Journal Article

DZNE-2026-00263

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Reduced osteogenic factors and early osteoblast senescence in SOD1(G93A) ALS mouse model.

Özkan, B. ; Ramge, J.-M. ; Wiesner, D.DZNE* ; Scekic-Zahirovic, J.DZNE* ; Antonucci, S. ; Nungeß, S. ; Gebauer, D. ; Ignatius, A. ; Weishaupt, J. H.DZNE* ; Haffner-Luntzer, M. ; Roselli, F. (Last author)DZNE*

2026
JCI Insight Ann Arbor, Michigan

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Please use a persistent id in citations: doi:10.1172/jci.insight.197475

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease. Emerging evidence suggests manifestations beyond the neuromuscular system. Bone alterations are part of the ALS clinical picture; it remains unclear whether they are secondary to muscle denervation or due to an autonomous process. We investigated skeletal involvement in the SOD1(G93A) mouse model at presymptomatic (P45) and symptomatic (P110) stages through biomechanical and transcriptomic approaches. Three-point bending revealed significant reductions in femoral rigidity and maximum bending force in SOD1 mutants at P45, indicating early structural deficits. Micro-CT analysis demonstrated reduced trabecular bone mineral density and thickness at P45, with progressive trabecular loss and cortical thinning by P110. Histological examination revealed marked osteoblast loss at P45, suggesting impaired bone formation as the primary early mechanism. Transcriptomics of bulk bone and cultured osteoblasts from P45 mice identified dysregulation of bone differentiation, including downregulation of osteoblast differentiation genes and upregulation of negative regulators of ossification and increased cell senescence signatures. Unfolded protein response was upregulated in SOD1 osteoblasts. Immunohistochemistry confirmed the senescence phenotype with increased p16Ink4a level in SOD1 osteoblasts. These findings suggest that bone deterioration precedes overt motor symptoms and is linked to osteoblast premature senescence.

Keyword(s): Animals (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: physiopathology (MeSH) ; Osteoblasts: metabolism (MeSH) ; Osteoblasts: pathology (MeSH) ; Disease Models, Animal (MeSH) ; Mice (MeSH) ; Superoxide Dismutase-1: genetics (MeSH) ; Superoxide Dismutase-1: metabolism (MeSH) ; Osteogenesis: genetics (MeSH) ; Mice, Transgenic (MeSH) ; Cellular Senescence: genetics (MeSH) ; X-Ray Microtomography (MeSH) ; Bone Density (MeSH) ; Male (MeSH) ; Humans (MeSH) ; Cell Differentiation (MeSH) ; Superoxide Dismutase (MeSH) ; Bone biology ; Cell biology ; Cellular senescence ; Neurodegeneration ; Neuroscience ; Osteoclast/osteoblast biology ; Superoxide Dismutase-1 ; SOD1 G93A protein ; Sod1 protein, mouse ; Superoxide Dismutase

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Contributing Institute(s):

1. Metabolic Changes in Neurodegeneration (AG Roselli)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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