let-7 enhances osteogenesis and bone formation while repressing adipogenesis of human stromal/mesenchymal stem cells by regulating HMGA2

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

Bone and fat cells share a common progenitor, stromal/mesenchymal stem cells (MSCs), that can differentiate into osteoblasts or adipocytes. Osteogenesis and adipogenesis of MSCs maintain homeostasis under physiological conditions. The disruption of this homeostasis leads to bone-related metabolic diseases. For instance, reduction in bone formation, which is usually accompanied by an increase in bone marrow adipogenesis, occurs with aging, immobility, or osteoporosis. Thus, it is crucial to gain an understanding of how osteogenic and adipogenic lineages of MSCs are regulated. Here, we present evidence that let-7 is a positive regulator of bone development. Using gain- and loss-of-function approaches, we demonstrate that let-7 markedly promotes osteogenesis and suppresses adipogenesis of MSCs in vitro. Moreover, let-7 could promote ectopic bone formation of MSCs in vivo. Subsequent studies further demonstrated that let-7's effects are mediated through the repression of high-mobility group AT-hook 2 (HMGA2) expression. RNAi depletion of HMGA2 could also enhance osteogenesis and repress adipogenesis. Overall, we found a novel role of let-7/HMGA2 axis in regulating the balance of osteogenesis and adipogenesis of MSCs. Thus, let-7 can be used as a novel therapeutic target for disorders that are associated with bone loss and adipocyte accumulation.

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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