Osteoclast-derived exosomal miR-214-3p inhibits osteoblastic bone formation

TLDR

Osteoclasts influence osteoblast bone formation, and microRNAs are key regulators, but it is unclear whether miRNAs mediate this osteoclast‑directed effect. Elevated osteoclast‑derived exosomal miR‑214‑3p suppresses osteoblast activity and bone formation, as shown by its association with reduced bone mass in humans and mice, its rescue by antagomir‑214‑3p, and the bone‑forming benefit of miR‑214‑3p inhibition.

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.