ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: SA-OR099

DMP1 Prevents Bone Alterations, FGF23 Elevations, and Cardiac Hypertrophy in Mice with CKD

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Dussold, Corey, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Gerber, Claire, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Neuburg, Samantha, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Francis, Connor, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Qi, Lixin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Liu, Ying, Texas A&M-Baylor College of Dentistry, Dallas, Texas, United States
  • Li, Chaoyuan, Texas A&M-Baylor College of Dentistry, Dallas, Texas, United States
  • Feng, Jian, Texas A&M-Baylor College of Dentistry, Dallas, Texas, United States
  • Wolf, Myles, Duke University, Durham, North Carolina, United States
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

Disordered bone and mineral metabolism is a common complication of CKD. Excessive secretion of the osteocyte-derived hormone fibroblast growth factor 23 (FGF23) during CKD progression is independently associated with increased risk of cardiovascular disease and mortality, perhaps by contributing to development of left ventricular hypertrophy (LVH). Dentin matrix protein 1 (DMP1), an extracellular matrix protein produced by osteocytes, is an established inhibitor of FGF23 production and a promoter of bone mineralization. We hypothesized that overexpression of DMP1 in CKD would improve bone health and prevent FGF23 elevations and consequent adverse cardiovascular outcomes in CKD.

Methods

We studied the Col4a3KO mouse, an established model of progressive CKD, which typically shows a shortened lifespan (21.4±0.6 weeks). We overexpressed DMP1 (DMP1Tg-3.6Kb ColIa1 promoter) in the bone of WT (DMP1Tg) and Col4a3KO (Col4a3KO/DMP1Tg) mice and we assessed renal function, serum FGF23 and phosphate (Pi) levels, bone and cardiac phenotype in 20 week-old mice, and overall survival.

Results

Col4a3KO mice showed impaired renal function (blood urea nitrogen: 94±18 vs 25±2 mg/dL), reduced bone mineral density (BMD: 1154±14 vs 1194±5 mg/cm3), altered osteocyte morphology and connectivity, an 8-fold increase in serum FGF23 levels, hyperphosphatemia (serum Pi: 9.2±0.6 vs 6.2±0.2 mg/dL), and LVH (LV Mass: 124±7 vs 101±4 mg) (p<0.05 vs WT for each). Overexpression of DMP1 in Col4a3KO/DMP1Tg did not improve renal function but corrected the reduction in BMD by 40% and fully prevented osteocyte alterations. Col4a3KO/DMP1Tg also showed lower FGF23 levels (631±124 vs 1161±196 pg/mL) resulting in higher serum phosphate levels (11.4±1.0 mg/dL) (p<0.05 vs Col4a3KO for each). As opposed to Col4a3KO, Col4a3KO/DMP1Tg mice did not have LVH (LV Mass: 93±5 mg; NS vs WT) and showed improved survival (24.2±0.9 weeks; p<0.05 vs Col4a3KO).

Conclusion

DMP1 prevented CKD-associated osteocyte alterations, FGF23 elevations and LVH, and improved survival, despite persistently impaired renal function and worsened hyperphosphatemia. This supports the contribution of FGF23 excess to cardiac injury in CKD and suggests that DMP1 represents a novel therapeutic approach to improve bone and cardiac outcomes in CKD.

Funding

  • NIDDK Support