Abstract
Methotrexate (MTX) treatment for childhood malignancies has shown decreased osteogenesis and increased adipogenesis in bone marrow stromal cells (BMSCs), leading to bone loss and bone marrow adiposity, for which the molecular mechanisms are not fully understood. Currently, microRNAs (miRNAs) are emerging as vital mediators involved in bone/bone marrow fat homeostasis and our previous studies have demonstrated that miR-6315 was upregulated in bones of MTX-treated rats, which might be associated with bone/fat imbalance by directly targeting Smad2. However, the underlying mechanisms by which miR-6315 regulates osteogenic and adipogenic differentiation require more investigations. Herein, we further explored and elucidated the regulatory roles of miR-6315 in osteogenesis and adipogenesis using in vitro cell models. We found that miR-6315 promotes osteogenic differentiation and it alleviates MTX-induced increased adipogenesis. Furthermore, our results suggest that the involvement of miR-6315 in osteogenesis/adipogenesis regulation might be partially through modulating the TGF-β/Smad2 signalling pathway. Our findings indicated that miR-6315 may be important in regulating osteogenesis and adipogenesis and might be a therapeutic target for preventing/attenuating MTX treatment-associated bone loss and marrow adiposity.
Highlights
We found that miR-6315 exerts a greater impact on preadipocyte viability and apoptosis than preosteoblasts. miR-6315 promotes osteogenic differentiation and attenuates MTX-induced increased adipogenesis
This study has shown that the MTX chemotherapy-induced bone/fat switch in the bone marrow may be associated with expression and function of miR-6315 in the bone (Figure 8)
MTX-induced decreased osteogenesis and increased adipogenesis via targeting Smad2, which a Biomedicines 2021, 9, x FOR PEER REVIEW may lead to partial suppression of TGF-β signalling
Summary
Bone marrow stromal cells (BMSCs) have the potential to undergo multiple differentiation into diverse cell types, such as osteoblasts, adipocytes, and chondrocytes [1,2]. Commitment and differentiation into various lineages are tightly regulated by the extracellular environment, and changes in the signals and/or molecules can result in abnormal differentiation of BMSCs [3]. Chemotherapy is the most vital modality for treating childhood cancers, owing to a cure rate of higher than 75% [4]. Lifelong bone-related side effects from chemotherapy have increased, such as bone growth impairments, low bone mass, marrow adiposity, and increased fracture risks, decreasing patient life quality [4]. With the greater success in treating cancers, the focus has turned to understanding how chemotherapy damages bone and minimizing these bone defects
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