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 (SMN1) 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 μCT 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 which enhance SMN levels in the central nervous system only.

中文翻译：

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在脊髓性肌萎缩症 (SMA) 中，随着软骨形成受损而改变的骨骼发育先于神经肌肉症状。

脊髓性肌萎缩症（SMA）是由运动神经元存活基因1（SMN1）的突变或缺失引起的新生儿和儿童的致命神经退行性疾病) 导致 SMN 蛋白水平低。虽然神经肌肉变性是该疾病的主要症状，但普遍表达的 SMN 的减少还会引起非运动神经元症状。骨骼发育受损是 SMA 的一个关键特征，但尚不清楚这是肌肉无力的间接功能后果还是由骨骼内在机制引起的。因此，我们在一项表征骨大小和骨矿物质密度 (BMD) 的前瞻性、非随机队列研究中对 SMA 患者进行放射学检查，并在出现症状前的 SMA 小鼠中进行了等效测量。SMA 患者的 BMD 和腰椎体尺寸显着降低。在神经肌肉症状出现之前，通过 μCT 在 SMA 小鼠中证实了这种生长缺陷而不是 BMD 降低，这表明它至少部分独立于神经肌肉变性。有趣的是，生长板肥大区的成软骨细胞数量显着减少。RNAseq 和来自发育中的 SMA 小鼠椎体的表达数据强调了这一点，这些数据揭示了与细胞分裂和软骨重塑相关的分子变化。总之，这些发现表明 SMA 存在骨内在缺陷。这种表型可能无法通过仅提高中枢神经系统中 SMN 水平的新型药物来挽救。RNAseq 和来自发育中的 SMA 小鼠椎体的表达数据强调了这一点，这些数据揭示了与细胞分裂和软骨重塑相关的分子变化。总之，这些发现表明 SMA 存在骨内在缺陷。这种表型可能无法通过仅提高中枢神经系统中 SMN 水平的新型药物来挽救。RNAseq 和来自发育中的 SMA 小鼠椎体的表达数据强调了这一点，这些数据揭示了与细胞分裂和软骨重塑相关的分子变化。总之，这些发现表明 SMA 存在骨内在缺陷。这种表型可能无法通过仅提高中枢神经系统中 SMN 水平的新型药物来挽救。