Osteoporosis is a degenerative disease characterized by reduced bone mass and damage to bone microarchitecture, as well as increased bone fragility. Previous research has shown that the conserved microRNA-378 (miR-378) suppresses osteogenesis of bone marrow stromal cells (BMSCs) and hinders fracture healing, but its exact role in osteoporosis remains unclear.
This research, published in the journal Genes & Diseases, by a team from the Chinese Academy of Sciences and the Chinese University of Hong Kong, investigated miR-378 in an ovariectomy (OVX)-induced osteoporosis model, exploring both osteoclastogenesis and osteogenesis.
Three-dimensional imaging and histological staining showed that miR-378 overexpressing transgenic (Tg) mice had significantly lower bone mineral density, thinner trabeculae, and reduced calcium deposition after OVX surgery. Furthermore, miR-378 enhanced osteoclast formation in BMSCs by activating the canonical and non-canonical NF-κB (Nuclear Factor Kappa-Light Chain Enhancer of Activated B) signaling pathways.
In silico analysis results identified Tumor Necrosis Factor Receptor Associated Factor 3 (Traf3) as one of the direct target genes for miR-378-5p, and its knockdown can lead to severe osteoclast formation. Further experiments showed that miR-378 overexpression increased Transforming Growth Factor Beta (TGFβ), which impaired osteogenesis in BMSCs by downregulating Wnt/β-catenin signaling in a Traf3-dependent manner.
Notably, tail vein injection of intravenous lentiviral anti-miR-378 therapy reversed bone loss, restored the bone formation rate, and reduced osteoclast numbers, significantly improving bone microarchitecture in OVX mice.
While these collected data highlight the key role of miR-378 in OVX-induced osteoporosis, further studies are needed to confirm the efficacy of anti-miR-378 therapy in wild-type mice. In conclusion, targeted treatment of miR-378 could offer a dual-action strategy, simultaneously inhibiting bone resorption and promoting bone formation. This dual action positions miR-378 inhibitors as attractive candidates for next-generation osteoporosis therapies, especially for postmenopausal women.
DOI:https://doi.org/10.1016/j.gendis.2025.101754
