Paraspeckle-Mediated Integration of Nuclear RNA Regulation in Skeletal Homeostasis and Pathological Disorder.

Abstract

Paraspeckles are NEAT1_2-dependent nuclear ribonucleoprotein condensates that regulate gene expression through RNA retention, protein sequestration, transcriptional control, and RNA processing. This review systematically summarizes paraspeckle organization and examines the roles of NEAT1 isoforms and paraspeckle-associated proteins in diverse skeletal diseases. By integrating evidence from osteoporosis, osteoarthritis, osteosarcoma, and intervertebral disc degeneration, we outline how paraspeckle-related pathways influence skeletal cell differentiation, stress responses, and disease progression. The strongest direct evidence comes from osteoblasts, in which mechanically induced NEAT1_2-dependent paraspeckles retain Smurf1 mRNA in the nucleus, reduce SMURF1 translation, stabilize RUNX2, and promote osteoblast function. In other skeletal contexts, however, many studies have examined total NEAT1 without directly verifying intact paraspeckle function. By distinguishing these levels of evidence, this review clarifies current mechanistic understanding and highlights the therapeutic potential of paraspeckle-related pathways in skeletal disorders.