MiR-30d-5p Regulates Bone Remodeling and Vessel Remodeling in Osteoporosis by Targeting GRP78

Abstract

Osteoporosis is one of the major bone disorders that has a close relationship with osteogenesis and angiogenesis. MiRNA coordinates a cascade of anabolic and catabolic processes in bone homeostasis and dynamic vascularization. Here, the role of miR-30d-5p in osteoporosis and its mechanism were investigated. To explore the effect of miR-30d-5p on osteogenesis and angiogenesis, an ovariectomized (OVX) mouse model, bioinformatics analysis, and multiple in vitro assays were used. Compared to the sham group, OVX mice reduced BV/TV, Tb.Th, Tb.N, and BMD, while it increased Tb.Sp. The number of osteoblasts and the density of microvessels were decreased in the OVX group, while the number of osteoclasts was increased. MiRNA sequencing and qRT-PCR revealed that miR-30d-5p was increased in the bone marrow cells of the OVX mice. Supplementing miR-30d-5p activity using miR-30d-5p agomir inhibited osteogenic differentiation in bone marrow-derived cells and prevented angiogenesis in HUVECs. Conversely, miR-30d-5p antagomir, an inhibitor of endogenous miR-30d-5p, reversed the inhibitory responses. Glucose regulating protein 78 (GRP78), a key regulator of endoplasmic reticulum stress, was demonstrated to be directly targeted by miR-30d-5p. Consistently, the overexpression of GRP78 improved miR-30d-5p-related osteoblast differentiation and angiogenesis. We concluded that miR-30d-5p significantly inhibited bone formation and blood vessel formation by targeting GRP78 in experiments in vitro. Therefore, miR-30d-5p may serve as a potential target for reversing osteoporosis.