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

Area of Science:

• Developmental Biology
• Skeletal Biology
• Molecular Endocrinology

Background:

• Longitudinal bone growth relies on endochondral ossification (EO), a complex process regulated by signaling molecules.
• Retinoid X Receptor (RXR), a nuclear receptor, influences cell death, development, and metabolism, but its role in EO is largely uncharacterized.

Purpose of the Study:

• To investigate the role of Retinoid X Receptor (RXR) activation in endochondral ossification (EO) and long bone development.
• To evaluate the effects of the RXR agonist SR11237 on the growth plate and long bone morphology in rodent models.

Main Methods:

• Administration of the RXR agonist SR11237 to rats and mice during critical postnatal growth periods.
• Histological analysis, immunostaining (p57, SOX9), TUNEL assays, and TRAP staining of bone tissues.
• Micro-computed tomography (microCT) for detailed morphological assessment of long bones.

Main Results:

• RXR agonist treatment resulted in significantly shorter long bones and growth plate dysmorphia in rats.
• Histological analysis revealed abnormal cell morphology and positioning within the growth plate, with altered SOX9 and p57 expression.
• Increased apoptosis and altered osteoclast activity were observed at the osteo-chondral junction, alongside significant morphological disorganization revealed by microCT.

Conclusions:

• Activation of Retinoid X Receptor (RXR) by SR11237 disrupts endochondral ossification.
• RXR stimulation leads to premature growth plate closure and irregular long bone development in rodent models.
• These findings suggest RXR signaling is a critical regulator of skeletal growth and endochondral ossification.