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@ARTICLE{zkan:285487,
      author       = {Özkan, Burak and Ramge, Jan-Moritz and Wiesner, Diana and
                      Scekic-Zahirovic, Jelena and Antonucci, Stefano and Nungeß,
                      Sandra and Gebauer, Dorothea and Ignatius, Anita and
                      Weishaupt, Jochen H and Haffner-Luntzer, Melanie and
                      Roselli, Francesco},
      title        = {{R}educed osteogenic factors and early osteoblast
                      senescence in {SOD}1({G}93{A}) {ALS} mouse model.},
      journal      = {JCI insight},
      volume       = {11},
      number       = {5},
      issn         = {2379-3708},
      address      = {Ann Arbor, Michigan},
      publisher    = {JCI Insight},
      reportid     = {DZNE-2026-00263},
      pages        = {e197475},
      year         = {2026},
      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.},
      keywords     = {Animals / Amyotrophic Lateral Sclerosis: genetics /
                      Amyotrophic Lateral Sclerosis: pathology / Amyotrophic
                      Lateral Sclerosis: metabolism / Amyotrophic Lateral
                      Sclerosis: physiopathology / Osteoblasts: metabolism /
                      Osteoblasts: pathology / Disease Models, Animal / Mice /
                      Superoxide Dismutase-1: genetics / Superoxide Dismutase-1:
                      metabolism / Osteogenesis: genetics / Mice, Transgenic /
                      Cellular Senescence: genetics / X-Ray Microtomography / Bone
                      Density / Male / Humans / Cell Differentiation / Superoxide
                      Dismutase / Bone biology (Other) / Cell biology (Other) /
                      Cellular senescence (Other) / Neurodegeneration (Other) /
                      Neuroscience (Other) / Osteoclast/osteoblast biology (Other)
                      / Superoxide Dismutase-1 (NLM Chemicals) / SOD1 G93A protein
                      (NLM Chemicals) / Sod1 protein, mouse (NLM Chemicals) /
                      Superoxide Dismutase (NLM Chemicals)},
      cin          = {AG Roselli},
      ddc          = {610},
      cid          = {I:(DE-2719)1910001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41569660},
      doi          = {10.1172/jci.insight.197475},
      url          = {https://pub.dzne.de/record/285487},
}