Targeting a newly identified lncRNA and its interaction with HuR to promote osteogenic cells migration to bone formation surface for reversing established age-related osteoporosis (Abstract)

Long noncoding RNAs (lncRNAs) have emerged as critical players in regulating osteogenic differentiation during bone formation. However, the role of lncRNAs in regulating osteogenic cells migration remains to be elucidated. Here we identify an elevated lncRNA (named lnc-PMIF) in connection with reduced osteogenic cells migration and decreased bone formation in age-related osteoporotic mice in both genders (Fig A). Using our established lnc-PMIF knockdown (KD) / overexpression (OE) cell lines, it was found that lncPMIF suppressed osteogenic cells migration without significantly affecting either cell differentiation or cell proliferation in vitro (Fig B). Further, in an intra-bone-marrow injection assay using labeled KD/OE cell lines ex vivo, it was found that overexpression of lnc-PMIF suppressed osteogenic cells migration to bone formation surfaces, whereas knockdown of lnc-PMIF promoted osteogenic cells migration to bone formation surfaces (Fig C). Towards mechanistic understandings, it was evidenced that lnc-PMIF could directly interact with HuR to inhibit Actin (Fig D). Moreover, an ortholog lncRNA of lnc-PMIF in human was also identified. Towards translational medicine, a cross-species functionally conserved HuR sequence (Peptide52) binding to mice / human lnc-PMIF was identified. Using our established targeted delivery system specifically approaching bone formation surface[1], it was found that either targeted silencing of lnc-PMIF by siRNA (Fig E) or blockading of the interaction between lnc-PMIF and HuR by exogenous Peptide52 supplementation (Fig F) in osteogenic cells, could facilitate their migration to bone formation surfaces for promoting bone formation in osteoblast-specific lnc-PMIF transgenic mice. These findings provide a new strategy to promote osteogenic cells migration for bone anabolic therapy to reverse established osteoporosis