ADO2 is a rare genetic disease characterized by dense yet fragile bones. To date, the radiological approach remains the gold standard for ADO2 diagnosis. However, recent observations unveiled that ADO2 is a systemic disease affecting various organs beyond bone, including lung, kidney, muscle and brain. Monitoring disease status and progression would greatly benefit from specific biomarkers shared by the affected organs.Inthiswork,dataderivedfromRNAdeepsequencing(RNA-dSeq) ofbone,lung,kidney,muscle,brainandosteoclastsisolatedfromwildtype and Clcn7 G213R ADO2 mice was subjected to Gene Ontology analyses, which identified shared modulated biological processes, molecular functions and cellular components, with Response to stimulus (p=4.26E-19), Cell communication (p=7.41E-17) and Extracellular space (p=3.34E-41) overrepresented in all ADO2 organs tested and in osteoclasts, and RNA processing (p=1.14E-06), Nucleic acid binding (p=3.70E-05) and Microtubule cytoskeleton (p=7.11E-04) underrepresented. KEGG pathway analysis also revealed the presence of common pathways altered in ADO2 organs and in osteoclasts, including Cytokine-cytokine receptor interaction (p=6.72E-06), Hematopoietic cell lineage (p=3.04E-05), JAK-STAT signaling pathway (p= 0.004), Chemokine signaling pathway (p=0.04), Protein processing in endoplasmic reticulum (p=0.006) and Ubiquitin mediated proteolysis (p=0.01). A deep analysis of the altered pathways allowed us to extrapolatealistofgenesmodulatedinallADO2organs,includingEpor, Ccl8 and Cd38 (pb 0.05), encoding the erythropoietin receptor, the monocyte chemoattractant protein 2 and the cyclic ADP ribose hydrolase, respectively. These genes were modulated also in circulating ADO2 monocytes (pb 0.05), thus representing potential candidate biomarkers of the disease. Given that monocytes give rise to osteoclasts and macrophages and that these two cell types are involved in ADO2 pathogenesis in bone and in visceral organs, respectively, we conclude that these transcriptional biomarkers could represent useful and inexpensive tools for ADO2 diagnosis and monitoring of disease status.
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