Journal of Advanced Research

Journal of Advanced Research

Volume 47, May 2023, Pages 123-135
Journal of Advanced Research

Original Article
Transforming growth factor-β receptor 1: An intervention target for genetic poor cartilage quality induced by prenatal dexamethasone exposure

https://doi.org/10.1016/j.jare.2022.08.002Get rights and content
Under a Creative Commons license
open access

Highlights

  • We confirmed that prenatal dexamethasone exposure leads to hereditary low cartilage quality;

  • Genetic low cartilage quality induced by dexamethasone exposure during pregnancy is associated with reduced cartilage matrix synthesis mediated by the inhibition of expression of the TGFβ signaling pathway;

  • Glucosamine can improve the hereditary low quality of cartilage caused by dexamethasone during pregnancy;

  • Glucosamine could reverse the poor genetic cartilage quality in offspring induced by PDE via up-regulating SP1 expression and promoting its binding to TGFβR1 promoter.

Abstract

Introduction

Fetal-originated osteoarthritis is relative to poor cartilage quality and may exhibit transgenerational genetic effects. Previous findings revealed prenatal dexamethasone exposure (PDE) induced poor cartilage quality in offspring.

Objectives

This study focused on further exploring molecular mechanism, heritability, and early intervention of fetal-originated osteoarthritis.

Methods

Pregnant rats (F0) were segregated into control and PDE groups depending upon whether dexamethasone was administered on gestational days (GDs) 9–20. Some female offspring were bred with healthy males during postnatal week (PW) 8 to attain the F2 and F3 generations. The F3-generation rats were administrated with glucosamine intragastrically at PW12 for 6 weeks. The knee cartilages of male and female rats at different time points were harvested to assay their morphologies and functions. Furthermore, primary chondrocytes from the F3-generation rats were isolated to confirm the mechanism and intervention target of glucosamine.

Results

Compared with the control, female and male rats in each generation of PDE group showed thinner cartilage thicknesses; shallower and uneven staining; fewer chondrocytes; higher Osteoarthritis Research Society International scores; and lower mRNA and protein expression of SP1, TGFβR1, Smad2, SOX9, ACAN and COL2A1. After F3-generation rats were treated with glucosamine, all of the above changes could be reversed. In primary chondrocytes isolated from the F3-generation rats of PDE group, glucosamine promoted SP1 expression and binding to TGFβR1 promoter to increase the expression of TGFβR1, p-Smad2, SOX9, ACAN and COL2A1, but these were prevented by SB431542 (a potent and selective inhibitor of TGFβR1).

Conclusions

PDE induced chondrodysplasia in offspring and stably inherited in F3-generation rats, which was related to decreased expression of SP1/TGFβR1/Smad2/SOX9 pathway to reduce the cartilage matrix synthesis, without major sex-based variations. Glucosamine could alleviate the poor genetic cartilage quality in offspring induced by PDE by up-regulating SP1/TGFβR1 signaling, which was prevented by a TGFβR1 inhibitor. This study elucidated the molecular mechanism and therapeutic target (TGFβR1) of genetic chondrodysplasia caused by PDE, which provides a research basis for precisely treating fetal-originated osteoarthritis.

Keywords

Poor cartilage quality
Transforming growth factor β receptor 1
Prenatal dexamethasone exposure
Transgenerational inheritance
Intervention target

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Peer review under responsibility of Cairo University.