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Abstract: PO0331

Reduced DMP1 Expression Precedes Bone Loss and FGF-23 Elevation in CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Lynch, Emily Patricia, Northwestern University, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University, Chicago, Illinois, United States
  • Feng, Jian, Texas A and M University, Dallas, Texas, United States
  • Nickolas, Tom, Columbia University Irving Medical Center, New York, New York, United States
  • David, Valentin, Northwestern University, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University, Chicago, Illinois, United States
Background

Chronic kidney disease (CKD) is associated with major disorders of bone and mineral metabolism, including renal osteodystrophy and increased secretion of the phosphaturic hormone FGF23 by bone, which is independently associated with cardiovascular mortality. Dentin matrix protein 1 (DMP1) is an extracellular matrix protein produced by osteocytes that stimulates osteoblast differentiation and inhibits FGF23 production. We previously showed that DMP1 supplementation prevents bone loss, FGF23 elevation and cardiovascular outcomes in mice with advanced CKD.

Methods

To determine if altered DMP1 expression contributes to the pathogenesis of renal osteodystrophy and FGF23 elevations during CKD progression, we measured bone DMP1 mRNA in wild-type (WT) and Col4a3KO mice with progressive CKD every 4 weeks from 4 weeks of age until their death (24 weeks). In parallel, we assessed kidney function, serum FGF23 levels and bone microarchitecture. We also assessed osteocyte morphology in mice and in patients with early CKD.

Results

Col4a3KO mice showed increased albumin to creatinine ratio (ACR) and blood urea nitrogen (BUN) levels starting respectively at 8 and 16 weeks, indicating onset of proteinuria and impaired kidney function. Consistent with BUN, FGF23 levels showed sustained increases starting at 16 weeks. This coincided with alterations in trabecular bone measured by 3D-microtomography of femurs from 16 to 24 week-old Col4a3KO mice. However, analysis of cortical (Ct) bone showed reductions in bone mineral density, Ct thickness and Ct area as early as 12 weeks of age, and alterations in osteocyte morphology as early as 10 weeks in Col4a3KO mice with early CKD and in patient with CKD stage 1-2. Bone DMP1 mRNA was reduced by 50% prior to the onset of proteinuria at 4 weeks of age and remained low at all time points throughout CKD progression; each p<0.05 vs. age-matched WT.

Conclusion

These data show that reduction in DMP1 expression occurs prior to major changes in kidney function and precedes altered osteocyte morphology, cortical bone loss, and FGF23 elevation in CKD. Although further studies are needed to identify the factors that suppress DMP1 expression in CKD, DMP1 administration might represent an effective therapeutic strategy to prevent alterations in bone and mineral metabolism in early CKD.

Funding

  • NIDDK Support