Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Hamburg, Germany.
Center for Molecular Neurobiology Hamburg (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Hamburg, Germany.
J Bone Miner Res. 2024 Oct 29;39(11):1606-1620. doi: 10.1093/jbmr/zjae156.
Spermine synthase, encoded by the SMS gene, is involved in polyamine metabolism, as it is required for the synthesis of spermine from its precursor molecule spermidine. Pathogenic variants of SMS are known to cause Snyder-Robinson syndrome (SRS), an X-linked recessive disorder causing various symptoms, including intellectual disability, muscular hypotonia, infertility, but also skeletal abnormalities, such as facial dysmorphisms and osteoporosis. Since the impact of a murine SMS deficiency has so far only been analyzed in Gy mice, where a large genomic deletion also includes the neighboring Phex gene, there is only limited knowledge about the potential role of SMS in bone cell regulation. In the present manuscript, we describe 2 patients carrying distinct SMS variants, both diagnosed with osteoporosis. Whereas the first patient displayed all characteristic hallmarks of SRS, the second patient was initially diagnosed, based on laboratory findings, as a case of adult-onset hypophosphatasia. To study the impact of SMS inactivation on bone remodeling, we took advantage of a newly developed mouse model carrying a pathogenic SMS variant (p.G56S). Compared to their wildtype littermates, 12-wk-old male SMSG56S/0 mice displayed reduced trabecular bone mass and cortical thickness, as assessed by μCT analysis of the femur. This phenotype was histologically confirmed by the analysis of spine and tibia sections, where we also observed a moderate enrichment of non-mineralized osteoid in SMSG56S/0 mice. Cellular and dynamic histomorphometry further identified a reduced bone formation rate as a main cause of the low bone mass phenotype. Likewise, primary bone marrow cells from SMSG56S/0 mice displayed reduced capacity to form a mineralized matrix ex vivo, thereby suggesting a cell-autonomous mechanism. Taken together, our data identify SMS as an enzyme with physiological relevance for osteoblast activity, thereby demonstrating an important role of polyamine metabolism in the control of bone remodeling.
精脒合酶，由 SMS 基因编码，参与多胺代谢，因为它是从其前体分子精脒合成精脒所必需的。已知 SMS 的致病性变体导致 Snyder-Robinson 综合征（SRS），这是一种 X 连锁隐性疾病，导致各种症状，包括智力残疾、肌肉张力减退、不育症，但也有骨骼异常，如面部畸形和骨质疏松症。由于迄今为止，SMS 缺乏的影响仅在 Gy 小鼠中进行了分析，在 Gy 小鼠中，大片段基因组缺失还包括邻近的 Phex 基因，因此对 SMS 在骨细胞调节中的潜在作用的了解非常有限。在本手稿中，我们描述了 2 名携带不同 SMS 变体的患者，均被诊断为骨质疏松症。虽然第一名患者表现出 SRS 的所有特征性标志，但第二名患者最初根据实验室发现被诊断为成人发病型低磷酸酯酶症。为了研究 SMS 失活对骨重塑的影响，我们利用携带致病性 SMS 变体（p.G56S）的新型小鼠模型。与它们的野生型同窝仔相比，12 周龄的 SMSG56S/0 雄性小鼠的股骨 μCT 分析显示其小梁骨量和皮质厚度降低。脊柱和胫骨切片的组织学分析进一步证实了这种表型，我们还观察到 SMSG56S/0 小鼠中非矿化类骨质的适度富集。细胞和动态组织形态计量学进一步确定了骨形成率降低是低骨量表型的主要原因。同样，SMSG56S/0 小鼠的原代骨髓细胞在体外形成矿化基质的能力降低，提示存在细胞自主机制。总之，我们的数据确定 SMS 作为一种具有生理相关性的酶，对成骨细胞活性具有重要作用，从而证明多胺代谢在控制骨重塑中的重要作用。
