Exposure to the RXR Agonist SR11237 in Early Life Causes Disturbed Skeletal Morphogenesis in a Rat Model.

Daniel B Hardy,Holly Dupuis,Frank Beier,Thin Xuan Vo,Ermina Hadzic,Michael Andrew Pest

doi:10.3390/ijms20205198

Daniel B Hardy, Holly Dupuis + Show 4 more

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https://doi.org/10.3390/ijms20205198

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Abstract

Longitudinal bone growth occurs through endochondral ossification (EO), controlled by various signaling molecules. Retinoid X Receptor (RXR) is a nuclear receptor with important roles in cell death, development, and metabolism. However, little is known about its role in EO. In this study, the agonist SR11237 was used to evaluate RXR activation in EO. Rats given SR11237 from post-natal day 5 to post-natal day 15 were harvested for micro-computed tomography (microCT) scanning and histology. In parallel, newborn CD1 mouse tibiae were cultured with increasing concentrations of SR11237 for histological and whole-mount evaluation. RXR agonist-treated rats had shorter long bones than the controls and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape, in correspondence with p57 immunostaining. Additionally, SOX9-positive cells were found surrounding the calcified tissue. The epiphysis of SR11237-treated bones showed increased TRAP staining and additional TUNEL staining at the osteo-chondral junction. MicroCT revealed morphological disorganization in the long bones of the treated animals. This study suggests that stimulation of RXR causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models

Highlights

Longitudinal bone growth occurs through the process of endochondral ossification, in which a cartilaginous model first expands through the activity of chondrocytes and is replaced by bone
Hypertrophic differentiation is driven by transcription factors such as runt-related transcription factor 2 (RUNX2) [4,5,6] and myocyte enhancer factor-2c (MEF2C) [7] that is required for Runx2 expression [1]
The reduced growth of tibiae cultured with the high concentration agonist suggests that at least a portion of the growth retardation observed was due to direct effects on growth-plate chondrocytes

Summary

Introduction

Longitudinal bone growth occurs through the process of endochondral ossification, in which a cartilaginous model first expands through the activity of chondrocytes and is replaced by bone. Chondrocytes begin expressing SRY (sex-determining region Y)-box (SOX9) and synthesize a matrix comprised largely of type II collagen and the proteoglycan aggrecan [1] These early cartilage cells have a distinct rounded shape, are scattered irregularly throughout the matrix, divide infrequently, and give rise to resting chondrocytes. The growth plate consists of the chondrocytes located between these two areas of ossification, with distinctly divided zones of resting, proliferating, and hypertrophic cells [10]. Throughout this process, proliferation and hypertrophy of chondrocytes drive the longitudinal growth of the bone [11]. Understanding these processes is crucial to elucidating the etiology of bone diseases along with developing interventions to ameliorate any adverse outcomes

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