Osteoporosis, fracture, osteoarthritis & sarcopenia: A systematic review of circulating microRNA association.

Circulating microRNAs (c-miRs) show promise as biomarkers. This systematic review explores their potential association with age-related fracture/osteoporosis (OP), osteoarthritis (OA) and sarcopenia (SP), as well as cross-disease association. Most overlap occurred between OA and OP, suggesting potentially shared microRNA activity. There was little agreement in results across studies. Few reported receiver operating characteristic analysis (ROC) and many identified significant dysregulation in disease, but direction of effect was commonly conflicting. c-miRs with most evidence for consistency in dysregulation included miR-146a, miR-155 and miR-98 for OA (upregulated). Area under the curve (AUC) for miR-146a biomarker performance was AUC 0.92, p = 0.028. miR-125b (AUC 0.76-0.89), miR-100, miR-148a and miR-24 were consistently upregulated in OP. Insufficient evidence exists for c-miRs in SP. Study quality was typically rated intermediate/high risk of bias. Wide study heterogeneity meant meta-analysis was not possible. We provide detailed critique and recommendations for future approaches in c-miR analyses based on this review.

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer.

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including splicing switches correlating with disease progression. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, treatment with the AR antagonist bicalutamide (Casodex) induced mesenchymal splicing patterns of genes including FLNB and CTNND1. Our data reveals a new mechanism of splicing control in prostate cancer with important implications for disease progression.