Transforming growth factor-ß receptor 1: An intervention target for genetic poor cartilage quality induced by prenatal dexamethasone exposure.
J Adv Res
; 47: 123-135, 2023 05.
Article
en En
| MEDLINE
| ID: mdl-35953031
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, TGFßR1, 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 TGFßR1 promoter to increase the expression of TGFßR1, p-Smad2, SOX9, ACAN and COL2A1, but these were prevented by SB431542 (a potent and selective inhibitor of TGFßR1).CONCLUSIONS:
PDE induced chondrodysplasia in offspring and stably inherited in F3-generation rats, which was related to decreased expression of SP1/TGFßR1/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/TGFßR1 signaling, which was prevented by a TGFßR1 inhibitor. This study elucidated the molecular mechanism and therapeutic target (TGFßR1) of genetic chondrodysplasia caused by PDE, which provides a research basis for precisely treating fetal-originated osteoarthritis.Palabras clave
Texto completo:
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Bases de datos:
MEDLINE
Asunto principal:
Osteoartritis
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Efectos Tardíos de la Exposición Prenatal
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Cartílago Articular
Límite:
Animals
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Female
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Humans
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Male
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Pregnancy
Idioma:
En
Revista:
J Adv Res
Año:
2023
Tipo del documento:
Article
País de afiliación:
China