E.H. Kang, Y.K. Lee, S.Y. Kim, Y.W. Song, K.H. Koo, Vascular endothelial growth factor polymorphisms in patients with steroid-induced femoral head osteonecrosis. J. Orthop. Res. 30(1), 21–27 (2012). doi:10.1002/jor.21492 CrossRefPubMed

R.S. Weinstein, Glucocorticoid-induced osteonecrosis. Endocrine 41(2), 183–190 (2012). doi:10.1007/s12020-011-9580-0 CrossRefPubMedPubMedCentral

J.S. Lee, L.S. Lee, H.L. Rob, C.H. Kim, J.S. Jung, K.T. Suh, Alterations in the differentiation ability of mesenchymal stem cells in patients with nontraumatic osteonecrosis of the femoral head: comparative analysis according to the risk factor. J. Orthop. Res. 24(4), 604–609 (2006). doi:10.1002/jor.20078 CrossRefPubMed

M.E. Nuttall, J.M. Gimble, Controlling the balance between osteoblastogenesis and adipogenesis and the consequent therapeutic implications. Curr. Opin. Pharmacol. 4(3), 199–201 (2004)CrossRef

E. Dejana, The role of wnt signaling in physiological and pathological angiogenesis. Circ. Res. 107(8), 943–952 (2010). doi:10.1161/circresaha.110.223750 CrossRefPubMed

E. Lammert, Developmental biology brain Wnts for blood vessels. Science 322(5905), 1195–1196 (2008). doi:10.1126/science.1167451 CrossRefPubMed

W. Young, Review of lithium effects on brain and blood. Cell Transplant. 18(9), 951–975 (2009). doi:10.3727/096368909x471251 CrossRefPubMed

C.M. Hedgepeth, L.J. Conrad, J. Zhang, H.C. Huang, V.M.Y. Lee, P.S. Klein, Activation of the wnt signaling pathway: a molecular mechanism for lithium action. Dev. Biol. 185(1), 82–91 (1997). doi:10.1006/dbio.1997.8552 CrossRefPubMed

10.

C. Galli, M. Piemontese, S. Lumetti, E. Manfredi, G.M. Macaluso, G. Passeri, GSK3b-inhibitor lithium chloride enhances activation of Wnt canonical signaling and osteoblast differentiation on hydrophilic titanium surfaces. Clin. Oral Implant Res. 24(8), 921–927 (2013). doi:10.1111/j.1600-0501.2012.02488.x CrossRef

11.

H.-X. Li, X. Luo, R.-X. Liu, Y.-J. Yang, G.-S. Yang, Roles of Wnt/beta-catenin signaling in adipogenic differentiation potential of adipose-derived mesenchymal stem cells. Mol. Cell. Endocrinol. 291(1–2), 116–124 (2008). doi:10.1016/j.mce.2008.05.005 CrossRefPubMed

12.

S. Guo, K. Arai, M.F. Stins, D.-M. Chuang, E.H. Lo, Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes. Stroke 40(2), 652–655 (2009). doi:10.1161/strokeaha.108.524504 CrossRefPubMedPubMedCentral

13.

S. Kaga, L.J. Zhan, E. Altaf, N. Maulik, Glycogen synthase kinase-3 beta/beta-catenin promotes angiogenic and anti-apoptotic signaling through the induction of VEGF, Bcl-2 and survivin expression in rat ischemic preconditioned myocardium. J. Mol. Cell. Cardiol. 40(1), 138–147 (2006). doi:10.1016/j.yjmcc.200509.009 CrossRefPubMed

14.

Y. Sun, Y. Feng, C. Zhang, The effect of bone marrow mononuclear cells on vascularization and bone regeneration in steroid-induced osteonecrosis of the femoral head. Joint Bone Spine 76(6), 685–690 (2009). doi:10.1016/j.jbspin.2009.04.002 CrossRefPubMed

15.

S.C. Low, G.I. Bain, D.M. Findlay, K. Eng, E. Perilli, External and internal bone micro-architecture in normal and Kienbock’s lunates: a whole-bone micro-computed tomography study. J. Orthop. Res. 32(6), 826–833 (2014). doi:10.1002/jor.22611 CrossRefPubMed

16.

T. Yamamoto, T. Irisa, Y. Sugioka, K. Sueishi, Effects of pulse methylprednisolone on bone and marrow tissues—corticosteroid-induced osteonecrosis in rabbits. Arthritis Rheum. 40(11), 2055–2064 (1997). doi:10.1002/art.1780401119 CrossRefPubMed

17.

C. Powell, C. Chang, M.E. Gershwin, Current concepts on the pathogenesis and natural history of steroid-induced osteonecrosis. Clin. Rev. Allergy Immunol. 41(1), 102–113 (2011). doi:10.1007/s12016-010-8217-z CrossRefPubMed

18.

H.S. Kim, S.C. Bae, T.H. Kim, S.Y. Kim, Endothelial nitric oxide synthase gene polymorphisms and the risk of osteonecrosis of the femoral head in systemic lupus erythematosus. Int. Orthop. 37(11), 2289–2296 (2013). doi:10.1007/s00264-013-1966-6 CrossRefPubMedPubMedCentral

19.

R. Takano-Murakami, K. Tokunaga, N. Kondo, T. Ito, H. Kitahara, M. Ito, N. Endo, Glucocorticoid inhibits bone regeneration after osteonecrosis of the femoral head in aged female rats. Tohoku J. Exp. Med. 217(1), 51–58 (2009)CrossRefPubMed

20.

L. Yin, Y.B. Li, Y.S. Wang, Dexamethasone-induced adipogenesis in primary marrow stromal cell cultures: mechanism of steroid-induced osteonecrosis. Chin. Med. J. 119(7), 581–588 (2006)PubMed

21.

S. Lee, W.K. Yang, J.H. Song, Y.M. Ra, J.-H. Jeong, W. Choe, I. Kang, S.-S. Kim, J. Ha, Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3. Biochem. Pharmacol. 85(7), 965–976 (2013). doi:10.1016/j.bcp.2012.12.023 CrossRefPubMed

22.

N.K. Satija, D. Sharma, F. Afrin, R.P. Tripathi, G. Gangenahalli, High throughput transcriptome profiling of lithium stimulated human mesenchymal stem cells reveals priming towards osteoblastic lineage. Plos One 8(1), e55769 (2013). doi:10.1371/journal.pone.0055769 CrossRefPubMedPubMedCentral

23.

K. Hughes, E. Nikolakaki, S.E. Plyte, N.F. Totty, J.R. Woodgett, Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 12(2), 803–808 (1993)PubMedPubMedCentral

24.

J.C. Garza, M. Guo, W. Zhang, X.Y. Lu, Leptin restores adult hippocampal neurogenesis in a chronic unpredictable stress model of depression and reverses glucocorticoid-induced inhibition of GSK-3 beta/beta-catenin signaling. Mol. Psychiatry 17(8), 790–808 (2012). doi:10.1038/mp.2011.161 CrossRefPubMedPubMedCentral

25.

S. Okazaki, Y. Nishitani, S. Nagoya, M. Kaya, T. Yamashita, H. Matsumoto, Femoral head osteonecrosis can be caused by disruption of the systemic immune response via the toll-like receptor 4 signalling pathway. Rheumatology 48(3), 227–232 (2009). doi:10.1093/rheumatology/ken462 CrossRefPubMed

26.

X.B. Zhang, J.P. Gaspard, D.C. Chung, Regulation of vascular endothelial growth factor by the Wnt and K-ras pathways in colonic neoplasia. Cancer Res. 61(16), 6050–6054 (2001)PubMed

27.

V. Easwaran, S.H. Lee, L. Inge, L. Guo, C. Goldbeck, E. Garrett, M. Wiesmann, P.A. Garcia, J.H. Fuller, V. Chan, F. Randazzo, R. Gundel, R.S. Warren, J. Escobedo, S.L. Aukerman, R.N. Taylor, W.J. Fantl, Beta-catenin regulates vascular endothelial growth factor expression in colon cancer. Cancer Res. 63(12), 3145–3153 (2003)PubMed

28.

M. Thirunavukkarasu, Z. Han, L. Zhan, S.V. Penumathsa, V.P. Menon, N. Maulik, Adeno-sh-beta-catenin abolishes ischemic preconditioning-mediated cardioprotection by downregulation of its target genes VEGF, Bcl-2, and survivin in ischemic rat myocardium. Antioxid. Redox Signal. 10(8), 1475–1484 (2008). doi:10.1089/ars.2008.2042 CrossRefPubMedPubMedCentral

29.

T.-H. Kim, J.M. Hong, F.K. Park, S.-Y. Kim, Peroxosome proliferator-activated receptor-gamma gene polymorphisms are not associated with ostenecrosis of the femoral head on the Korean population. Mol. Cells 24(3), 388–393 (2007)PubMed

30.

J. Watt, J.J. Schlezinger, Structurally-diverse, PPARgamma-activating environmental toxicants induce adipogenesis and suppress osteogenesis in bone marrow mesenchymal stromal cells. Toxicology 331, 66–77 (2015). doi:10.1016/j.tox.2015.03.006 CrossRefPubMed

31.

T.K. Sampath, J.E. Coughlin, R.M. Whetstone, D. Banach, C. Corbett, R.J. Ridge, E. Ozkaynak, H. Oppermann, D.C. Rueger, Bovine osteogenic protein is composed of dimers of OP-1 and BMP-2A, 2 members of the transforming growth-factor-beta superfamily. J. Biol. Chem. 265(22), 13198–13205 (1990)PubMed

32.

S.E. Ross, N. Hemati, K.A. Longo, C.N. Bennett, P.C. Lucas, R.L. Erickson, O.A. MacDougald, Inhibition of adipogenesis by Wnt signaling. Science 289(5481), 950–953 (2000). doi:10.1126/science.289.5481.950 CrossRefPubMed

33.

J.J. Liu, S.R. Farmer, Regulating the balance between peroxisome proliferator-activated receptor gamma and beta-catenin signaling during adipogenesis—a glycogen synthase kinase 3 beta phosphorylation-defective mutant of beta-catenin inhibits expression of a subset of adipogenic genes. J. Biol. Chem. 279(43), 45020–45027 (2004). doi:10.1074/jbc.M407050200 CrossRefPubMed

34.

C.N. Bennett, S.E. Ross, K.A. Longo, L. Bajnok, N. Hemati, K.W. Johnson, S.D. Harrison, O.A. MacDougald, Regulation of Wnt signaling during adipogenesis. J. Biol. Chem. 277(34), 30998–31004 (2002). doi:10.1074/jbc.M204527200 CrossRefPubMed

35.

E.E. Beier, T.J. Sheu, T. Buckley, K. Yukata, R. O’Keefe, M.J. Zuscik, J.E. Puzas, Inhibition of beta-catenin signaling by Pb leads to incomplete fracture healing. J. Orthop. Res. 32(11), 1397–1405 (2014). doi:10.1002/jor.22677 CrossRefPubMedPubMedCentral

Title: Lithium prevents rat steroid-related osteonecrosis of the femoral head by β-catenin activation
Authors: Zefeng Yu
Lihong Fan
Jia Li
Zhaogang Ge
Xiaoqian Dang
Kunzheng Wang
Publication date: 01-05-2016
Publisher: Springer US
Published in: Endocrine / Issue 2/2016
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-015-0747-y

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Lithium prevents rat steroid-related osteonecrosis of the femoral head by β-catenin activation

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2016

Effect of reducing iodine excess on children’s goiter prevalence in areas with high iodine in drinking water

The role of ANGPTL3 in controlling lipoprotein metabolism

Reducing glucose variability with continuous subcutaneous insulin infusion increases endothelial progenitor cells in type 1 diabetes: an observational study

Caffeine and saliva steroids in young healthy recreationally trained women: impact of regular caffeine intake

Investigation of common and rare genetic variation in the BAMBI genomic region in light of human obesity

Preclinical testing of selective Aurora kinase inhibitors on a medullary thyroid carcinoma-derived cell line

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page