Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation.
Parathyroid hormone-related peptide-depleted mice show abnormal epiphyseal cartilage development and altered endochondral bone formation.
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DOI：
10.1083/jcb.126.6.1611
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发表时间：
1994-09
期刊：
影响因子：
--
通讯作者：
Karaplis AC
中科院分区：
文献类型：
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作者：
Amizuka N;Warshawsky H;Henderson JE;Goltzman D;Karaplis AC
为了阐明PTHrP在骨骼发育中的作用，我们检测了野生型（PTHrP正常）18- 19 d龄胎鼠和软骨营养不良幼崽的胫骨近端骨骺和干骺端，这些幼崽通过胚胎干细胞同源重组产生的PTHrP等位基因被破坏（PTHrP缺失）。在PTHrP正常的骨骺中，免疫细胞化学显示PTHrP定位于静息区和增生区与肥厚区交界处的软骨细胞中。在pthrp缺失的骨骺中，在静息区和增殖区观察到[3H]胸腺嘧啶标记指数降低，导致骨骺软骨细胞数量减少，骨骺板变薄。在突变型增生性区，增大的软骨细胞散布着不增厚的细胞团，但类似于静止或增殖的软骨细胞。尽管骨骺板中II型胶原的总体含量减少，但这些非肥厚软骨细胞的腔隙确实对II型胶原发生反应。此外，细胞膜相关硫酸软骨素免疫反应性在这些细胞上是明显的。尽管在这些非肥大软骨细胞上存在碱性磷酸酶活性，但邻近的软骨基质没有钙化，它们的持续存在解释了软骨柱扭曲和钙化软骨的零星分布。因此，在干骺端，骨沉积在不规则和稀疏的钙化软骨支架上，导致混合针状体不平行于胫骨纵轴，因此不适合骨伸长。因此，PTHrP似乎调节软骨细胞的增殖和分化，它的缺失改变了骨骺软骨发育的时间和空间顺序，以及随后长骨正常伸长所必需的软骨内骨形成。
To elucidate the role of PTHrP in skeletal development, we examined the proximal tibial epiphysis and metaphysis of wild-type (PTHrP-normal) 18- 19-d-old fetal mice and of chondrodystrophic litter mates homozygous for a disrupted PTHrP allele generated via homologous recombination in embryonic stem cells (PTHrP-depleted). In the PTHrP-normal epiphysis, immunocytochemistry showed PTHrP to be localized in chondrocytes within the resting zone and at the junction between proliferative and hypertrophic zones. In PTHrP-depleted epiphyses, a diminished [3H]thymidine-labeling index was observed in the resting and proliferative zones accounting for reduced numbers of epiphyseal chondrocytes and for a thinner epiphyseal plate. In the mutant hypertrophic zone, enlarged chondrocytes were interspersed with clusters of cells that did not hypertrophy, but resembled resting or proliferative chondrocytes. Although the overall content of type II collagen in the epiphyseal plate was diminished, the lacunae of these non-hypertrophic chondrocytes did react for type II collagen. Moreover, cell membrane-associated chondroitin sulfate immunoreactivity was evident on these cells. Despite the presence of alkaline phosphatase activity on these nonhypertrophic chondrocytes, the adjacent cartilage matrix did not calcify and their persistence accounted for distorted chondrocyte columns and sporadic distribution of calcified cartilage. Consequently, in the metaphysis, bone deposited on the irregular and sparse scaffold of calcified cartilage and resulted in mixed spicules that did not parallel the longitudinal axis of the tibia and were, therefore, inappropriate for bone elongation. Thus, PTHrP appears to modulate both the proliferation and differentiation of chondrocytes and its absence alters the temporal and spatial sequence of epiphyseal cartilage development and of subsequent endochondral bone formation necessary for normal elongation of long bones.