Vie wing Safety of Rare2Earth2Based Drugs from Effect of Rare Earth on Bone Metabolism

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1 PROGRESS IN CHEMISTRY Vol. 21 No. 5 May, , ,3 1,3 4 ( ; ; ; ),,, ;,,,,,, : (1) ; (2) ; (3), : R914 : A : X(2009) Vie wing Safety of Rare2Earth2Based Drugs from Effect of Rare Earth on Bone Metabolism Zhang Jinchao 1,3 3 3 Wang Peng 2 Sun Jing 2 Liu Cuilian 1,3 Chen Hua 1,3 Huang Jian 4 (1. Chemical Biology Laboratory, College of Chemistry & Enviromental Science, Hebei University, Baoding , China ; 2. Affiliated Hospital of Hebei University, Baoding , China ; 3. Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of Ministry of Education, Hebei University, Baoding , China ; 4. Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing , China) Abstract Some essential trace elements were reported to be involved in the normal bone metabolism. Nowadays rare earth elements are widely used in many fields and more and more rare earth elements enter the environment and food chains. They are enriched in bone and difficult to be excreted. Because the similarity between rare earth ions (Ln 3 + ) and Ca 2 +, they will intervene and regulate bone formation and remodeling. On one hand, rare earth are presumed to be drug candidates for bone disease ; on the other hand, they have negative effects on bone metabolism. So the safety of rare2earth2based drugs deserves an answer. We review the effect of rare earth ions on bone metabolism as the following three aspects : (1) effect of rare earth ions on differentiation and function expression of osteoblasts and osteoclasts ; (2) effect of rare earth ions on the osteogenic and adipogenic differentiation of bone marrow stromal cells ; (3) effect of rare earth ions on bone mineral phase of animals. In addition, the scarcities and future developing perspectives in this field are also discussed. Key words rare earth ions ; bone metabolism ; osteoblasts ; osteoclasts ; bone marrow stromal cells : ( ) 3 (No , ) (No. B ) 3 3 e2mail com. cn

2 Contents 1 Introduction 2 Effect of rare earth ions on differentiation and function expression of osteoblasts and osteoclasts 2. 1 Effect of rare earth ions on differentiation and function expression of osteoblasts 2. 2 Effect of rare earth ions on differentiation and function expression of osteoclasts 2. 3 Effect of rare earth ions on bone resorption function of osteoclasts regulated by osteoblasts 3 Effect of rare earth ions on osteogenic and adipogenic differentiation of bone marrow stromal cells 4 Effect of rare earth ions on bone mineral phase of animals 5 Conclusion 1,,,, [1 ],,, [2 ] Moonga [3 ], Leek [1 ],,, X,, D 3,,,,,,,, 20 40,,, :,,, DNA, [4 ],,,,,, ( ) [5,6 ],,, :, ;, [8 ] 2, ;, ;,, (osteoblast, OB) (osteoclast, OC), ; ( ),,,,Paget,,,, [9, 10 ] 2. 1

3 , Quarles [11 ] MC3T32E1 DNA, G, Hartle [12 ] (PGE) (camp), (PTH) camp [13 ] (UMR106), (MTT) (ALP) Ln 3 + (La 3 +,Sm 3 +,Dy 3 +, Nd 3 +,Er 3 + Gd 3 + ) UMR106, UMR106, molπl, UMR106,,La 3 +,Sm 3 +,Dy 3 +,Nd 3 +, Er 3 + Gd %,4109 %,18130 %,19139 %,22102 % % molπl,,la 3 +,, molπl, %, Sm 3 +,Dy 3 +,Nd 3 +,Er 3 + Gd 3 + ( Sm 3 +, Dy 3 + Nd molπl, Er 3 + Gd molπl ) ( 1) La 3 +, Sm 3 +, Dy 3 +, Nd 3 +, Er 3 + Gd UMR106 [13 ] Fig. 1 The effect of rare earth ions on proliferation of osteoblast UMR106 [13 ] 10-7 molπl, ( P < 0101), 10-7 molπl molπl 10-7 molπl, :La 3 + > Sm 3 + > Dy 3 + > Er 3 + > Gd 3 + > Nd 3 + ; molπl, : La 3 + > Dy 3 + > Nd 3 + > Er 3 + > Sm 3 +, Gd 3 + ( 2) La (UMR106) [13 ] Fig. 2 The effect of rare earth ions on ALP activity of osteoblast UMR106 [13 ] G 0 ΠG 1 S, DNA, DNA, ( molπl) La 3 +,,,,, ; ( molπl) La 3 + [14 ], La 3 + Gd 3 + ( molπl), molπl La 3 + Gd 3 +, molπl La molπl Gd 3 +, 27 % 17 % molπl, La 3 + Gd 3 + La 3 +, molπl Gd 3 +,

4 Gd [15 ], Ln 3 + (La 3 +, Sm 3 +,Dy 3 +,,, Nd 3 +,Er 3 + Gd 3 + ), ( 3 4),,6 [18 ], :La 3 + Fluo232AM, La , ( n = 10) [15 ] Fig. 3 The effect of rare earth ions on the surface area of lacunae produced by osteoclasts cultured on bone slices for 3 days( n = 10) [15 ] Sm 3 + Er Nd 3 + Gd 3 + Dy 3 +, La 3 + Sm 3 + Er molπl,, ; Nd 3 + Gd 3 + Dy molπl,, 10-7 molπl,, La 3 + Sm 3 + Er molπl Nd 3 + Gd 3 + Dy 3 + ; 10-7 molπl Nd 3 + Gd 3 + Dy 3 +, 10-6 molπl,6, Gd 3 +,,,,, [16 ] Shankar [17 ], mmolΠL,La 3 +, La 3 + ( 5 6),, molπl La 3 +,,,,La 3 + ; La , ( n = 10) [15 ] Fig. 4 The effect of rare earth ions on the surface area of lacunae produced by osteoclasts cultured on bone slices for 7 days( n = 10) [15 ] molπl,, La 3 +,,,,

5 La 3 + [18 ] Fig. 5 The effect of La 3 + on [ Ca 2 + ] i of rabbit mature osteoclasts [18 ] 7 La 3 + 1,252 D3 (, 3 P < 01001, n = 10) [20 ] Fig. 7 The effect of La 3 + on the surface area of lacunae produced by rabbit osteoclast2like cells induced by 1, 252 dihydroxyvitamin D3 from rabbit bone marrow cells ( compared with the control group, 3 P < 01001, n = 10) [20 ] 6 La 3 + [18 ] Fig. 6 Effect of La 3 + area [18 ] on rabbit mature osteoclast spread David [19 ], [20 ], La 3 + ( 7), : (1)La 3 + : molπl La 3 + ( P > 0105), molπl, ( P < 01001) ; (2) molπl La 3 + ( P < 01001), molπl, ( P < 01001) ; (3) La , 2 Π,,, [21 ], [22 ], [23 ], La 3 + ( 8),,,La 3 + :La 3 + ( molπl), molπl, ( P < 0101), La 3 + ( P > 0105) ;, La 3 +

6 , La 3 + [23 ] (a) 3d ; (b) 7d La 3 + ; La OC; La OC2OB ( ) ; La OC2OB ( ) ( n = 4) Fig. 8 Effects of La 3 + osteoclasts in presence of osteoblasts [23 ] on pit numbers of rabbit mature (a) 3d ; (b) 7d. In the absence of La 3 + and OB ; La OC; La OC2OB ( contact) ; La OC2OB (out of contact) ( n = 4),,,,, ( P < 0101),,,,, ( P > 0105), ( ), La 3 +,, : La 3 +,,,,, Π, La (TNF2 ) 26 ( IL26),, [29, 31 ],,,, 3 (MSCs), [24 ],,, [25 ],,, ;,,,,, [26 ],, [27 ] Benayahu [28 ]

7 ,Nuttal [32 ], ; 2002, [33 ] :, ;,, 2, [34 ] La 3 +,, La Dy 3 + ( n = 6,, 3 P < 0. 05) [35 ] Fig. 11 Effect of Dy 3 + on the adipogenic differentiation of BMSCs ( n = 6, 3 P < 0105, significant compared to control group) [35 ] 9 Dy 3 + ( n = 6,, 3 3 P < 0. 05, 3 P < 0101) [35 ] Fig. 9 Effect of Dy 3 + on the osteogenic differentiation of BMSCs ( n = 6, 3 P < 0105, compared to control group) [35 ] 3 3 P < 0101, significant 12 Dy 3 + (10 ) ( n = 6,, 3 P < 0105) [35 ] Fig. 12 Effect of Dy 3 + on the adipocytic trans2differentiation of OBs for 10 days ( n = 6, 3 P < 0105, significant compared to control group) [35 ] 10 Dy 3 + ( n = 6,, 3 3 P < 0. 05, 3 P < 0101) [35 ] Fig. 10 Effect of Dy 3 + on the mineralized nodule formation of BMSCs ( n = 6, 3 P < 0105, 3 3 P < 0101, significant compared to control group) [35 ] MSCs, ALP, mrna ;, La 3 + MSCs, La 3 + mrna, ALP, Western Blot La 3 + MSCs (MAPK), MAPK PD98059 La 3 + MSCs ALP, La 3 + MSCs La 3 + MAPK

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