Histological and Molecular Features of Bone Remodeling at Early Stages of Chronic Kidney Disease: an Experimental Study

Mineral and bone disorders in chronic kidney disease (CKD–MBD) have traditionally been associated with hyperphosphatemia and secondary hyperparathyroidism. However, accumulated evidence indicate the development of CKD–MBD long before the emergence of apparent systemic changes, suggesting the existence of unexplored early pathogenetic mechanisms. The aim of the study was to assess histomorphometric and molecular-genetic changes in bone tissue in models of chronic kidney dysfunction (CKD). Early CKD stages were modeled in spontaneously hypertensive (SHR) rats, including sham-operated animals followed up for 6 months (SO6 group) and those in which constitutional hypertension was combined with 3/4 nephrectomy, followed up for 2 and 6 months (Nx2 and Nx6 groups, respectively). Wistar Kyoto (WKY) and SHR rats, sham-operated and followed up for 2 months (K2 and SO2 groups, respectively), served as controls. In all groups, creatinine clearance, albuminuria, renal interstitial fibrosis, as well as serum concentrations of inorganic phosphate (Pi), intact parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, Dickkopf-1, and sclerostin were assessed; bone histomorphometry and immunohistochemical examination, gene expression analysis of Pi transporters and osteogenic signaling pathways were performed. Serum concentrations of Pi, Dickkopf-1, and sclerostin were found to be significantly increased in Nx6, while serum PTH and FGF23 levels and urinary Pi excretion did not differ significantly vs. controls. A decrease in trabecular bone area and osteocyte counts was found in SO6, Nx2 and Nx6 groups, reduced osteoblast counts—in Nx2 and Nx6 groups, a lower eroded perimeter (bone resorption index)—in Nx6 group. In Nx2 and Nx6, histological changes were paralleled by a downregulation of genes encoding Pi transporters, as well as MAPK, BMP, and Wnt signaling pathways. Thus, histological features of reduced bone turnover were detected at the initial CKD stages with normal levels of Pi metabolism systemic regulators (PTH, FGF23). The identified changes may be underlain by a local suppression of the gene expression of Pi transporters and intracellular signaling pathways critical to osteoblastogenesis.