Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.
Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China; Hubei Provincial Key Laboratory of Developmentally Originated Disease, Wuhan 430071, China.
J Adv Res. 2023 May;47:123-135. doi: 10.1016/j.jare.2022.08.002. Epub 2022 Aug 9.
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.
This study focused on further exploring molecular mechanism, heritability, and early intervention of fetal-originated osteoarthritis.
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.
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).
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.
胎儿来源的骨关节炎与软骨质量差有关，并且可能表现出跨代遗传效应。先前的研究结果表明，产前地塞米松暴露（PDE）会导致后代的软骨质量变差。
本研究旨在进一步探讨胎儿来源的骨关节炎的分子机制、遗传性和早期干预。
将孕鼠（F0）分为对照组和 PDE 组，根据是否在妊娠第 9-20 天给予地塞米松。一些雌性后代在产后第 8 周与健康雄性交配以获得 F2 和 F3 代。在 F3 代大鼠的产后第 12 周给予氨基葡萄糖灌胃 6 周。在不同时间点收获雄性和雌性大鼠的膝关节软骨，以检测其形态和功能。此外，从 F3 代大鼠中分离原代软骨细胞，以证实氨基葡萄糖的作用机制和干预靶点。
与对照组相比，PDE 组各代雌性和雄性大鼠的软骨厚度较薄；染色较浅且不均匀；软骨细胞较少；OARSI 评分较高；SP1、TGFβR1、Smad2、SOX9、ACAN 和 COL2A1 的 mRNA 和蛋白表达较低。F3 代大鼠用氨基葡萄糖治疗后，上述变化均得到逆转。在从 PDE 组 F3 代大鼠分离的原代软骨细胞中，氨基葡萄糖促进 SP1 的表达并与 TGFβR1 启动子结合以增加 TGFβR1、p-Smad2、SOX9、ACAN 和 COL2A1 的表达，但这些作用被 SB431542（一种有效的、选择性的 TGFβR1 抑制剂）所阻断。
PDE 诱导后代的软骨发育不良，并在 F3 代大鼠中稳定遗传，这与 SP1/TGFβR1/Smad2/SOX9 通路表达降低导致软骨基质合成减少有关，而与主要的性别差异无关。氨基葡萄糖可通过上调 SP1/TGFβR1 信号减轻 PDE 诱导的后代遗传软骨质量差，而 TGFβR1 抑制剂可阻断这一作用。本研究阐明了 PDE 引起的遗传软骨发育不良的分子机制和治疗靶点（TGFβR1），为精准治疗胎儿来源的骨关节炎提供了研究基础。
