Dysregulation of the miR-146a-Smad4 axis impairs osteogenesis of bone mesenchymal stem cells under inflammation

Abstract

Osteoporosis is a common disease that affects patient quality of life, especially among the elderly population. Although inflammation contributes significantly to osteoporosis, the underlying mechanism is unclear. In this study, we found that tumor necrosis factor (TNF)-α, an inflammatory environment mimic, inhibits osteogenesis of bone mesenchymal stem cells (BMSCs), induces miR-146a and decreases Smad4. Moreover, overexpression of miR-146a inhibited the osteogenic ability of BMSCs, whereas blocking miR-146a partially rescued the osteogenesis deficiency under TNF-α treatment. Molecularly, miR-146a decreased Smad4 expression at the protein level by binding to an element located in the Smad4 3′-untranslated region, and restoration of Smad4 reversed the inhibitory effects of miR-146a on osteogenesis. Together, our results showed that the inflammatory environment mimic TNF-α inhibits osteogenesis via upregulation of miR-146a and subsequent downregulation of Smad4, thus suggesting that therapeutic manipulation of miR-146a maybe a potential strategy to improve osteogenesis in the context of osteoporosis.

Osteoporosis: Explaining the link with inflammation

A molecular mechanism that blocks bone cell formation as a result of inflammation suggests a new therapeutic strategy in osteoporosis. Inflammation is known to contribute to osteoporosis, but the underlying mechanism is unknown. Jiali Tan from the Sun Yat-sen University, Guangzhou, China, and colleagues suspected involvement of the small RNA molecule miR-146a, as it is involved in bone cell production and is targeted by the pro-inflammatory protein TNF-α. The researchers tested their hypothesis by treating mouse bone stem cells with TNF-α, and found that levels of miR-146a in the cells were increased. This increase led to a decrease in levels of another protein, Smad4, which is essential for bone cell development. The findings suggest that manipulation of miR-146a levels in bone stem cells could encourage bone growth in osteoporosis.

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