miR-6315 Attenuates Methotrexate Treatment-Induced Decreased Osteogenesis and Increased Adipogenesis Potentially through Modulating TGF-β/Smad2 Signalling

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.

miR-6315 silencing protects against spinal cord injury through the Smo and anti-ferroptosis pathway

“…A study analyzed miRNAs for elucidating changes in mTOR pathway activation following T10 SCT [ 38 ]. Another study indicated that miR-6315 may participate in osteogenesis/adipogenesis by regulating the TGF-β/Smad2 signaling pathway [ 39 ]; however, no study has focused on miR-6315 in SCI. The in vivo and in vitro experiments revealed that the expression of miR-6315 was significantly up-regulated after SCI or Glu treatment, and the results were consistent with sequencing results.…”

Post-Transcriptional Regulatory Crosstalk between MicroRNAs and Canonical TGF-β/BMP Signalling Cascades on Osteoblast Lineage: A Comprehensive Review

“…The upregulation of miR-214-5p also decreased TGF-β, p-Smad2, and collagen type IV α1 chain (COL4A1) protein expression in human BMSCs [ 216 ]. Another miRNA miR-6315, was found to promote osteogenic differentiation and to alleviate methotrexate (MTX)-induced increased adipogenesis [ 217 ]. MTX is an antimetabolite-based cancer chemotherapeutic agent proven to induce bone loss and bone marrow adiposity [ 218 ] It was also shown that the effects of miR-6315 involvement in osteogenesis/adipogenesis regulation is potentially via inhibition of TGF-β/Smad2 signalling.…”

“…MTX is an antimetabolite-based cancer chemotherapeutic agent proven to induce bone loss and bone marrow adiposity [ 218 ] It was also shown that the effects of miR-6315 involvement in osteogenesis/adipogenesis regulation is potentially via inhibition of TGF-β/Smad2 signalling. MiR-6315 might be applied as a potential therapeutic target in treatment of long-term skeletal side effects from intensive chemotherapy [ 217 , 218 ].…”