A Signature of Circulating miRNAs Associated With Fibrous Dysplasia of Bone: the mirDys Study

Abstract

Fibrous dysplasia (FD) is a rare bone disease caused by activating mutations of GNAS encoding the Gsα protein, enhancing cyclic adenosine monophosphate (cAMP) production by overstimulation of adenylyl cyclase and impairing osteoblastic differentiation. The clinical presentation ranges from asymptomatic to polyostotic forms with severe disability, explained by the mosaic distribution of the GNAS mutation. Physicians have to deal with the gap of knowledge in FD pathogenesis, the absence of prognostic markers and the lack of specific treatment. The identification of specific biomarkers for FD is an important step to improve the clinical and therapeutic approaches. An epigenetic regulation driven by microRNAs (miRNAs), known as promising biomarkers in bone disease, could be involved in FD. We have sought circulating miRNAs that are differentially expressed in FD patients compared to controls and would reflect dysregulations of osteogenesis-related genes and bone disorder. The global miRNA profiling was performed using Next Generation Sequencing in patient serum collected from a discovery cohort of 20 patients (10 polyostotic and 10 monostotic) and 10 controls. From these, we selected 19 miRNAs for a miRNA validation phase from serum of 82 patients and 82 controls, using real-time qPCR. Discovery screening identified 111 miRNAs differentially expressed in patient serum, after adjusting for the false discovery rate (FDR). Among the 82 patients, 55% were polyostotic, and 73% were women with a mean age of 42 years. Six miRNAs (miR-25-3p, miR-93-5p, miR-182-5p, miR-324-5p, miR-363-3p, and miR-451a) were significantly overexpressed in serum, with FDR <0.05. The expression level of these six miRNAs was not associated with the FD severity. In conclusion, we identified a signature of circulating miRNAs associated with FD. These miRNAs are potential negative regulators of gene expression in bone cell progenitors, suggesting their activity in FD by interfering with osteoblastic and osteoclastic differentiation to impair bone mineralization and remodeling processes.

Multiple targets identified with genome wide profiling of small RNA and mRNA expression are linked to fracture healing in mice

“…In addition, a few of the bone-associated miRNAs, e.g., miR-150-5p, miR-223-3p, miR-93-5p have been detected in matrix particles or circulating exosomes ( Kelch et al, 2017 ; Legrand et al, 2020 ; Lu et al, 2019 ; Mäkitie et al, 2018 ; Perez-Sanchez et al, 2018 ; Hosokawa et al, 2017 ) and may therefore be important in cell-cell communication and systemic regulation of body functions.…”

A CREB1-miR-181a-5p loop regulates the pathophysiologic features of bone marrow stromal cells in fibrous dysplasia of bone

“…Existing studies have shown that miRNAs are involved in a series of biological processes, such as cell proliferation and differentiation. A recent report identified a number of circulating miRNAs that are potential negative regulators of gene expression in bone cell progenitors and were associated with FD (Legrand et al 2020 ). In this study, we performed miRNA sequencing analysis of normal BMSCs and FD BMSCs, and the results showed that miR-181a-5p, miR-145-3p, miR-98-3p and miR-92b-5p were significantly differentially expressed miRNAs.…”

Sustained Morphine Delivery Suppresses Bone Formation and Alters Metabolic and Circulating miRNA Profiles in Male C57BL/6J Mice

“…Bai et al, (28) Pan et al, (29) and Legrand et al (30) miR-6769b-5p À3.372 0.009 Overexpressed by bone marrow-derived macrophages leading to a phenotypic switch to fibrolytic macrophages with increased MMP9 expression and reduced ATF4 and inflammatory cytokine production.…”

“…Bai et al (24) , Pan et al (25) , and Legrand et al (26) miR-6769b-5p -3.372 0.009 Potentially, it is expression by bone marrow-derived macrophages. miR-351-5p -2.751 0.002 Yes, it is involved in the regulation of Dishevelled 2 (Dvl-2), a key mediator of the Wnt/β-catenin signaling pathway.…”