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

## TL;DR

This study shows that bone cells in an ALS mouse model age prematurely before motor symptoms appear, leading to early bone deterioration.

## Contribution

The study reveals that bone deterioration in ALS is an autonomous process linked to early osteoblast senescence, independent of motor symptoms.

## Key findings

- Bone structural deficits and reduced bone mineral density are observed in presymptomatic ALS mice.
- Osteoblast loss and premature senescence are identified as early mechanisms of bone deterioration.
- Transcriptomic analysis shows dysregulation of osteoblast differentiation and upregulation of cell senescence pathways.

## 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.

In an ALS mouse model we show that bone cells undergo accelerated senescence already before the onset of neurological symptoms, due to their insensitivity to osteogenic mediators