Auteurs
Samee N - Belz L - Narboux-Nême N - Roux JC - Panayotis N - Levi G
Journal
Cells
Abstract
Rett syndrome is a severe neurodevelopmental disorder caused predominantly by loss-of-function mutations in the X-linked gene . In addition to a vast array of neurological and physiological impairments, patients also frequently develop severe osteopenia with increased fracture risk; however, the mechanisms underlying these skeletal defects are not completely understood. Previous work in -null mouse models has suggested that osteopenia is mainly due to impaired osteoblast function and reduced bone formation. Here, we examined bone mass, microarchitecture, and remodeling parameters in a -null mouse model during postnatal development, with a particular focus on osteoclast involvement. Microcomputed tomography and histomorphometric analyses showed reduced bone mineral density and trabecular bone volume, which are associated with increased trabecular separation and cortical thinning. These structural alterations were accompanied by increased osteoclast number per bone surface, elevated urinary deoxypyridinoline, and higher expression of osteoclast-associated genes, including . Furthermore, gene expression analysis revealed an age-dependent shift in bone remodeling. At postnatal day 35, mutant mice showed reduced expression of and , consistent with low bone turnover. By postnatal day 55, and were markedly upregulated, suggesting an increase in osteoclast resorptive activity, while key osteoblast markers and the RANKL/OPG ratio did not change significantly. A potential cell-autonomous contribution of to osteoclast maturation is also suggested by the analysis of public transcriptomic datasets on human osteoclast differentiation. Together, our findings identify increased osteoclast activity as a significant contributor to Rett-associated osteopenia and suggest that skeletal pathology in deficiency progresses from an early low-turnover state to a later phase of increased osteoclast resorption.