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Abstract: PO1553

Primary Cilia Defects Reflect Specific Bone Cell Activity in Human ADPKD Osteoblast Cells

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Pereira, Renata C., University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
  • Gitomer, Berenice Y., University of Colorado Denver School of Medicine, Aurora, Colorado, United States
  • Harris, Peter C., Mayo Clinic Minnesota, Rochester, Minnesota, United States
  • Salusky, Isidro B., University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
  • Albrecht, Lauren V., University of California Los Angeles David Geffen School of Medicine, Los Angeles, California, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is predominately caused by mutations in primary cilium genes polycystic kidney disease PKD1 and PKD2. Recent studies show that ADPKD is associated with abnormal bone health with decreased bone formation and low bone serum alkaline phosphatase, even when kidney function is preserved. Knowledge of the regulatory links between ADPKD, cilia, and human bone health is lacking.

Methods

We assessed primary cilia in cultured pre-osteoblasts derived from ADPKD patients with PKD1 or PKD2 mutations, relative to healthy controls and non-ADPKD chronic kidney disease (CKD) patients. Cilia were quantified by immunofluorescence staining of pericentrin and acetylated-α-tubulin. Cilia responsiveness was examined following treatment with lithium chloride (LiCl), an activator of the canonical Wnt signaling pathway that is known to induce cilia elongation. Biochemical osteoblast analyses included bone turnover by alkaline phosphatase (ALP) activity and mineralization assays.

Results

Compared to healthy control cells, ADPKD osteoblasts displayed longer cilia at baseline and were significantly more responsive to elongation with LiCl. In contrast, non-ADPKD CKD osteoblasts had shorter cilia and lacked LiCl responsiveness. Despite similar histological features and adynamic bone characteristics, ADPKD osteoblasts mineralized faster than osteoblasts from non-ADPKD CKD. The ALP activity levels were decreased in ADPKD osteoblast cells, which is consistent with the lowered circulating bone ALP levels.

Conclusion

Together, these data support a model whereby altered cilia responsiveness in ADPKD osteoblasts is linked to bone cell activity and mineralization defects that are distinct from adynamic bone of non-ADPKD CKD patients.

Funding

  • NIDDK Support