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Based on our previous findings that prenatal ethanol exposure in offspring increased susceptibility to adult osteoarthritis, this study aimed to further investigate the direct toxicity of ethanol on fetal articular cartilage development. Rat bone marrow-derived stroma cells were capsulated in alginate beads, incubated in a chondrogenic differentiation medium, and cultured for 4 weeks with ethanol treatment at concentrations of 0,4, 20, and 100 mM. Pregnant rats were treated with ethanol (4 g/kg/day) from gestational days (GDs) 9 to 20. At GD20 and postnatal weeks 2, 6, and 12, 8 male offspring were sacrificed, and 8 male offspring rats of 8-weeks old in each group were treated with or without intraarticular injection of papain for 4 weeks to verify the susceptibility of adult osteoarthritis. Ethanol treatment resulted in poor differentiation of bone marrow-derived stroma cells to chondrocytes and suppressed the expression of the transforming growth factor-β (TGFβ)-smad2/3-Sox9 signaling pathway. In animal experiments, the shape of articular cartilage in the ethanol treatment group was more disordered than that of the control group, the matrix was not deep, and the cartilage was thin, which showed poor cartilage development. The TGFβ signaling pathway in the ethanol treatment group was persistently low at all time points. After intraarticular injection of papain, histological analyses, and the Mankin score revealed increased cartilage destruction in the ethanol treatment group. Ethanol caused articular cartilage dysplasia that was programmed in adulthood via a low-functional TGFβ signaling pathway, and the tolerance of this articular cartilage to external stimuli was significantly decreased. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) development is associated with hypercholesterolemia in adults. Our previous study demonstrated that offspring with intrauterine growth retardation (IUGR) due to prenatal ethanol exposure (PEE) had a high risk of developing hypercholesterolemia and metabolic syndrome when fed a post-weaning high-fat diet (HFD). In this study, we examined the changes in articular chondrocytes of IUGR offspring induced by PEE and explored its intrauterine programming mechanisms related to cholesterol metabolism. Using the PEE/IUGR model, serum and tibias from female fetuses and adult female offspring fed a post-weaning HFD were collected and examined for cholesterol metabolism and histology. The results showed that PEE adult offspring manifested significant catch-up growth. Their serum total cholesterol (TCH) and low-density lipoprotein-cholesterol increased and high-density lipoprotein-cholesterol decreased; the osteoarthritis-like phenotype and an increased TCH content were observed in articular cartilage; and the expression of insulin-like growth factor1 (IGF1) and cholesterol efflux pathway, including ATP-binding-cassette transporter A1 and liver X receptor, was reduced. The expression of IGF1 and cholesterol efflux pathway was also lower in the PEE fetuses. This study showed PEE could induce an enhanced susceptibility to HFD-induced OA in adult female IUGR offspring. The underlying mechanism related to cholesterol accumulation in cartilage mediated by intrauterine programming. [ABSTRACT FROM AUTHOR]

Our previous in vivo studies showed that prenatal caffeine exposure (PCE) could restrain the development of chondrogenesis, which may delay fetal articular cartilage development and increase susceptibility to osteoarthritis in adults. So, the goal of the current study is to clarify theincreasing susceptibility to adult osteoarthritis in caffeine-exposed female offspring and its’mechanism. Pregnant rats were treated with 120 mg/kg·d caffeine or equal volumes of saline from gestational day (GD) 9 to 20. knee joints were collected from GD20 female fetuses and 18-week old female offspring which was treated with strenuous running for 6 weeks (55 min/day at 20 m/min) load to induce osteoarthritis. Knee joints from GD20 fetuses and adult offspring were collected for histochemistry and immunohistochemistry. Next, chondrocytes were isolated from 1-day-old newborn rats and in vitro studies were conducted where the cells in primary culture were exposed to 1, 10, and 100 μM caffeine and 250, 500, and 1,250 nM corticosterone. Insulin-like growth factor 1 (IGF-1) signal pathway genes’ expression levels in fetal chondrocytes were studied, and IGF-1 histone acetylation was detected in vitro. Immunohistochemical results showed low expression levels of IGF-1 signaling genes (IGF-1, IRS-1, AKT, and COL2A1) both in fetal and adult cartilage with PCE. For adult offspring, histological results and Mankin score revealed increased cartilage destruction and accelerated osteoarthritis progression in PCE group with strenuous running exercise. Analysis in vitro revealed that caffeine and corticosterone impeded the expression of IGF-1 signaling pathway aggrecan and COL2A1 genes, but only corticosterone decreased H3K9 and H3K27 acetylation in the IGF-1 promoter region. In concluson, PCE low functional programmed cartilage IGF-1 by histone acetylation modification via overexposure to corticosterone and delayed articular cartilage development from fetus to adults. Then, the delayed cartilage development increased susceptibility to osteoarthritis in offsprings. [ABSTRACT FROM AUTHOR]

Prenatal caffeine exposure (PCE) induces developmental toxicity of multi-organ and susceptibility to multi-disease in offspring. However, the effects of PCE on osteoarthritis susceptibility in adult offspring and its intrauterine programming mechanism remain to be further investigated. Here, we found that PCE induced susceptibility to osteoarthritis in male adult offspring rats, which was related to the inhibited function of cartilage matrix synthesis from fetuses to adults. Meanwhile, PCE consistently downregulated the H3K9ac and expression levels of transforming growth factor β receptor 1 (TGFβR1), and then blocked TGFβ signaling pathway, which contributed to the suppressed cartilage matrix synthesis. Moreover, the high level of corticosterone caused by PCE reduced the H3K9ac level on TGFβR1 promoter region through acting on glucocorticoids receptor (GR) and recruiting histone deacetylase 2 (HDAC2) into the nucleus of fetal chondrocytes. Taken together, PCE induced osteoarthritis susceptibility in male adult offspring rats, which was attributed to the low-functional programming of TGFβR1 induced by corticosterone via GR/HDAC2 signaling. • Prenatal caffeine exposure (PCE) caused osteoarthritis susceptibility in offspring. • The low-expressional TGFβR1 contributed to the inhibited cartilage matrix synthesis. • PCE induced-high corticosterone decreased H3K9ac of TGFβR1 via GR/HDAC2 signaling. [ABSTRACT FROM AUTHOR]