Prenatal ethanol exposure increases osteoarthritis susceptibility in female rat offspring by programming a low-functioning IGF-1 signaling pathway.

Qubo Ni,Liaobin Chen,Xianrong Zhang,Jacques Magdalou,Hanwen Luo,Hui Wang,Yang Tan,Yu Deng

doi:10.1038/srep14711

Abstract

Epidemiological evidence indicates that osteoarthritis (OA) and prenatal ethanol exposure (PEE) are both associated with low birth weight but possible causal interrelationships have not been investigated. To investigate the effects of PEE on the susceptibility to OA in adult rats that experienced intrauterine growth retardation (IUGR), and to explore potential intrauterine mechanisms, we established the rat model of IUGR by PEE and dexamethasone, and the female fetus and 24-week-old adult offspring subjected to strenuous running for 6 weeks were sacrificed. Knee joints were collected from fetuses and adult offspring for histochemistry, immunohistochemistry and qPCR assays. Histological analyses and the Mankin score revealed increased cartilage destruction and accelerated OA progression in adult offspring from the PEE group compared to the control group. Immunohistochemistry showed reduced expression of insulin-like growth factor-1 (IGF-1) signaling pathway components. Furthermore, fetuses in the PEE group experienced IUGR but exhibited a higher postnatal growth rate. The expression of many IGF-1 signaling components was downregulated, which coincided with reduced amounts of type II collagen in the epiphyseal cartilage of fetuses in the PEE group. These results suggest that PEE enhances the susceptibility to OA in female adult rat offspring by down-regulating IGF-1 signaling and retarding articular cartilage development.

Highlights

The high incidence of OA, its etiology and pathogenesis are unclear
Our previous studies found that prenatal ethanol exposure (PEE) results in fetal exposure to high levels of maternal glucocorticoids (GC), reduces fetal blood and liver insulin-like growth factor-1 (IGF-1) levels and increases the incidence of IUGR12,16
These previous findings indicate that PEE-induced excessive fetal exposure to maternal GC can downregulate blood levels of IGF-1 and local cartilage IGF-1 signaling, which results in articular cartilage dysplasia, reduces the quality of the articular cartilage after birth and increases the susceptibility to OA in adult offspring

Summary

Introduction

The high incidence of OA, its etiology and pathogenesis are unclear. Epidemiological data showed that hand OA and lumbar spine OA were significantly associated with low birth weight[3,4]. Cartilage dysplasia can induce OA because it alters joint geometry, mechanical loading and cartilage matrix composition[5] These reports indicate that changes in cartilage during the intrauterine development period increase the susceptibility to OA. Our previous studies found that prenatal ethanol exposure (PEE) results in fetal exposure to high levels of maternal glucocorticoids (GC), reduces fetal blood and liver IGF-1 levels and increases the incidence of IUGR12,16. One of the possible underlying mechanisms involves the intrauterine programming of low IGF-1 signaling that is induced by over-exposure to maternal GC Taken together, these previous findings indicate that PEE-induced excessive fetal exposure to maternal GC can downregulate blood levels of IGF-1 and local cartilage IGF-1 signaling, which results in articular cartilage dysplasia, reduces the quality of the articular cartilage after birth and increases the susceptibility to OA in adult offspring. This study may increase the understanding of the etiopathogenesis of adult OA and provide evidence for the development of novel strategies for the early prevention and treatment of OA of fetal origin

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Results

Conclusion