Excluding monogenic bone disorders, it is now well established that in complex multifactorial diseases, with a recognized hereditary component, such as Paget?s disease of bone and osteoporosis, the associated genetic variants have a limited impact on gene expression and explain only a small fraction of the disease risk. Moreover, a larger proportion of variants associated to many human traits or diseases fall in loci which do not encode proteins, suggesting that additional mechanisms other than gene-gene and gene-environment interactions might be involved. In this setting, we focus our attention on Paget?s disease of bone, osteoporosis, and hyperparathyroidism to clarify epigenetic mechanisms involved in their pathogenesis. MicroRNAs (miRNAs) are small (?22 nt), noncoding single-stranded RNAs that have emerged as important posttranscriptional regulators of gene expression, with an essential role in vertebrate development and several biological processes. They contribute to every step of osteogenesis and bone homeostasis, from embryonic skeletal development to maintenance of adult bone tissue, by regulating the growth, differentiation, and activity of different cell systems inside and outside the skeleton. However, despite the rising number of experimental reports about this issue, our understanding of the exact mechanisms through which miRNAs are involved in the pathogenesis of Paget?s disease of bone, osteoporosis, and hyperparathyroidism remain unclear. For these reasons, we performed a miRNAs expression profiling in peripheric mononuclear cells (PBMCs) and serum of wild type pagetic patients (PDB-WT) and with mutations on the SQSTM1 gene (PDB-MUT) and osteoporotic subjects (OP) compared to healthy controls, using TaqMan Low Density MicroRNA Array Cards. After that, we performed the same analysis in serum of patients with hypercalcemic primary hyperparathyroidism and osteoporosis (H-PHPT) and normocalcemic primary hyperparathyroidism without osteoporosis (N-PHPT), compared to healthy controls. Differentially expressed miRNAs identified in PBMCs of pagetic and osteoporotic patients were then validated in single assay, while the validation of miRNAs identified in the serum of all subjects is ongoing. A bioinformatic analysis (Gene Ontology analysis) was performed to find putative functional pathways and biological processes linked to some differentially expressed miRNAs. These analyses identified numerous genes and pathways involved in regulation of osteoclasts, osteoblasts differentiation and bone metabolism in all the three pathologies considered. These results could be used not only to better understand new molecular mechanisms involved in Paget?s disease, osteoporosis, and hyperparathyroidism pathogenesis, but also as a resource of new biomarkers that could be introduced in the clinical practice as diagnostic tools.
Simone Bianciardi (Fri,) studied this question.