Prenatal caffeine exprosure increases adult female offspring rat's susceptibility to osteoarthritis via low-functional programming of cartilage IGF-1 with histone acetylation

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.