Gaucher disease (GD) is caused by pathogenic mutations in GBA1, the gene that encodes the lysosomal enzyme β-glucocerebrosidase. Until now, treatments for GD cannot completely reverse bone problems. The aim of this work was to evaluate the potential of MSCs from GD patients (GD MSCs) to differentiate towards the osteoblast (GD Ob) and adipocyte (GD Ad) lineages, and their role in osteoclastogenesis. We observed that GD Ob exhibited reduced mineralization, collagen deposition and alkaline phosphatase activity (ALP), as well as decreased gene expression of RUNX2, COLA1 and ALP. We also evaluated the process of osteoclastogenesis and observed that conditioned media from GD MSCs supernatants induced an increase in the number of osteoclasts. In this model, osteoclastogenesis was induced by RANKL and IL-1β. Furthermore, results showed that in GD MSCs there was a promotion in NLRP3 and PPAR-γ gene expression. Adipogenic differentiation revealed that GD Ad had an increase in PPAR-γ and a reduced RUNX2 gene expression, promoting adipocyte differentiation. In conclusion, our results show that GD MSCs exhibited deficient GD Ob differentiation and increased adipogenesis. In addition, we show that GD MSCs promoted increased osteoclastogenesis through RANKL and IL-1β. These changes in GD MSCs are likely to contribute to skeletal imbalance observed in GD patients.

高雪氏病（GD）是由GBA1中的致病性突变引起的，该基因编码溶酶体酶β-葡萄糖脑苷脂酶。到目前为止，GD治疗尚不能完全逆转骨骼问题。这项工作的目的是评估GD患者的MSC（GD MSC）分化为成骨细胞（GD Ob）和脂肪细胞（GD Ad）谱系的潜力，以及它们在破骨细胞形成中的作用。我们观察到GD Ob表现出减少的矿化，胶原蛋白沉积和碱性磷酸酶活性（ALP），以及RUNX2，COLA1和ALP的基因表达降低。我们还评估了破骨细胞形成的过程，并观察到来自GD MSCs上清液的条件培养基诱导了破骨细胞数量的增加。在该模型中，破骨细胞形成是由RANKL和IL-1β诱导的。此外，结果表明，在GD MSC中，NLRP3和PPAR-γ基因表达得到促进。成脂分化表明，GD Ad具有增加的PPAR-γ和减少的RUNX2基因表达，促进脂肪细胞分化。总之，我们的结果表明，GD MSCs表现出不足的GD Ob分化能力和增加的脂肪生成。此外，我们表明GD MSC通过RANKL和IL-1β促进了破骨细胞的生成。GD MSC中的这些变化可能会导致GD患者中观察到的骨骼失衡。