Autophagy inhibition mediated by intrauterine miR-1912-3p/CTSD programming participated in the susceptibility to osteoarthritis induced by prenatal dexamethasone exposure in male adult offspring rats.

Huasong Shi, Bin Li, Dingmei Zhang, Hui Han, Hangyuan He, Jiayong Zhu, Hui Wang, Liaobin Chen

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2023 Jul

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Autophagy inhibition is known to be involved in the development of adult osteoarthritis. Dexamethasone, as a synthetic glucocorticoid, is widely used for premature delivery and related pregnancy diseases in clinics. We have previously shown that prenatal dexamethasone exposure (PDE) was associated with increased susceptibility to postnatal osteoarthritis in offspring. However, whether the occurrence of fetal-originated adult osteoarthritis induced by PDE is related to autophagy remains unclear. In this study, we first found that PDE could increase the mRNA and protein expression of cartilage matrix-degrading enzymes (MMP3, MMP13, and ADAMTS5) and decrease the cartilage matrix contents in adult offspring, and the in vitro results suggested that this might be related to the autophagy inhibition of chondrocytes. Further, we demonstrated a persistent autophagy inhibition with autolysosome accumulation, low expression of cathepsin D (CTSD), increased H3K9ac level, and expression of miR-1912-3p in the cartilage of PDE offspring from fetus to adulthood. In vitro experiments showed that dexamethasone inhibited autophagy flux and CTSD expression in fetal chondrocytes, while overexpression of CTSD could alleviate the inhibition of autophagic flux induced by dexamethasone. Finally, we confirmed that dexamethasone increased the H3K9ac level and expression of miR-1912-3p through activation of the glucocorticoid receptor (GR), resulting in the decreased expression of CTSD and inhibition of autophagy flux in fetal chondrocytes. In conclusion, intrauterine miR-1912-3p/CTSD programming-mediated autophagy inhibition promoted the susceptibility to osteoarthritis in PDE adult offspring rats. This study provides new ideas for exploring early prevention and therapeutic targets in fetal-originated osteoarthritis. © 2023 Federation of American Societies for Experimental Biology.

Citation

Huasong Shi, Bin Li, Dingmei Zhang, Hui Han, Hangyuan He, Jiayong Zhu, Hui Wang, Liaobin Chen. Autophagy inhibition mediated by intrauterine miR-1912-3p/CTSD programming participated in the susceptibility to osteoarthritis induced by prenatal dexamethasone exposure in male adult offspring rats. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2023 Jul;37(7):e23011