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Abstract <p>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 longbefore the emergence of apparent systemic changes, suggesting theexistence of unexplored early pathogenetic mechanisms. The aim ofthe study was to assess histomorphometric and molecular-genetic changesin bone tissue in models of chronic kidney dysfunction (CKD). EarlyCKD stages were modeled in spontaneously hypertensive (SHR) rats, includingsham-operated animals followed up for 6 months (SO6 group) and thosein 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&#xa0;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 parathyroidhormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, Dickkopf-1,and sclerostin were assessed; bone histomorphometry and immunohistochemicalexamination, gene expression analysis of Pi transporters and osteogenicsignaling 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 notdiffer significantly vs. controls. A decrease in trabecular bonearea and osteocyte counts was found in SO6, Nx2 and Nx6 groups,reduced osteoblast counts—in Nx2 and Nx6 groups, a lower erodedperimeter (bone resorption index)—in Nx6 group. In Nx2 and Nx6,histological changes were paralleled by a downregulation of genesencoding Pi transporters, as well as MAPK, BMP, and Wnt signalingpathways. Thus, histological features of reduced bone turnover weredetected at the initial CKD stages with normal levels of Pi metabolismsystemic regulators (PTH, FGF23). The identified changes may beunderlain by a local suppression of the gene expression of Pi transportersand intracellular signaling pathways critical to osteoblastogenesis. </p>

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

  • 期刊论文

  • 发表日期：

    2025年12月19日

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  • E. O. Bogdanova,
  • A. M. Sadykov,
  • G. T. Ivanova,
  • I. M. Zubina,
  • O. N. Beresneva,
  • O. V. Galkina,
  • V. V. Sharoyko,
  • N. Yu. Semenova,
  • M. M. Parastaeva,
  • V. A. Dobronravov

摘要

Abstract

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 longbefore the emergence of apparent systemic changes, suggesting theexistence of unexplored early pathogenetic mechanisms. The aim ofthe study was to assess histomorphometric and molecular-genetic changesin bone tissue in models of chronic kidney dysfunction (CKD). EarlyCKD stages were modeled in spontaneously hypertensive (SHR) rats, includingsham-operated animals followed up for 6 months (SO6 group) and thosein 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 parathyroidhormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, Dickkopf-1,and sclerostin were assessed; bone histomorphometry and immunohistochemicalexamination, gene expression analysis of Pi transporters and osteogenicsignaling 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 notdiffer significantly vs. controls. A decrease in trabecular bonearea and osteocyte counts was found in SO6, Nx2 and Nx6 groups,reduced osteoblast counts—in Nx2 and Nx6 groups, a lower erodedperimeter (bone resorption index)—in Nx6 group. In Nx2 and Nx6,histological changes were paralleled by a downregulation of genesencoding Pi transporters, as well as MAPK, BMP, and Wnt signalingpathways. Thus, histological features of reduced bone turnover weredetected at the initial CKD stages with normal levels of Pi metabolismsystemic regulators (PTH, FGF23). The identified changes may beunderlain by a local suppression of the gene expression of Pi transportersand intracellular signaling pathways critical to osteoblastogenesis.