let-7Enhances Osteogenesis and Bone Formation While Repressing Adipogenesis of Human Stromal/Mesenchymal Stem Cells by Regulating HMGA2

Abstract

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.

Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation

“…Indeed, it was reported that let-7 levels are increased during osteogenic lineage commitment of mesenchymal stem cells [55], and that ectopic expression of let-7 enhances osteoblast formation in vitro and in vivo by targeting HMGA2 [27]. Our in vitro data confirmed these effects in both donors on the level of ALP expression and in one donor on the level of Alizarin staining.…”

Identification and Characterization of Long Non-Coding RNAs in Osteogenic Differentiation of Human Adipose-Derived Stem Cells

“…It was reported that H19 also served as a competing endogenous RNA for the let-7 family of microRNAs and its deletion resulted in overexpression of let-7 [40]. Moreover, let-7 has been showed to enhance osteogenesis and suppress adipogenesis by negatively regulating high mobility group AT hook 2 ( HMGA2 ) in ASCs [41]. Therefore, we attempted to determine whether H19 could act as a molecular sponge for let-7 to regulate the function of HMGA2 in ASCs.…”

miRNA regulation of white and brown adipose tissue differentiation and function

“…Interestingly, let-7-mediated repression of adipogenesis was also found to promote osteogenesis [58]. HMGA2 and let-7 have been found be important regulators of tumor growth and are known to be dysregulated in lipomas and liposarcomas from human patients [59, 60].…”