Osteoporosis is a degenerative disease characterized by decreased bone mass and damage to bone microarchitecture, as well as increased bone fragility. Previous research showed that the conserved microRNA-378 (miR-378) suppresses bone marrow stromal cell (BMSC) osteogenesis and hinders fracture healing, but its precise role in osteoporosis remains unclear.
This research, published in the Genes & Diseases journal by a team from Chinese Academy of Sciences and The Chinese University of Hong Kong, examined 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 experienced significantly lower bone mineral density, thinner trabeculae, and reduced calcium deposition after OVX surgery. Additionally, miR-378 increased BMSC’s osteoclastogenesis by activating both the canonical and non-canonical nuclear factor kappa-light-chain-enhancer of activated B (NF- κB) 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 may result in severe osteoclastogenesis. Further experiments indicated that miR-378 overexpression elevated transforming growth factor beta (TGFβ), which impaired BMSC osteogenesis by downregulating Wnt/β-catenin signaling in a Traf3-dependent manner.
Remarkably, intravenous injection of an anti-miR-378 lentiviral therapy via tail-vein injection reversed bone loss, restored bone formation rates, and reduced osteoclast numbers, significantly improving bone microarchitecture in OVX mice.
While these collective data highlight the key role of miR-378 in OVX-induced osteoporosis, additional studies are needed to confirm the efficacy of anti-miR-378 therapy in wild-type mice. In conclusion, targeting miR-378 could offer a dual-action strategy, simultaneously inhibiting bone resorption and boosting bone formation. This dual action positions miR-378 inhibitors as compelling candidates for next-generation osteoporosis therapies, especially for postmenopausal women.
Reference
Title of Original Paper: MiR-378 mediates the ovariectomy induced bone loss via exaggerating osteoclastogenesis and transforming growth factor beta impaired osteogenesis
Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.
DOI: https://doi.org/10.1016/j.gendis.2025.101754
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