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Published on: December 3, 2016
Transforming growth factor-β receptor 1: An intervention target for genetic poor cartilage quality induced by
Liang Liu1, Bin Li1, Qingxian Li1
1Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Insights
Prenatal dexamethasone exposure causes inherited poor cartilage quality in offspring, leading to osteoarthritis. Glucosamine treatment reversed these effects by targeting the SP1/TGFβR1 pathway, offering a potential intervention for fetal-originated osteoarthritis.
Area of Science:
- Biomedical Science
- Genetics
- Osteoarthritis Research
Background:
- Prenatal dexamethasone exposure (PDE) is linked to poor offspring cartilage quality and potential transgenerational genetic effects.
- Fetal-originated osteoarthritis may stem from inherited poor cartilage quality.
Purpose of the Study:
- To investigate the molecular mechanisms behind PDE-induced osteoarthritis.
- To explore the heritability of this condition across generations.
- To identify early intervention strategies for fetal-originated osteoarthritis.
Main Methods:
- Rats were exposed to dexamethasone during gestation (F0 generation).
- Offspring (F1, F2, F3 generations) were bred to assess heritability.
- F3 generation received glucosamine treatment to evaluate intervention efficacy.
- Cartilage morphology, function, and molecular markers (SP1, TGFβR1, Smad2, SOX9, ACAN, COL2A1) were analyzed.
Main Results:
- PDE induced thinner cartilage, reduced chondrocytes, and higher osteoarthritis scores across generations.
- Expression of SP1, TGFβR1, Smad2, SOX9, ACAN, and COL2A1 was decreased in PDE offspring.
- Glucosamine treatment reversed these detrimental changes in F3 offspring.
- Glucosamine upregulated SP1 and TGFβR1 signaling in chondrocytes, promoting matrix synthesis.
Conclusions:
- PDE causes heritable chondrodysplasia via the SP1/TGFβR1/Smad2/SOX9 pathway, impacting cartilage matrix synthesis.
- Glucosamine effectively alleviates PDE-induced poor cartilage quality by modulating this pathway.
- TGFβR1 is identified as a key therapeutic target for fetal-originated osteoarthritis.
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.
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