Bone fragility is an adverse outcome of
type 2 diabetes mellitus (T2DM). The underlying molecular mechanisms have, however, remained largely unknown.
MicroRNAs (
miRNAs) are short non-coding RNAs that control gene expression in health and disease states. The aim of this study was to investigate the genome-wide regulation of
miRNAs in T2DM
bone disease by analyzing serum and bone tissue samples from a well-established rat model of T2DM, the Zucker Diabetic Fatty (ZDF) model. We performed small
RNA-sequencing analysis to detect dysregulated
miRNAs in the serum and ulna bone of the ZDF model under placebo and also under anti-sclerostin, PTH, and
insulin treatments. The dysregulated circulating
miRNAs were investigated for their cell-type enrichment to identify putative donor cells and were used to construct gene target networks. Our results show that unique sets of
miRNAs are dysregulated in the serum (n = 12, FDR < 0.2) and bone tissue (n = 34, FDR < 0.2) of ZDF rats.
Insulin treatment was found to induce a strong dysregulation of circulating
miRNAs which are mainly involved in metabolism, thereby restoring seven circulating
miRNAs in the ZDF model to normal levels. The effects of anti-sclerostin treatment on serum
miRNA levels were weaker, but affected
miRNAs were shown to be enriched in bone tissue. PTH treatment did not produce any effect on circulating or bone
miRNAs in the ZDF rats. Altogether, this study provides the first comprehensive insights into the dysregulation of bone and serum
miRNAs in the context of T2DM and the effect of
insulin, PTH, and anti-sclerostin treatments on circulating
miRNAs.