Abstract
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)2D3 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.
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