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Publication : Altered bone development with impaired cartilage formation precedes neuromuscular symptoms in spinal muscular atrophy.

First Author  Hensel N Year  2020
Journal  Hum Mol Genet Volume  29
Issue  16 Pages  2662-2673
PubMed ID  32644125 Mgi Jnum  J:296434
Mgi Id  MGI:6467213 Doi  10.1093/hmg/ddaa145
Citation  Hensel N, et al. (2020) Altered bone development with impaired cartilage formation precedes neuromuscular symptoms in spinal muscular atrophy. Hum Mol Genet 29(16):2662-2673
abstractText  Spinal muscular atrophy (SMA) is a fatal neurodegenerative disease of newborns and children caused by mutations or deletions of the survival of motoneuron gene 1 resulting in low levels of the SMN protein. While neuromuscular degeneration is the cardinal symptom of the disease, the reduction of the ubiquitously expressed SMN additionally elicits non-motoneuron symptoms. Impaired bone development is a key feature of SMA, but it is yet unknown whether this is an indirect functional consequence of muscle weakness or caused by bone-intrinsic mechanisms. Therefore, we radiologically examined SMA patients in a prospective, non-randomized cohort study characterizing bone size and bone mineral density (BMD) and performed equivalent measurements in pre-symptomatic SMA mice. BMD as well as lumbar vertebral body size were significantly reduced in SMA patients. This growth defect but not BMD reduction was confirmed in SMA mice by muCT before the onset of neuromuscular symptoms indicating that it is at least partially independent of neuromuscular degeneration. Interestingly, the number of chondroblasts in the hypertrophic zone of the growth plate was significantly reduced. This was underlined by RNAseq and expression data from developing SMA mice vertebral bodies, which revealed molecular changes related to cell division and cartilage remodeling. Together, these findings suggest a bone intrinsic defect in SMA. This phenotype may not be rescued by novel drugs that enhance SMN levels in the central nervous system only.
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