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Abstract: TH-PO523

Effect of Reduction of Bone Advanced Glycation End Products (AGE) Accumulation on Bone Mechanical Properties in a Rat Model of CKD-Mineral Bone Disorder (CKD-MBD)

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Chen, Neal X., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Srinivasan, Shruthi, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Allen, Matthew R., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Nickolas, Tom, Columbia University Medical Center, New York, New York, United States
  • Wallace, Joseph M., Indiana University Purdue University Indianapolis, Indianapolis, Indiana, United States
  • Dominguez, James M., Indiana University School of Medicine, Indianapolis, Indiana, United States
  • O'Neill, Kalisha, Indiana University School of Medicine, Indianapolis, Indiana, United States
  • Avin, Keith G., Indiana University-Indianapolis, Indianapolis, Indiana, United States
  • Moe, Sharon M., Indiana University School of Medicine, Indianapolis, Indiana, United States
Background

Reduced bone quality is a key determinant of skeletal fragility in CKD. We have previously demonstrated that treatment with an AGE breaker ALT-711 decreased serum FGF23, reduced aorta expression of receptor for AGE (RAGE) and calcification in a rat model of CKD-MBD. We hypothesized that reduction in AGE accumulation and/or RAGE activation in bone will improve CKD-induced bone fragility.

Methods

Using a slowly progressive rat model of CKD, the Cy/+ rat, we compared four groups of animals [1: Normal (NL); 2: CKD; 3:CKD+ALT-711(3mg/kg); and 4: CKD+ 3% calcium in drinking water (Ca, lowering PTH and reducing bone remodeling). Treatment was started at 25 weeks of age (~50% kidney function) and ended at 35 weeks (~15% function). Bone AGE content was determined in demineralized femur shaft using fluorescence plate reader, normalized by collagen (hydroxyproline) content. Bone marrow (BM) were collected and RAGE expression determined by real time PCR. Bone geometry/architecture were determined with microCT. Bone mechanical properties were assessed by 4-point bending.

Results

There was increased AGE accumulation in bone and RAGE expression in BM in CKD rats vs. NL. Treatment with ALT-711 or calcium normalized both bone AGE levels and BM RAGE expression in CKD. MicroCT assessment of proximal tibial bone demonstrated lower trabecular bone volume fraction (BV/TV) in CKD rats. Calcium but not ALT-711 treatment increased trabecular BV/TV in CKD rats. CKD rats also had higher cortical porosity compared to NL and ALT-711 or calcium treatment each significantly reduced the cortical porosity in CKD rats. Bone mechanical analysis demonstrated that while several properties were lower in CKD rats, calcium, but not ALT-711 treatment, normalized these mechanical properties in CKD rats.

Conclusion

There is increased AGE accumulation in bone and RAGE expression in BM from CKD rats. Treatment with the AGE breaker ALT-711 early in the course of CKD decreased bone AGE levels and RAGE expression in BM in association with reduction in cortical porosity but without improvement of bone mechanics. Calcium treatment (which lowers PTH) showed similar bone efficacy to ALT-711 but increased serum levels of calcium and FGF23.

Funding

  • Other NIH Support