Mice Deficient in NF-κB p50 and p52 or RANK Have Defective Growth Plate Formation and Post-natal Dwarfism.
Mice Deficient in NF-κB p50 and p52 or RANK Have Defective Growth Plate Formation and Post-natal Dwarfism.
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DOI：
10.4248/br201304004
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发表时间：
2013-12
期刊：
影响因子：
12.7
通讯作者：
Boyce BF
中科院分区：
文献类型：
--
作者：
Xing L;Chen D;Boyce BF
NF-κ Bp 50/p52双敲除（dKO）和RANK KO小鼠无破骨细胞，并发生与侏儒症相关的重度骨硬化症。相比之下，Op/Op小鼠，形成很少的破骨细胞，和Src KO小鼠，其中有破骨细胞与有缺陷的吸收功能，是骨硬化，但他们不是侏儒。在这里，我们比较了p50/p52 dKO、RANK KO、Op/Op和Src KO小鼠长骨的形态学特征，试图解释它们长骨长度的差异。我们发现，p50/p52 dKO和RANK KO小鼠的生长板明显比WT小鼠的生长板厚，这是由于与正常增殖软骨细胞区相关的肥大软骨细胞区增加了2-3倍。当动物变老时，这种生长板异常消失，但它们的侏儒症仍然存在。Op/Op或Src KO小鼠具有相对正常的生长板形态。来自p50/p52 dKO小鼠的长骨的原位杂交研究显示含有10型胶原表达软骨细胞的生长板区域显著增厚。用RANKL处理微团软骨细胞培养物不影响2型胶原和Sox 9（增殖软骨细胞的标志物）的表达水平，但RANKL减少了表达10型胶原的肥大软骨细胞的数量。因此，RANK/NF-κB信号传导在出生后软骨内骨化中发挥调节作用，维持正常小鼠的肥大转化并防止侏儒症。
NF-κBp50/p52 double knockout (dKO) and RANK KO mice have no osteoclasts and develop severe osteopetrosis associated with dwarfism. In contrast, Op/Op mice, which form few osteoclasts, and Src KO mice, which have osteoclasts with defective resorptive function, are osteopetrotic, but they are not dwarfed. Here, we compared the morphologic features of long bones from p50/p52 dKO, RANK KO, Op/Op and Src KO mice to attempt to explain the differences in their long bone lengths. We found that growth plates in p50/p52 dKO and RANK KO mice are significantly thicker than those in WT mice due to a 2–3-fold increase in the hypertrophic chondrocyte zone associated with normal a proliferative chondrocyte zone. This growth plate abnormality disappears when animals become older, but their dwarfism persists. Op/Op or Src KO mice have relatively normal growth plate morphology. In-situ hybridization study of long bones from p50/p52 dKO mice showed marked thickening of the growth plate region containing type 10 collagen-expressing chondrocytes. Treatment of micro-mass chondrocyte cultures with RANKL did not affect expression levels of type 2 collagen and Sox9, markers for proliferative chondrocytes, but RANKL reduced the number of type 10 collagen-expressing hypertrophic chondrocytes. Thus, RANK/NF-κB signaling plays a regulatory role in post-natal endochondral ossification that maintains hypertrophic conversion and prevents dwarfism in normal mice.