Tgfbr2 is required in osterix expressing cells for postnatal skeletal development.
Tgfbr2 is required in osterix expressing cells for postnatal skeletal development.
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DOI：
10.1016/j.bone.2016.12.017
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发表时间：
2017-04
期刊：
影响因子：
4.1
通讯作者：
Serra R
中科院分区：
文献类型：
--
作者：
Peters SB;Wang Y;Serra R
转化生长因子β（Transforming growth factor β，TGFβ）在早期骨骼发育中起重要作用。我们先前证明，表达Prx 1-Cre的间充质中TGFβ受体II（Tgfbr 2）的缺失导致小鼠长骨、关节和颅骨穹窿的缺陷，这是由于幼稚间充质增殖和冷凝减少而中断成骨细胞分化。相反，其他人已经表明，在完全分化的成熟成骨细胞中Tgfbr 2的缺失导致骨体积增加。为了研究Tgfbr 2在未成熟成骨细胞中的作用，我们产生了Osx-Cre; Tgfbr 2fl/fl小鼠，并发现与对照组相比，颅骨穹窿和长骨的出生后发育存在缺陷。在新生小鼠中未观察到明显的骨骼缺陷;然而，在出生后第24天（P24），Tgfbr 2缺失小鼠表现出与生长板增殖减少相关的身材矮小。来自P24小鼠的长骨和颅骨的X射线和microCT分析显示骨体积减少。组织形态计量学表明成骨细胞数量减少，但破骨细胞数量没有减少。定量实时PCR显示成骨细胞标记物Runx 2的mRNA水平没有改变，但成熟成骨细胞标记物Bglap的mRNA水平在突变体颅骨中相对于对照组下降。增殖标记物增殖核细胞抗原（PCNA）的mRNA也减少，而Bcl-2：Bcl-2的比例不变，表明细胞凋亡没有变化。这些结果表明未成熟成骨细胞的增殖和成熟需要Tgfbr 2信号传导，并且Osx-Cre; Tgfbr 2fl/fl小鼠中骨量减少可能是因为成熟成骨细胞很少。
Transforming growth factor β (TGFβ) is known to play an important role in early skeletal development. We previously demonstrated that loss of TGFβ receptor II (Tgfbr2) in Prx1-Cre-expressing mesenchyme results in defects in long bones, joints, and the skull vault in mice resulting from reduced naïve mesenchymal proliferation and condensation that interrupted osteoblast differentiation. In contrast, others have shown that the loss of Tgfbr2 in fully differentiated mature osteoblasts results in increased bone volume. To study the role of Tgfbr2 in immature osteoblasts, we generated Osx-Cre;Tgfbr2fl/fl mice and found defects in the postnatal development of the skull vault and long bones as compared to controls. No discernible skeletal defects were observed in newborn mice; however, at postnatal day 24 (P24), Tgfbr2-deleted mice demonstrated short stature that correlated with reduced proliferation in the growth plate. X-ray and microCT analysis of long bone and skull from P24 mice showed reduced bone volume. Histomorphometry indicated reductions in osteoblast number but not osteoclast number. Quantitative real-time PCR demonstrated mRNA levels for the osteoblast marker, Runx2 were not altered but mRNA levels of a marker for mature osteoblasts, Bglap, were down in mutant calvaria relative to controls. The mRNA of a proliferation marker, proliferative nuclear cell antigen (PCNA), was also reduced whereas the ratio of Bax2:Bcl2 was unaltered to demonstrate no change in apoptosis. These results suggest proliferation and maturation of immature osteoblasts requires Tgfbr2 signaling and that decreased bone volume in Osx-Cre;Tgfbr2fl/fl mice is likely because there are very few mature osteoblasts.