PT  - JOURNAL ARTICLE
AU  - Holly Dupuis
AU  - Michael Andrew Pest
AU  - Ermina Hadzic
AU  - Thin Xuan Vo
AU  - Daniel B. Hardy
AU  - Frank Beier
TI  - Exposure to the RXR agonist SR11237 in early life causes disturbed skeletal morphogenesis in a rat model
AID  - 10.1101/774851
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 774851
4099  - http://biorxiv.org/content/early/2019/09/20/774851.short
4100  - http://biorxiv.org/content/early/2019/09/20/774851.full
AB  - 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 on EO.Rats given SR11237 from post-natal day 5 to 15 were harvested for micro-computed tomography 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 were smaller than controls, and developed dysmorphia of the growth plate. Cells invading the calcified and dysmorphic growth plate appeared pre-hypertrophic in size and shape corresponding 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 treated animals. Isolated mouse long bones treated with SR11237 grew significantly less than their DMSO controls.This study demonstrates that stimulation of the RXR receptor causes irregular ossification, premature closure of the growth plate, and disrupted long bone growth in rodent models.EOendochondral ossificationRXRretinoid x receptorSOX9sex determining region-box 9RUNX2runt-related transcription factor 2MEF2Cmyocyte enhancer factor–2cPPARperoxisome proliferator-activated receptorFXRfarnesoid x receptorLXRliver x receptorRARretinoic acid receptorVDRvitamin d receptorTRthyroid receptorIPintraperitonealDMSOdimethyl sulfoxideGLPglucagon-like peptideMEMminimum essential medium eagleTRAPtartrate resistant acid phosphataseTUNELterminal deoxynucleotidyl transferase dUTP nick end labellingPCNAproliferating cell nuclear antigenRANKLreceptor activator of nuclear factor of kappa-B ligand