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Abstract: SA-PO177

Uremia and Parathyroid Tormone Have Distinct Effects on Protein and Gene Expression on Bone

Session Information

Category: Bone and Mineral Metabolism

  • 402 Bone and Mineral Metabolism: Clinical

Authors

  • Martins, Carolina Steller wagner, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • dos Reis, Luciene, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Martinez-Calle, Marta, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Oliveira, Ivone Braga de, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Coelho, Ana C.E., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Martin, Aline, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Jorgetti, Vanda, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Elias, Rosilene M., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • David, Valentin, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Moyses, Rosa M.A., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil

Group or Team Name

  • Laboratório de Investigação Médica 16, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
Background

Bone disease is a well-recognized complication of chronic kidney disease (CKD), characterized by reductions in bone quantity and quality. The uncoupling of bone formation and resorption can be found in high and low bone turnover conditions. Parathyroid hormone (PTH) is a main regulator of bone turnover and increased serum PTH levels is a classical alteration of mineral metabolism in CKD. However, the specific effect of PTH on the bone environment in CKD is still unclear.

Methods

To separate these effects, we analyzed bone samples from 76 patients on hemodialysis [grouped according to serum PTH levels: < 130 (n= 28), 130-600 (n= 20) and > 600 pg/ml (n=28)] and 19 healthy controls. Protein and gene expression were quantified through immunohistochemistry and RNA sequencing (RNAseq).

Results

Most PTH<130 patients (79%) had low, whereas 93% of those with PTH>600 had a high bone turnover. In comparison with healthy controls, PTH<130 group presented a lower osteocytic number, as well as a higher bone expression of DKK1. In patients with PTH>600, we observed a normal osteocytic number and DKK1 expression, but a decrease in bone sclerostin, phosphorylated beta catenin, and osteoprotegerin. Using RNAseq, we found a significant difference in the expression of almost 2,000 genes between CKD and healthy controls. CKD was associated with an increase in inflammatory signaling, cell death, and impairment of osteoblastic differentiation and bone quantity. In contrast, these changes were attenuated in patients with PTH>600, showing a significant increase in the expression of genes associated with fibrosis, matrix proteins and remodeling. In addition, the increase in PTH did not influence the genes related to bone quantity.

Conclusion

Using an unprecedented approach, we showed that CKD bone disease is characterized by an increased expression of markers related to suppression in bone formation. An increase in PTH favors bone resorption more significantly than bone formation further aggravating the formation/resorption uncoupling. These findings help us to better understand the complex physiopathology of renal osteodystrophy, creating a perspective of new therapeutic strategies for these patients.

Funding

  • Government Support – Non-U.S.