AUTHOR=Elli Francesca Marta , Mattinzoli Deborah , Ikehata Masami , Bagnaresi Francesca , Maffini Maria A. , Del Sindaco Giulia , Pagnano Angela , Lucca Camilla , Messa Piergiorgio , Arosio Maura , Castellano Giuseppe , Alfieri Carlo M. , Mantovani Giovanna 

TITLE=Targeted silencing of GNAS in a human model of osteoprogenitor cells results in the deregulation of the osteogenic differentiation program

JOURNAL=Frontiers in Endocrinology

VOLUME=15

YEAR=2024

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1296886

DOI=10.3389/fendo.2024.1296886

ISSN=1664-2392

ABSTRACT=<sec><title>Introduction</title><p>The dysregulation of cell fate toward osteoprecursor cells associated with most <italic>GNAS</italic>-based disorders may lead to episodic <italic>de novo</italic> extraskeletal or ectopic bone formation in subcutaneous tissues. The bony lesion distribution suggests the involvement of abnormal differentiation of mesenchymal stem cells (MSCs) and/or more committed precursor cells. Data from transgenic mice support the concept that <italic>GNAS</italic> is a crucial factor in regulating lineage switching between osteoblasts (OBs) and adipocyte fates. The mosaic nature of heterotopic bone lesions suggests that <italic>GNAS</italic> genetic defects provide a sensitized background for ectopic osteodifferentiation, but the underlying molecular mechanism remains largely unknown.</p></sec><sec><title>Methods</title><p>The effect of <italic>GNAS</italic> silencing in the presence and/or absence of osteoblastic stimuli was evaluated in the human L88/5 MSC line during osteodifferentiation. A comparison of the data obtained with data coming from a bony lesion from a <italic>GNAS</italic>-mutated patient was also provided.</p></sec><sec><title>Results</title><p>Our study adds some dowels to the current fragmented notions about the role of <italic>GNAS</italic> during osteoblastic differentiation, such as the premature transition of immature OBs into osteocytes and the characterization of the differences in the deposed bone matrix.</p></sec><sec><title>Conclusion</title><p>We demonstrated that our cell model partially replicates the <italic>in vivo</italic> behavior results, resulting in an applicable human model to elucidate the pathophysiology of ectopic bone formation in <italic>GNAS</italic>-based disorders.</p></sec>