Human Genome Center, Department of Genetics and Evolutive Biology, Institute of Bioscience, University of Sao Paulo, Rua do Matão, 277, São Paulo, SP CEP 05508-900, Brazil.
Stem Cell Rev Rep. 2012 Sep;8(3):685-95. doi: 10.1007/s12015-011-9327-6.
Gain-of-function mutations in FGFR2 cause Apert syndrome (AS), a disease characterized by craniosynostosis and limb bone defects both due to abnormalities in bone differentiation and remodeling. Although the periosteum is an important cell source for bone remodeling, its role in craniosynostosis remains poorly characterized. We hypothesized that periosteal mesenchymal stem cells (MSCs) and fibroblasts from AS patients have abnormal cell phenotypes that contribute to the recurrent fusion of the coronal sutures. MSCs and fibroblasts were obtained from the periostea of 3 AS patients (S252W) and 3 control individuals (WT). We evaluated the proliferation, migration, and osteogenic differentiation of these cells. Interestingly, S252W mutation had opposite effects on different cell types: S252W MSCs proliferated less than WT MSCs, while S252W fibroblasts proliferated more than WT fibroblasts. Under restrictive media conditions, only S252W fibroblasts showed enhanced migration. The presence of S252W mutation increased in vitro and in vivo osteogenic differentiation in both studied cell types, though the difference compared to WT cells was more pronounced in S252W fibroblasts. This osteogenic differentiation was reversed through inhibition of JNK. We demonstrated that S252W fibroblasts can induce osteogenic differentiation in periosteal MSCs but not in MSCs from another tissue. MSCs and fibroblasts responded differently to the pathogenic effects of the FGFR2(S252W) mutation. We propose that cells from the periosteum have a more important role in the premature fusion of cranial sutures than previously thought and that molecules in JNK pathway are strong candidates for the treatment of AS patients.
成纤维细胞生长因子受体 2（FGFR2）功能获得性突变导致 Apert 综合征（AS），该病的特征为颅缝早闭和肢体骨骼缺陷，这两种表现均归因于骨分化和重塑的异常。虽然骨膜是骨重塑的重要细胞来源，但它在颅缝早闭中的作用仍未得到充分描述。我们假设 AS 患者的骨膜间充质干细胞（MSCs）和成纤维细胞具有异常的细胞表型，这有助于冠状缝的反复融合。从 3 名 AS 患者（S252W）和 3 名对照个体（WT）的骨膜中获得 MSCs 和成纤维细胞。我们评估了这些细胞的增殖、迁移和成骨分化。有趣的是，S252W 突变对不同细胞类型有相反的影响：S252W MSCs 的增殖能力低于 WT MSCs，而 S252W 成纤维细胞的增殖能力高于 WT 成纤维细胞。在限制培养基条件下，只有 S252W 成纤维细胞显示出增强的迁移。体外和体内研究均表明，S252W 突变增加了两种研究细胞类型的成骨分化，尽管与 WT 细胞相比，S252W 成纤维细胞的差异更为显著。这种成骨分化通过抑制 JNK 而逆转。我们证明 S252W 成纤维细胞可以诱导骨膜 MSCs 发生成骨分化，但不能诱导另一种组织来源的 MSCs 发生成骨分化。MSCs 和成纤维细胞对 FGFR2（S252W）突变的致病作用有不同的反应。我们提出，骨膜细胞在颅缝过早融合中的作用比以前认为的更为重要，而 JNK 通路中的分子是治疗 AS 患者的有力候选药物。
