Gene-environment interactions in Paget's disease of bone

• Published in: Joint, bone, spine : revue du rhumatisme bone, spine : revue du rhumatisme, 2019-05, Vol.86 (3), p.373-380
• Main Authors: Numan, Mohamed S., Jean, Sonia, Dessay, Mariam, Gagnon, Edith, Amiable, Nathalie, Brown, Jacques P., Michou, Laëtitia
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Age Factors; Air Pollutants - adverse effects; Cadmium; Cadmium - adverse effects; Cross-Sectional Studies; Environmental Exposure - adverse effects; Female; Gene Expression Regulation; Gene-Environment Interaction; Genetic Predisposition to Disease - epidemiology; Heavy metals; Humans; Incidence; Logistic Models; Male; Middle Aged; Multivariate Analysis; Mutation; Osteitis Deformans - epidemiology; Osteitis Deformans - etiology; Osteitis Deformans - genetics; Osteoclast; Osteoclasts - drug effects; Oxidative stress; Paget's disease of bone; Quebec; RANK Ligand - metabolism; Reference Values; Risk Assessment; Sequestosome-1 Protein - genetics; Sex Factors; SQSTM1gene; Tobacco Smoke Pollution - adverse effects
• ISSN: 1297-319X; 1778-7254
• DOI: 10.1016/j.jbspin.2018.12.007

This study explored the role of outdoor and indoor air pollutants in Paget's disease of bone (PDB). We performed a survey in 140 French-Canadian patients with PDB, including 39 carriers of p.Pro392Leu mutation (SQSTM1 gene) and 113 healthy not mutated controls. The survey covered outdoor air pollution near the residence and indoor air pollutants by focusing on heating fuels and exposure to tobacco smoke. In a subgroup of patients, urinary concentrations of 17 heavy metals and 11 polycyclic aromatic hydrocarbons were measured by mass spectrometry. In light of what we learned from the survey and urinary assays, we explored the in vitro effects of certain toxics on osteoclasts in PDB. We conducted in vitro monocytes differentiation from peripheral blood of more than 40 participants, whose osteoclasts were treated with or without the toxic. The morphology of osteoclasts, their bone resorption abilities, gene and protein expression levels, and cellular oxidative stress levels were assayed. An inhibitory effect of cigarette smoke condensate and heavy metals was observed on morphology and bone resorption activity of patients’ osteoclasts. SQSTM1 gene expression was upregulated in osteoclasts from patients with PDB versus healthy controls in presence of cadmium, and SQSTM1 protein expression was upregulated in presence of bismuth and tobacco smoke condensates, in particular in osteoclasts from carriers of the SQSTM1 mutation. Furthermore, high levels of oxidative stress in patients’ osteoclasts were observed. Our in vitro experiments suggest an interaction between SQSTM1 gene and exposure to cadmium and tobacco smoke condensates.