Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia

Abstract

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in GNAS, encoding for Gαs, which leads to excessive cAMP signaling in bone marrow stromal cells (BMSCs). Despite advancements in our understanding of FD pathophysiology, the effect of Gαs activation in the BMSC transcriptome remains unclear, as well as how this translates into their local influence in the lesional microenvironment. In this study, we analyzed changes induced by Gαs activation in BMSC transcriptome and performed a comprehensive analysis of their production of cytokines and other secreted factors. We performed RNAseq of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, and combined their transcriptomic profiles to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. In addition, a comprehensive profile of their secreted cytokines and other factors was performed to identify modulation of several key factors we hypothesized to be involved in FD pathogenesis. We also screened circulating cytokines in a collection of plasma samples from patients with FD, finding positive correlations of several cytokines with their disease burden, as well as with other cytokines and bone turnover markers. Overall, these data support a pro-inflammatory, pro-osteoclastic behavior of BMSCs bearing hyperactive Gαs variants, and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

Vitamin D Attenuates Fibrotic Properties of Fibrous Dysplasia-Derived Cells for the Transit towards Osteocytic Phenotype

“…The pathogenesis of FD involves atypical pre-osteoblastic and mesenchymal stromal fibroblastic cell populations, whose actions drive the pathological alterations observed in FD lesions [1,2]. Central to these aberrations is the GNAS mutation in bone marrow mesenchymal stem cells (BMSCs), which disrupt cyclic AMP (cAMP)-associated pathways to trigger a cascade of pathological events [3].…”