Exosomes rewire the cartilage microenvironment in osteoarthritis:from intercellular communication to therapeutic strategies

Osteoarthritis(OA)is a prevalent degenerative joint disease characterized by cartilage loss and accounts for a major source of pain and disability worldwide.However,effective strategies for cartilage repair are lacking,and patients with advanced OA usually need joint replacement.Better comprehending OA pathogenesis may lead to transformative therapeutics.Recently studies have reported that exosomes act as a new means of cell-to-cell communication by delivering multiple bioactive molecules to create a particular microenvironment that tunes cartilage behavior.Specifically,exosome cargos,such as noncoding RNAs(ncRNAs)and proteins,play a crucial role in OA progression by regulating the proliferation,apoptosis,autophagy,and inflammatory response of joint cells,rendering them promising candidates for OA monitoring and treatment.This review systematically summarizes the current insight regarding the biogenesis and function of exosomes and their potential as therapeutic tools targeting cell-to-cell communication in OA,suggesting new realms to improve OA management.

The Role of Exportin-5 in MicroRNA Biogenesis and Cancer

MicroRNAs （miRNAs） are conserved small non-coding RNAs that play an important role in the regulation of gene expression and participate in a variety of biological processes. The biogenesis of miRNAs is tightly controlled at multiple steps, such as transcription of miRNA genes, processing by Drosha and Dicer, and transportation of precursor miRNAs （pre-miRNAs） from the nucleus to the cytoplasm by exportin-5 （XPO5）. Given the critical role of nuclear export of premiRNAs in miRNA biogenesis, any alterations of XPO5, resulting from either genetic mutation, epigenetic change, abnormal expression level or posttranslational modification, could affect miRNA expression and thus have profound effects on tumorigenesis. Importantly, XPO5 phosphorylation by ERK kinase and its cis/trans isomerization by the prolyl isomerase Pinl impair XPO5＇s nucleo-to-cytoplasmic transport ability of pre-miRNAs, leading to downregulation of mature miRNAs in hepatocellular carcinoma. In this review, we focus on how XPO5 transports pre-miRNAs in the cells and summarize the dysregnlation of XPO5 in human tumors.

Cysteine-113 covalency inspires the development of Pin1 inhibitor

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1(Pin1)controls the functional switch of phosphoproteins and plays an oncogenic role in human cancer,but the discovery of effective Pin1 inhibitors remains challenging.A recent study by Pinch et al.developed a novel Pin1 inhibitor by endowing molecule with covalent reactivity toward Pin1 cysteine-113,1 providing new insights into the design of anticancer Pin1 inhibitors.