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ResearchIn-Press PreviewBone biologyCell biologyNeuroscience Open Access | 10.1172/jci.insight.197475

Reduced osteogenic factors and early osteoblast senescence in SOD1(G93A) ALS mouse model

Burak Özkan,1 Jan-Moritz Ramge,2 Diana Wiesner,3 Jelena Scekic-Zahirovic,3 Stefano Antonucci,1 Sandra Nungeß,2 Dorothea Gebauer,2 Anita Ignatius,2 Jochen H. Weishaupt,1 Melanie Haffner-Luntzer,2 and Francesco Roselli1

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

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1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Ramge, J. in: PubMed | Google Scholar

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Wiesner, D. in: PubMed | Google Scholar

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Scekic-Zahirovic, J. in: PubMed | Google Scholar

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Antonucci, S. in: PubMed | Google Scholar

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Nungeß, S. in: PubMed | Google Scholar

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Gebauer, D. in: PubMed | Google Scholar

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Ignatius, A. in: PubMed | Google Scholar

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Weishaupt, J. in: PubMed | Google Scholar

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Haffner-Luntzer, M. in: PubMed | Google Scholar

1Dept. of Neurology, Ulm University, Ulm, Germany

2Inst. of Orthopaedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany

3German Center for Neurodegenerative Diseases, Ulm, Germany

Find articles by Roselli, F. in: PubMed | Google Scholar |

Published January 22, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.197475.
Copyright © 2026, Özkan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 22, 2026 - Version history
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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) stage 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 precede overt motor symptoms and are linked to osteoblast premature senescence.

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Version history
  • Version 1 (January 22, 2026): In-Press Preview
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