Advanced glycation end products suppress lysyl oxidase and induce bone collagen degradation in a rat model of renal osteodystrophy

被引:29
作者
Aoki, Chiharu [1 ,2 ]
Uto, Kenta [1 ]
Honda, Kazuho [1 ]
Kato, Yoshiharu [2 ]
Oda, Hideaki [1 ]
机构
[1] Tokyo Womens Med Univ, Dept Pathol, Tokyo 1628666, Japan
[2] Tokyo Womens Med Univ, Dept Orthoped, Tokyo 1628666, Japan
关键词
advanced glycation end products; bone collagen; lysyl oxidase; mineralization; osteoblast; renal osteodystrophy; CHRONIC KIDNEY-DISEASE; HIP FRACTURE; CORTICAL BONE; GROWTH-FACTOR; CROSS-LINKS; SECONDARY HYPERPARATHYROIDISM; OSTEOBLASTIC DIFFERENTIATION; TRABECULAR BONE; INCREASED RISK; FAILURE RATS;
D O I
10.1038/labinvest.2013.105
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Renal osteodystrophy (ROD) is a major problem in patients with renal insufficiency. The present study was designed to elucidate the role of bone collagen changes and osteoblast differentiation in a rat model of ROD pathogenesis induced by adenine. Typical characteristics of renal failure, including increased serum urea nitrogen, creatinine, inorganic phosphorus, and intact parathyroid hormone levels, and decreased serum calcium and 1,25(OH)(2)D-3 levels, were observed in adenine-induced rats. Micro-computed tomography analysis of the femur in adenine-induced rats showed decreased bone mineral density and osteoporotic changes, confirmed by the three-point bending test. The cancellous bone histomorphometric parameters of the tibia showed increased osteoblast number, decreased osteoclast surface with peritrabecular fibrosis, and increased osteoid tissue, indicating a severe mineralization disorder similar to clinical ROD. Scanning and transmission electron microscopy revealed irregular alignment and increased diameter of bone collagen fibrils in adenine-induced rats. Protein expression analysis showed greater accumulation of advanced glycation end products (AGEs) in peritrabecular osteoblasts of adenine-induced rats than in the controls. In contrast, suppressed expression of runt-related transcription factor 2, alkaline phosphatase, secreted phosphoprotein 1 (Spp1), and lysyl oxidase (Lox) mRNA levels, particularly the amount of active LOX protein, were observed. In in-vitro experiments, mineralizing MC3T3-E1 osteoblastic cells stimulated with AGE-modified bovine serum albumin had attenuated the expression of Spp1 mRNA levels and active LOX protein, with a decrease in extracellular nodules of mineralization. These observations provide clues to ROD pathogenesis, as they indicate that the suppression of osteoblast differentiation and decreased active LOX protein associated with accumulation of AGEs in osteoblasts caused structural abnormalities of bone collagen fibrils and a severe mineralization disorder, leading to bone fragility.
引用
收藏
页码:1170 / 1183
页数:14
相关论文
共 82 条
[1]   Increased risk of hip fracture among patients with end-stage renal disease [J].
Alem, AM ;
Sherrard, DJ ;
Gillen, DL ;
Weiss, NS ;
Beresford, SA ;
Heckbert, SR ;
Wong, C ;
Stehman-Breen, C .
KIDNEY INTERNATIONAL, 2000, 58 (01) :396-399
[2]   3-DIMENSIONAL ANALYSIS OF THE SPINE IN AUTOPSY CASES WITH RENAL OSTEODYSTROPHY [J].
AMLING, M ;
GROTE, HJ ;
VOGEL, M ;
HAHN, M ;
DELLING, G .
KIDNEY INTERNATIONAL, 1994, 46 (03) :733-743
[3]   Lysyl Oxidase Binds Transforming Growth Factor-β and Regulates Its Signaling via Amine Oxidase Activity [J].
Atsawasuwan, Phimon ;
Mochida, Yoshiyuki ;
Katafuchi, Michitsuna ;
Kaku, Masaru ;
Fong, Keith S. K. ;
Csiszar, Katalin ;
Yamauchi, Mitsuo .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (49) :34229-34240
[4]   Proteasomal degradation of Runx2 shortens parathyroid hormone-induced anti-apoptotic signaling in osteoblasts - A putative explanation for why intermittent administration is needed for bone anabolism [J].
Bellido, T ;
Ali, AA ;
Plotkin, LI ;
Fu, Q ;
Gubrij, I ;
Roberson, PK ;
Weinstein, RS ;
O'Brien, CA ;
Manolagas, SC ;
Jilka, RL .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (50) :50259-50272
[5]   CORNEAL AND SCLERAL COLLAGEN FIBER FORMATION INVITRO [J].
BIRK, DE ;
LANDE, MA .
BIOCHIMICA ET BIOPHYSICA ACTA, 1981, 670 (03) :362-369
[6]   REGULATION OF LYSYL OXIDASE EXPRESSION IN LUNG FIBROBLASTS BY TRANSFORMING GROWTH FACTOR-BETA(1) AND PROSTAGLANDIN E(2) [J].
BOAK, AM ;
ROY, R ;
BERK, J ;
TAYLOR, L ;
POLGAR, P ;
GOLDSTEIN, RH ;
KAGAN, HM .
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 1994, 11 (06) :751-755
[7]   BONE CHANGES IN HEMODIALYZED UREMIC SUBJECTS - COMPARATIVE LIGHT AND ELECTRON-MICROSCOPE INVESTIGATIONS [J].
BONUCCI, E ;
GHERARDI, G ;
FARAGGIANA, T ;
MIONI, G ;
CANNELLA, G ;
CASTELLANI, A ;
MAIORCA, R .
VIRCHOWS ARCHIV A-PATHOLOGICAL ANATOMY AND HISTOPATHOLOGY, 1976, 371 (03) :183-198
[8]   Long-term treatment with lanthanum carbonate reduces mineral and bone abnormalities in rats with chronic renal failure [J].
Damment, Stephen ;
Secker, Roger ;
Shen, Victor ;
Lorenzo, Victor ;
Rodriguez, Mariano .
NEPHROLOGY DIALYSIS TRANSPLANTATION, 2011, 26 (06) :1803-1812
[9]   PTH and the risks for hip, vertebral, and pelvic fractures among patients on dialysis [J].
Danese, MD ;
Kim, J ;
Doan, QV ;
Dylan, M ;
Griffiths, R ;
Chertow, GM .
AMERICAN JOURNAL OF KIDNEY DISEASES, 2006, 47 (01) :149-156
[10]   Renal function and risk of hip and vertebral fractures in older women [J].
Ensrud, Kristine E. ;
Lui, Li-Ying ;
Taylor, Brent C. ;
Ishani, Areef ;
Shlipak, Michael G. ;
Stone, Katie L. ;
Cauley, Jane A. ;
Jamal, Sophie A. ;
Antoniucci, Diana M. ;
Cummings, Steven R. .
ARCHIVES OF INTERNAL MEDICINE, 2007, 167 (02) :133-139