Abstract
MicroRNAs let-7c and let-7f, two members of the let-7 family, were involved in regulating osteoblast differentiation and have an important role in bone formation. Let-7e-5p, which also belonged to the let-7 family, presented in the differentiation of adipose-derived stem cells and mouse embryonic stem cells. However, the role of let-7e-5p in osteoblast differentiation was unclear. Thus, this study aimed to elucidate the function of let-7e-5p in osteoblast differentiation and its mechanism. Firstly, we found that the let-7e-5p mimic promoted osteoblast differentiation but not the proliferation of MC3T3-E1 cells by positively regulating the expression levels of osteogenic-associated genes (RUNX2, OCN, OPN, and OSX), the activity of ALP, and formation of mineralized nodules. Moreover, we ascertained that the let-7e-5p mimic downregulated the post-transcriptional expression of SOCS1 by specifically binding to the 3′ untranslated region of SOCS1 mRNA. Also, let-7e-5p-induced SOCS1 downregulation increased the protein levels of p-STAT5 and IGF-1, which were both modulated by SOCS1 molecules. Furthermore, let-7e-5p abrogated the inhibition of osteogenic differentiation mediated by SOCS1 overexpression. Therefore, these results suggested that let-7e-5p regulated the differentiation of MC3T3-E1 cells through the JAK2/STAT5 pathway to upregulate IGF-1 gene expression by inhibiting SOCS1. These findings may provide a new insight into the regulatory role of let-7e-5p in osteogenic differentiation and imply the existence of a novel mechanism underlying let-7e-5p-mediated osteogenic differentiation.
Highlights
Bone repair in trauma, congenital malformations, infections, surgery, and radiotherapy largely depends on the capability of bone formation (Majidinia et al, 2018; Wang T. et al, 2020)
MiRNAs have been regarded as the pivotal regulators that participate in bone repair and regeneration caused by trauma, congenital malformations, infections, surgery, and radiotherapy (Zhang et al, 2017; Chen et al, 2019; Hosseinpour et al, 2019; Zhai et al, 2020)
Many miRNAs exert a considerable effect on osteoblast differentiation and bone formation by increasing the activity of alkaline phosphatase (ALP) and regulating the expression of genes related to osteogenic differentiation (COL-1-α1, OPN, OCN, RUNX2, and OSX) (Itoh et al, 2009; Kim et al, 2009; Li et al, 2009)
Summary
Congenital malformations, infections, surgery, and radiotherapy largely depends on the capability of bone formation (Majidinia et al, 2018; Wang T. et al, 2020). Bone formation and resorption are affected by the balance between osteoblast and osteoclast activities, and osteoblast differentiation is a key stage in bone formation that is closely regulated by factors, such as microRNAs (miRNAs) (Dong et al, 2012; Chen et al, 2015; Castano et al, 2020). Insulinlike growth factor 1 (IGF-1) is regulated by JAK2/STAT5, the downstream signaling pathway of GHR (Darvin et al, 2013). In this process, SOCS1 proteins bind to phosphoserine residues on JAK2 or GHR and suppress GH signaling by inhibiting JAK2 activity or inducing GHR complex degradation (Pass et al, 2009). IGF-1 is essential for the regulation of osteoblast differentiation (Darvin et al, 2013)
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