Epigenome-wide association study shows that smoking alters DNA methylation in blood cells triggering aggressive bone resorption of osteoclasts in vivo and in vitro

Salah Eddine Masmoudi, Anaïs M.J. Møller, Jonas S. Madsen, Jean-Marie Delaissé, Bjarne W. Rasnussen, Qihua Tan, Kent Søe
2021 Bone Reports  
Background/Introduction: Src-homology (SH) 2 domaincontaining inositol-5-phosphatase 1 (SHIP1) is a lipid phosphatase expressed mainly in hematopoietic cells. SHIP1 regulates cell proliferation, differentiation, and survival via the PI3K/Akt signaling pathway. SHIP1-deficient (Styx) mice are osteoporotic, which is associated with an increased number of osteoclasts (OC). Purpose: This study aimed to investigate the underlying mechanisms through which SHIP1 controls osteoporosis. Methods:
more » ... st progenitor cells (OPC) were generated by incubating bone marrow cells with CSF-1. To develop OC, OPC from Styx, Styx het (heterozygous) and wt (wild type) mice were cultured with RANKL and CSF-1. Osteoclastogenesis was evaluated using an XTT cell viability assay, TRAP activity (OC marker) and qRT-PCR. Micro-computed tomography (Micro-CT) of vertebrae and femora were performed to evaluate the bone structure. Results: Deficiency in SHIP1 affected several aspects of bone. Compared to Styx het and wt controls, OPC-derived Styx OC presented several developmental defects, including a lower TRAP/ XTT ratio and a 52% decrease in Calcr transcripts (encoding for the Calcitonin Receptor) (pb0.001). In vivo, there was a strong reduction of BV/TV in vertebrae and femora of Styx versus wt animals (39.6% and 35%, respectively, pb0.01). In particular, trabeculae in Styx vertebrae were increased by 8% (pb0.05) in numbers while decreased by 37% in thickness (pb0.001). In contrast, in Styx femora both the number and thickness of the trabeculae were decreased by 16% and 14%, respectively. These different phenotypes in Styx femora versus vertebrae indicate different paths to osteoporosis in bones with primary or secondary spongiosa. Conclusion(s): Taken together, our data indicate a central role for SHIP1-dependent PI3K/Akt signalling in bone remodeling. Further investigation will address the role of osteoblasts in the development of osteoporosis in SHIP1-deficient Styx mice.
doi:10.1016/j.bonr.2021.100796 fatcat:drjhlwlc5nd6tbv3bafvu2rrte