Update on the pathogenesis and genetics of Paget's disease of bone

Studies over the past two decades have led to major advances in the pathogenesis of Paget's disease of bone (PDB) and particularly on the role of genetic factors. Germline mutations of different genes have been identified, as a possible cause of this disorder, and most of the underlying pathways are implicated in the regulation of osteoclast differentiation and function, whereas other are involved in cell autophagy mechanisms. In particular, about 30 different germline mutations of the Sequestosome 1 gene (SQSTM1) have been described in a significant proportion of familial and sporadic PDB cases. The majority of SQSTM1 mutations affect the ubiquitin-binding domain of the protein and are associated to a more severe clinical expression of the disease. Also, germline mutations in the ZNF687 and PFN1 genes have been associated to severe, early onset, polyostotic PDB with increased susceptibly to neoplastic degeneration, particularly giant cell tumor. Mutations in the VCP (Valosin Containing Protein) gene cause the autosomal dominant syndrome "Inclusion Body Myopathy, PDB, Fronto-temporal Dementia," characterized by pagetic manifestations, associated with myopathy, amyotrophic lateral sclerosis and fronto-temporal dementia. Moreover, germline mutations in the TNFRSF11A gene, which encodes for RANK, were associated with rare syndromes showing some histopathological, radiological, and clinical overlap with PDB and in two cases of early onset PDB-like disease. Likewise, genome wide association studies performed in unrelated PDB cases identified other potential predisposition genes and/or susceptibility loci. Thus, it is likely that polygenic factors are involved in the PDB pathogenesis in many individuals and that modifying genes may contribute in refining the clinical phenotype. Moreover, the contribution of somatic mutations of SQSTM1 gene and/or epigenetic mechanisms in the pathogenesis of skeletal pagetic abnormalities and eventually neoplastic degeneration, cannot be excluded. Indeed, clinical and experimental observations indicate that genetic susceptibility might not be a sufficient condition for the clinical development of PDB without the concomitant intervention of viral infection, in primis paramixoviruses, and/or other environmental factors (e.g., pesticides, heavy metals or tobacco exposure), at least in a subset of cases. This review summarizes the most important advances that have been made in the field of cellular and molecular biology PDB over the past decades. © 2022 Gennari, Rendina, Merlotti, Cavati, Mingiano, Cosso, Materozzi, Pirrotta, Abate, Calabrese and Falchetti

The Potential Role of miRNAs as New Biomarkers for Osteoporosis

Osteoporosis is the most common metabolic bone disorder affecting up to 40% of postmenopausal women, characterized by a reduction in bone mass and strength leading to bone fragility and fractures. Despite the available tools for diagnosis and stratification of a fracture risk, bone loss occurs insidiously and osteoporosis is often diagnosed after the first fracture has occurred, with important health-related outcomes. Therefore, the need of markers that could efficiently diagnose bone fragility and osteoporosis is still necessary. Over the past few years, novel studies have focused on miRNAs, small noncoding RNAs that are differentially expressed in many pathological conditions, making them attractive biomarkers. To date, the role of miRNAs in bone disorders remains in great part unclear. In particular, limited and partly conflicting information is available concerning their use as potential biomarkers for osteoporosis, due to differences in patient selection, type of samples, and analytical methods. Despite these limits, concordant information about some specific miRNAs is now arising, making likely their use as additional tools to stratify the risk of osteoporosis and possibly fractures. In this review, we summarize the most relevant studies concerning circulating miRNAs differentially expressed in osteoporotic patients along with their function in bone cells and bone turnover

Benzene toxicity in C57Bl mice after gastic subchronic administration.

Risultati preliminari del progett

Effetto del trattamento subcronico con benzene in topi C57BL

Abstarct accettato e incluso nella tavola rotonda "Valutazione del rischi dell'esposizione professionale ed ambientale a benzene: studio dei meccanismi di attivazione e tossicit\ue0 e degli indicatori di esposizione, effetto e suscettibilit\ue0

Recent advances in models for screening potential osteoporosis drugs

Osteoporosis is a growing health and health-economic problem due to the increased proportion of elderly people in the population. Basic and clinical advances in research over the past two decades have led to the development of different compounds with antiresorptive or anabolic activity on bone that improved substantially the management of patients with osteoporosis over calcitonin or estrogen replacement. New compounds are in preclinical and clinical development. Areas covered: In this review, the authors review the approaches for the preclinical and clinical development of antiresorptive and anabolic agents for osteoporosis, particularly focusing on the recent advances in technology and in the understanding of skeletal biology, together with their implications on novel osteoporosis drug discovery. Expert opinion: Based on the available evidence from the approved drugs for the treatment osteoporosis as well as from the different compounds under clinical development, it has become clear that long term nonclinical pharmacological studies with either bone quality and off-target effects as the main outcomes should be required for new drugs intended to treat osteoporosis. At the same time, basic and clinical advances in research have underlined the necessity to develop new technologies and new models for a thorough screening of the effects of new drugs on the different components of skeletal aging and bone fragility that cannot be assessed by bone mass measurement

Paget’s disease of bone: an update on epidemiology, pathogenesis and pharmacotherapy

Introduction: Paget’s disease of bone (PDB) is a chronic bone disorder, which affects middle-aged or older adults and results in enlarged and deformed bones in one or more skeletal regions. Family history has been reported in up to 40% of cases, suggesting a consistent genetic predisposition. At affected sites, the characteristic feature of PDB is an increased resorption followed by an increased bone formation, producing a disorganized and structurally abnormal bone. Consequently, bone pain, arthritis, deformities, and fractures can occur. In less than 1%, neoplastic degeneration in osteosarcoma, or giant cell tumor has been described at PDB sites. Areas covered: We provide a contemporary overview of the epidemiology, pathogenesis and treatment of PDB. Expert opinion: While recent epidemiological evidence indicates a decreasing prevalence and severity of PDB, over the past two decades there have been consistent advances on the genetic mechanisms of PDB. It is now clear that PDB is a genetically heterogeneous disorder, with at least three different genes (SQSTM1, ZNF687, FKBP5) involved in the classic form and four additional genes identified in PDB-related syndromes. The clinical management of PDB has also evolved, with the development of the most potent aminobisphosphonate, zoledronic acid, which allows long-term remission in the majority of patients