Abstract
Emerging evidence indicates that osteoclasts direct osteoblastic bone formation. MicroRNAs (miRNAs) have a crucial role in regulating osteoclast and osteoblast function. However, whether miRNAs mediate osteoclast-directed osteoblastic bone formation is mostly unknown. Here, we show that increased osteoclastic miR-214-3p associates with both elevated serum exosomal miR-214-3p and reduced bone formation in elderly women with fractures and in ovariectomized (OVX) mice. Osteoclast-specific miR-214-3p knock-in mice have elevated serum exosomal miR-214-3p and reduced bone formation that is rescued by osteoclast-targeted antagomir-214-3p treatment. We further demonstrate that osteoclast-derived exosomal miR-214-3p is transferred to osteoblasts to inhibit osteoblast activity in vitro and reduce bone formation in vivo. Moreover, osteoclast-targeted miR-214-3p inhibition promotes bone formation in ageing OVX mice. Collectively, our results suggest that osteoclast-derived exosomal miR-214-3p transfers to osteoblasts to inhibit bone formation. Inhibition of miR-214-3p in osteoclasts may be a strategy for treating skeletal disorders involving a reduction in bone formation.
Highlights
Emerging evidence indicates that osteoclasts direct osteoblastic bone formation
The serum exosomal miR-214-3p level was positively correlated with the intra-osseous miR-214-3p level (Fig. 1e), whereas we found a negative correlation between serum exosomal miR-214-3p level and intra-osseous BGLAP mRNA level and between intra-osseous miR-214-3p level and intra-osseous BGLAP mRNA level, respectively (Fig. 1e)
As we have previously demonstrated that miR-214-3p directly targets the 30-untranslated region (UTR) of ATF4 mRNA to inhibit osteoblast activity[23], to further verify whether the downregulated osteoblast activity was caused by the miR-2143p in the co-cultured osteoclasts, we transfected osteoblasts with lentiviral vector for expression of exogenous ATF4 mRNA 30UTR (LV-ATF4 30UTR) before co-culture with OC-miR-214-3p osteoclasts
Summary
Emerging evidence indicates that osteoclasts direct osteoblastic bone formation. MicroRNAs (miRNAs) have a crucial role in regulating osteoclast and osteoblast function. We show that increased osteoclastic miR-214-3p associates with both elevated serum exosomal miR-214-3p and reduced bone formation in elderly women with fractures and in ovariectomized (OVX) mice. Aside from the well-documented regulatory mechanism of osteoblast-directed osteoclastic bone resorption, accumulating evidence indicates that osteoclasts in turn regulate osteoblastic bone formation either by direct cell–cell contact[5,6] or indirectly via cytokines[7]. We examine the expression of bone metabolism-related miRNAs in bone specimens and serum exosomes from elderly bone-fracture women as well as ageing ovariectomized (OVX) mice and show that increased osteoclastic miR-214-3p level associates with both elevated serum exosomal miR-214-3p level and reduced bone formation. We present in vitro and in vivo evidence to demonstrate that osteoclast-derived exosomal miR-214-3p could transfer to osteoblasts to inhibit osteoblastic bone formation. We show that osteoclast-targeted antagomir-214-3p treatment could promote bone formation in ageing OVX mice
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