Effects of FGF-21 on Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells in High Glucose Environment

LI Xi, CHEN Cheng, AN Zhen-mei. et al

Abstract

To determine the effect of fibroblast growth factor-21（FGF-21）on the osteogenic differention of human bone mesenchymal stem cells (hBMSCs) exposed to a hyperglycemia condition in vitro. Methods hBMSCs were isolated from adult bone marrows, and identified by Alizarin red and oil red O staining. The expressions of immunophenotype were analysed using flow cytometry (CD105, CD90, CD73, CD44).HBMSCs were divided into control group 〔glucose (Glu) concentration of 5.5 mmol/L〕, Glu A, B, C groups (Glu 16.5, 25, 40 mmol/L), FGF-21 group (Glu 5.5mmol/ L+ FGF-21 ),Glu B+ FGF-21 group, and Glu B +FGF-21+cell mitogen activated protein kinase (MAPK) blocker (PD98059, SP600125 ,and SB203580) groups. The effect of FGF-21 on the differentiation of hBMSCs was detected using indicators as follows: alkaline phosphatase （ALP） on day 14, mRNA expressions ofALP, osteocalcin（OCN）and Runx2, protein expressions and phosphorylation of extracellular signal regulated kinase （ERK）, mitogen-activated protein kinase（P38） and c-Jun N-terminal kinases（JNK） on day 21. Results ①hBMSCs differentiated into osteoblast cells and lipocyte. The hBMSCs were identified by flow cytometry. ②Compared with control group, significant increases of ALP mRNA, OCN mRNA and Runx2mRNA levels, as well as phosphorylation of ERK, P38 and JNK were observed in Glu A, B, C groups. ③Compared with Glu B group, ALP, OCN and Runx2 mRNA levels, and phosphorylation of ERK, P38 and JNK were decreased in Glu B+FGF-21 group . ④Compared with Glu B+FGF-21 group, ALP and Runx2 mRNA levels, and phosphorylation of ERK, JNK and P38 were decreased in Glu B +FGF-21 +MAPK blocker groups. Conclusion High glucose could promote the biomineralization of hBMSCs. FGF-21 in high glucose environment could inhibit the osteogenic differentiation of hBMSCs.

 

Keywords: FGF-21, Human bone mesenchymal stem cells, Osteogenic differentiation, High glucose, MAPK signaling 

 

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References


STROTMEYER ES, CAULEY JA. Diabetes mellitus, bone mineral density, and fracture risk. Curr Opin Endocrinol Diabetes Obes, 2007,14(6);429-435.

KABACK LA, SOUNG ГХ) Y. NAIK A, elal. Osterix/Sp7 regulates mesenchymal stem cell mediated endochondral ossification. J Cell Physiol,2008,214(1) : 173-182.

KAMIMURA N, NISHIMAKI K. OHSAWA I, et al. Molecular hydrogen improves obesity and diabetes by inducing hepatic FGF21 and stimulating energy metabolism in db/db mice. Obesity,2011,19(7) ; 1396-1403.

FLIER JS. Hormone resistance in diabetes and obesity: insulin, leptin, and FGF21. Yale J Biol Med, 2012, 85 ( 3): 405-414.

WEI W, DUTCHAK PA, WANG X, et al. Fibroblast growth factor 21 promotes bone loss by potentiating the effects of peroxisome proliferator-activated receptor y. Proc Natl Acad Sci,2012.109(8) ;3143-3148.

PITTENGER MF, MACKAY AM, BECK SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999,284(5411): 143-147.

KARNER E. UNGER C, CERNY R. et al. Differentiation of human embryonic stem cells into osteogenic or hematopoietic lineages; a dose-dependent effect of osterix over-expression. J Cell Physiol.2009.218(2) ;323-333.

JI Z, CHENG Y. YUAN P. et al. Panax notoginseng stimulates alkaline phosphatase activity, collagen synthesis, and mineralization in osteoblastic MC3T3-E1 cells. In Vitro Cell Dev Biol Anim,2015,51(9): 1-8.

WU J, XU S, QIU Z, et al. Comparison of human mesenchymal stem cells proliferation and differentiation on poly (methyl methacrylate) bone cements with and without mineralized collagen incorporation. J Biomater Appl,2016,30 (6):722-731.

LI YM. SCHILLING T, BENISCH P, et al. Effects of high glucose on mesenchymal stem cell proliferation and differentiation. Biochem Biophys Res Commun. 2007. 363 (1):209-215.

KHARITONENKOV A, WROBLEWSKI VJ, KOESTER A. et al. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology ,2007,148(2): 774-781.

DICEMBRINI I, MANNUCCI E. ROTELLA CM. Bone: incretin hormones perceiver or receiver? Exp Diabetes Res, 2012(2012): 519784 [2015-12-02]. http://www. ncbi. nlm. nih.gov/pubmed/22761607.doi: 10. 1155/2012/519784.

KIM HK. KIM MG, LEEM KH. Osteogenic activity of collagen peptide via ERK/MAPK pathway mediated boosting of collagen synthesis and its therapeutic efficacy in osteoporotic bone by back-scattered electron imaging and microarchitecture analysis. Molecules, 2013, 18( 12): 15474- 15489.

PLOTNIKOV A, ZEHORAI E, PROCACCIA S, et al. The МАРК cascades; signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta, 2011,1813(9):1619-1633.

LIANG X, SO YH, CUI J, et al. The low-dose ionizing radiation stimulates cell proliferation via activation of the MAPK/ERK pathway in rat cultured mesenchymal stem cells. J Radiat Res,2011 ,52(3) ;380-386.

FU L. TANG T, MIAO Y, et al. Stimulation of osteogenic differentiation and inhibition of adipogenic differentiation in bone marrow stromal cells by alendronate via ERK and JNK activation. Bone.2008.43(1):40-47.

YI C. LIU D. FONG CC. etal. Gold nanoparticles promote osteogenic differentiation of mesenchymal stem cells through p38 МАРК pathway. Acs Nano,2010,4( 11); 6439-6448.

GAUNDAR SS, BRADSTOCK KF, BENDALL LJ. p38MAPK inhibitors attenuate cytokine production by bone marrow stromal cells and reduce stroma-mediated proliferation of acute lymphoblastic leukemia cells. Cell Cycle,2009,8( 18) :2977-2985.

ARAFAT A, KACZMAREK P. SKRZYPSKI M, et al. Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon-stimulated lipolysis? Diabetologia, 2013,56(3):588-597.

JIN P. ZHANG X, WU Y, et al. Streptozotocin-induced diabetic rat-derived bone marrow mesenchymal stem cells have impaired abilities in proliferation, paracrine, antiapoptosis, and myogenic differentiation. Transplant Proc,2010,42(7):2745-2752.

GORMAN E, CHUDYK AM, MADDEN KM, et al. Bone health and type 2 diabetes mellitus: a systematic review. Physiotherapy Canada,2011 ,63(1) :8-20.

XIAJ, ZHONG Y, HUANG G, et al. The relationship between insulin resistance and osteoporosis in elderly male type 2 diabetes mellitus and diabetic nephropathy. Ann Endocrinol (Paris) ,2012,73(6);546-551.


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