Kidney Week

Abstract: SA-OR099

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

Session Information

• Vascular Calcification, FGF-23, and Phosphate
  October 27, 2018 | Location: 33C, San Diego Convention Center
  Abstract Time: 04:42 PM - 04:54 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Dussold, Corey, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Corey Dussold, MS

• Gerber, Claire, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Claire Gerber,

• Neuburg, Samantha, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Samantha Neuburg,

• Wang, Xueyan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Xueyan Wang,

• Francis, Connor, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Connor Francis,

• Qi, Lixin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Lixin Qi,

• Liu, Ying, Texas A&M-Baylor College of Dentistry, Dallas, Texas, United States

Ying Liu,

• Li, Chaoyuan, Texas A&M-Baylor College of Dentistry, Dallas, Texas, United States

Chaoyuan Li,

• Feng, Jian, Texas A&M-Baylor College of Dentistry, Dallas, Texas, United States

Jian Feng,

• Wolf, Myles, Duke University, Durham, North Carolina, United States

Myles Wolf,

• David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Valentin David,

• Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States

Aline Martin,

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 Col4a3^KO mouse, an established model of progressive CKD, which typically shows a shortened lifespan (21.4±0.6 weeks). We overexpressed DMP1 (DMP1^{Tg-3.6Kb ColIa1 promoter}) in the bone of WT (DMP1^Tg) and Col4a3^KO (Col4a3^KO/DMP1^Tg) 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

Col4a3^KO 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 Col4a3^KO/DMP1^Tg did not improve renal function but corrected the reduction in BMD by 40% and fully prevented osteocyte alterations. Col4a3^KO/DMP1^Tg 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 Col4a3^KO for each). As opposed to Col4a3^KO, Col4a3^KO/DMP1^Tg 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 Col4a3^KO).

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