Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
PLoS One. 2011;6(9):e24917. doi: 10.1371/journal.pone.0024917. Epub 2011 Sep 29.
Germline mutations in the NF1 tumor suppressor gene cause neurofibromatosis type 1 (NF1), a complex genetic disorder with a high predisposition of numerous skeletal dysplasias including short stature, osteoporosis, kyphoscoliosis, and fracture non-union (pseudoarthrosis). We have developed murine models that phenocopy many of the skeletal dysplasias observed in NF1 patients, including reduced bone mass and fracture non-union. We also show that the development of these skeletal manifestations requires an Nf1 haploinsufficient background in addition to nullizygous loss of Nf1 in mesenchymal stem/progenitor cells (MSCs) and/or their progenies. This is replicated in two animal models of NF1, PeriCre(+);Nf1(flox/-) and Col2.3Cre(+);Nf1(flox/-) mice. Adoptive transfer experiments demonstrate a critical role of the Nf1+/- marrow microenvironment in the impaired fracture healing in both models and adoptive transfer of WT bone marrow cells improves fracture healing in these mice. To our knowledge, this is the first demonstration of a non-cell autonomous mechanism in non-malignant NF1 manifestations. Collectively, these data provide evidence of a combinatory effect between nullizygous loss of Nf1 in osteoblast progenitors and haploinsufficiency in hematopoietic cells in the development of non-malignant NF1 manifestations.
NF1 肿瘤抑制基因胚系突变导致 1 型神经纤维瘤病（NF1），这是一种复杂的遗传疾病，易发生多种骨骼发育不良，包括身材矮小、骨质疏松症、脊柱侧凸和骨折不愈合（假关节）。我们已经开发出了一些啮齿动物模型，这些模型模拟了 NF1 患者中观察到的许多骨骼发育不良，包括骨量减少和骨折不愈合。我们还表明，这些骨骼表现的发展除了需要骨髓间充质干细胞（MSCs）及其后代中 Nf1 的纯合缺失外，还需要 Nf1 杂合不足的背景。这在两种 NF1 动物模型中得到了复制，即 PeriCre(+);Nf1(flox/-)和 Col2.3Cre(+);Nf1(flox/-)小鼠。过继转移实验表明，Nf1+/-骨髓微环境在这两种模型中的骨折愈合受损中起着关键作用，并且过继转移 WT 骨髓细胞可改善这些小鼠的骨折愈合。据我们所知，这是首次在非恶性 NF1 表现中证明非细胞自主机制的存在。综上所述，这些数据为成骨细胞祖细胞中 Nf1 的纯合缺失和造血细胞中的杂合不足在非恶性 NF1 表现发展中的组合效应提供了证据。
