Osteocytes are key regulators of skeletal mineralization and their function is dysregulated in pediatric patients with chronic kidney disease, contributing to such adverse consequences including poor growth, boney deformities, bone pain and fractures. A more complete understanding of osteoblast/osteocyte biology and the process of skeletal mineralization is critical to improving skeletal outcomes. HYPOTHESIS: Osteoblasts harvested from CKD patients have intrinsic abnormalities in mineralization potential and these abnormalities are ameliorated and/or potentiated by changes in circulating hormone concentrations. METHODS: Paired samples of primary osteoblast cells from pediatric patients with stage V chronic kidney disease, obtained before and after active vitamin D sterol therapy, will be used to assess, in vitro, osteoblast maturation and mineralization characteristics and the effects of systemic vitamin D sterol therapy on these characteristics. Subsequently, alterations in mineral and hormonal content will be made to the cell culture media to evaluate the separate effects of these circulating factors on skeletal mineralization. IMPLICATIONS: The current study presents a novel system in which to study the pathophysiology of defective skeletal mineralization. Its advantages are the ability to discriminate whether defective mineralization is due to intrinsic changes in cells of osteoblast/osteocyte lineage, to alterations in extrinsic factrs (changes in media mineral and hormone content), or to a combination of both. These results will yield considerable knowledge which can, in future, be used to develop new therapeutic strategies for the treatment of renal osteodystrophy.

Public Health Relevance

Bone mineralization is abnormal in children with chronic kidney disease, contributing to bone pain, poor growth, fractures, and bone deformities in over 50% of this population. Coincidentally, osteocytes, the mature form of osteoblasts, are key regulators of bone mineralization and we have identified that their function is abnormal in children with chronic kidney disease, likely contributing to abnormal bone mineralization. The current proposal outlines experiments that will define the intrinsic abnormalities that develop in osteoblasts and osteocytes from pediatric patients with chronic kidney disease and how changes in calcium, phosphorus, and hormones found in the blood can change how well bone mineralizes and how osteoblasts mature. The results from these experiments will yield considerable knowledge which will guide the development of new treatments for abnormal bone mineralization.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Rankin, Tracy L
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Wesseling-Perry, Katherine; Mäkitie, Riikka E; Välimäki, Ville-Valtteri et al. (2017) Osteocyte Protein Expression Is Altered in Low-Turnover Osteoporosis Caused by Mutations in WNT1 and PLS3. J Clin Endocrinol Metab 102:2340-2348
Pereira, Renata C; Valta, Helena; Tumber, Navdeep et al. (2015) Altered Osteocyte-Specific Protein Expression in Bone after Childhood Solid Organ Transplantation. PLoS One 10:e0138156
Carvalho, Catarina G; Pereira, Renata C; Gales, Barbara et al. (2015) Cortical and trabecular bone in pediatric end-stage kidney disease. Pediatr Nephrol 30:497-502
Pereira, Renata C; Delany, Anne M; Khouzam, Nadine M et al. (2015) Primary osteoblast-like cells from patients with end-stage kidney disease reflect gene expression, proliferation, and mineralization characteristics ex vivo. Kidney Int 87:593-601