Loss of HIF-1α in the notochord results in cell death and complete disappearance of the nucleus pulposus.
Loss of HIF-1α in the notochord results in cell death and complete disappearance of the nucleus pulposus.
复制标题
DOI：
10.1371/journal.pone.0110768
复制
发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Risbud MV
中科院分区：
文献类型：
--
作者：
Merceron C;Mangiavini L;Robling A;Wilson TL;Giaccia AJ;Shapiro IM;Schipani E;Risbud MV
椎间盘是脊椎动物最大的无血管器官之一。髓核（NP）是一种高度水合和富含蛋白多糖的组织，形成了IVD的内部。NP被多层纤维软骨结构，纤维环（AF）包围。软骨终板（CEP）覆盖该结构的上级和下层。NP是IVD内的独特组织，因为它是脊索细胞分化的结果，而AF和CEP来自于硬节。缺氧诱导因子-1 α（hypoxia inducible factor-1α，HIF-1α）在NP细胞中表达，但其在NP发育和稳态中的功能在很大程度上是未知的。因此，我们有条件地删除了脊索细胞中的HIF-1α，并研究了这种转录因子的缺失如何影响E15.5，出生，1和4个月龄时的NP形成和稳态。进行组织学分析、细胞谱系研究和TUNEL测定。早在E15.5，随后，出生后，由一个新的组织，类似纤维软骨的NP逐渐消失和更换的突变NP细胞的形态变化被确定。值得注意的是，谱系研究和TUNEL测定明确证明，NP细胞没有转分化成软骨细胞样细胞，而是经历了大量的细胞死亡，并完全被属于不同于脊索谱系的细胞群所取代。最后，为了评估NP中HIF-1α缺失的功能后果，对突变体IVD进行了生物力学测试。突变小鼠中NP的丢失通过降低其吸收机械应力的能力而显著降低了IVD的生物力学性质。这些发现与人类IVD变性过程中通常观察到的变化相似。因此，我们的研究表明，HIF-1α是必不可少的NP的发展和稳态，它提出了有趣的可能性，这种转录因子可能参与人类IVD变性。
The intervertebral disc (IVD) is one of the largest avascular organs in vertebrates. The nucleus pulposus (NP), a highly hydrated and proteoglycan-enriched tissue, forms the inner portion of the IVD. The NP is surrounded by a multi-lamellar fibrocartilaginous structure, the annulus fibrosus (AF). This structure is covered superior and inferior side by cartilaginous endplates (CEP). The NP is a unique tissue within the IVD as it results from the differentiation of notochordal cells, whereas, AF and CEP derive from the sclerotome. The hypoxia inducible factor-1α (HIF-1α) is expressed in NP cells but its function in NP development and homeostasis is largely unknown. We thus conditionally deleted HIF-1α in notochordal cells and investigated how loss of this transcription factor impacts NP formation and homeostasis at E15.5, birth, 1 and 4 months of age, respectively. Histological analysis, cell lineage studies, and TUNEL assay were performed. Morphologic changes of the mutant NP cells were identified as early as E15.5, followed, postnatally, by the progressive disappearance and replacement of the NP with a novel tissue that resembles fibrocartilage. Notably, lineage studies and TUNEL assay unequivocally proved that NP cells did not transdifferentiate into chondrocyte-like cells but they rather underwent massive cell death, and were completely replaced by a cell population belonging to a lineage distinct from the notochordal one. Finally, to evaluate the functional consequences of HIF-1α deletion in the NP, biomechanical testing of mutant IVD was performed. Loss of the NP in mutant mice significantly reduced the IVD biomechanical properties by decreasing its ability to absorb mechanical stress. These findings are similar to the changes usually observed during human IVD degeneration. Our study thus demonstrates that HIF-1α is essential for NP development and homeostasis, and it raises the intriguing possibility that this transcription factor could be involved in IVD degeneration in humans.
登录
查看更多内容
影响因子：
2.5
作者：
Choi, Kyung-Suk;Cohn, Martin J.;Harfe, Brian D.
通讯作者：
Harfe, Brian D.
影响因子：
4
作者：
Pfander, D;Cramer, T;Johnson, RS
通讯作者：
Johnson, RS
DOI：
10.3109/17453676908989540
发表时间：
1969-01-01
期刊：
ACTA ORTHOPAEDICA SCANDINAVICA
影响因子：
--
作者：
HASSLER, O
通讯作者：
HASSLER, O
影响因子：
--
作者：
Agrawal, Amit;Gajghate, Sachin;Risbud, Makarand V.
通讯作者：
Risbud, Makarand V.
影响因子：
2.8
作者：
Moon, Sung M.;Yoder, Jonathon H.;Elliott, Dawn M.
通讯作者：
Elliott, Dawn M.