Innovative Three-Dimensional Microscopic Analysis of Uremic Growth Plate Discloses Alterations in the Process of Chondrocyte Hypertrophy: Effects of Growth Hormone Treatment.

Ángela Fernández-Iglesias,Helena Gil-Peña,José Manuel López,Fernando Santos,Rocío Fuente,María García-Bengoa,Laura Alonso-Durán

doi:10.3390/ijms21124519

Abstract

Chronic kidney disease (CKD) alters the morphology and function of the growth plate (GP) of long bones by disturbing chondrocyte maturation. GP chondrocytes were analyzed in growth-retarded young rats with CKD induced by adenine intake (AD), control rats fed ad libitum (C) or pair-fed with the AD group (PF), and CKD rats treated with growth hormone (ADGH). In order to study the alterations in the process of GP maturation, we applied a procedure recently described by our group to obtain high-quality three-dimensional images of whole chondrocytes that can be used to analyze quantitative parameters like cytoplasm density, cell volume, and shape. The final chondrocyte volume was found to be decreased in AD rats, but GH treatment was able to normalize it. The pattern of variation in the cell cytoplasm density suggests that uremia could be causing a delay to the beginning of the chondrocyte hypertrophy process. Growth hormone treatment appears to be able to compensate for this disturbance by triggering an early chondrocyte enlargement that may be mediated by Nkcc1 action, an important membrane cotransporter in the GP chondrocyte enlargement.

Highlights

Growth impairment remains a major complication in pediatric patients with chronic kidney disease (CKD) and only 30% of adults with childhood onset CKD reach a normal final height [1,2]
Phosphorus levels were significantly reduced in the adenine intake (AD), ADGH, and PF groups in comparison with the control group, but no significant differences in calcium levels were observed among all groups
It is of note that a similar degree of growth retardation was found in the AD and PF groups

Summary

Introduction

Growth impairment remains a major complication in pediatric patients with chronic kidney disease (CKD) and only 30% of adults with childhood onset CKD reach a normal final height [1,2]. Chondrocytes within the GP elongate the bone by the proliferation, progression, hypertrophy, and synthesis of the extracellular matrix [4]. The columnar or proliferative chondrocytes exit the cell cycle and begin to increase their cell volume and change their cell shape to form prehypertrophic and hypertrophic chondrocytes. The hypertrophic cells mineralize their extracellular matrix and either they are degraded by osteoclasts and replaced by invading osteoblasts or they transdifferentiate into bone-forming osteoblasts [5]

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