Targeting miR-378 could offer a dual-action strategy against osteoporosis

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.