A regulatory cascade involving retinoic acid, Cbfa1, and matrix metalloproteinases is coupled to the development of a process of perichondrial invasion and osteogenic differentiation during bone formation.
A regulatory cascade involving retinoic acid, Cbfa1, and matrix metalloproteinases is coupled to the development of a process of perichondrial invasion and osteogenic differentiation during bone formation.
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DOI：
10.1083/jcb.200106147
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发表时间：
2001-12-24
期刊：
影响因子：
--
通讯作者：
López-Otín C
中科院分区：
文献类型：
--
作者：
Jiménez MJ;Balbín M;Alvarez J;Komori T;Bianco P;Holmbeck K;Birkedal-Hansen H;López JM;López-Otín C
组织重塑过程主要由基质金属蛋白酶（MMP）内肽酶家族成员介导，其表达在空间和时间上都受到严格控制。在这篇文章中，我们研究了在骨形成过程中可能有助于调节胶原酶-3和MT1-MMP等MMPs表达的分子机制。我们发现，通常下调MMPs的全反式维甲酸（RA）在胚胎跖软骨初级和软骨细胞培养中强烈诱导胶原酶-3的表达。这种效应是剂量和时间依赖性的，需要蛋白质的从头合成，并由RAR-RXR异源二聚体介导。对RA上调胶原酶-3表达的信号转导机制的分析表明，该因子通过p38丝裂原活化蛋白激酶的信号通路起作用。关节炎对软骨细胞的治疗也诱导MT1-MMP的产生，MT1-MMP是一种膜结合的金属蛋白酶，对骨骼的形成至关重要，它参与了胶原酶-3的蛋白水解级联反应。这些MMPs的产生伴随着ra诱导的分化程序的发展，其特征是矿化骨基质的形成，软骨细胞标记物（如II型胶原）的下调，成骨细胞标记物（如骨钙素）的上调。这些影响在跖骨雏形中减弱，其中RA诱导从软骨膜到软骨雏形的软骨膜成骨细胞的入侵。RA治疗还导致Cbfa1上调，Cbfa1是成骨细胞中负责胶原酶-3和骨钙素诱导的转录因子。Cbfa1、MMPs和骨钙素表达的动态与这些基因可能是RA启动的调控级联的一部分并导致Cbfa1的诱导，进而上调其一些靶基因如胶原酶-3和骨钙素的表达这一事实相一致。
Tissue-remodeling processes are largely mediated by members of the matrix metalloproteinase (MMP) family of endopeptidases whose expression is strictly controlled both spatially and temporally. In this article, we have examined the molecular mechanisms that could contribute to modulate the expression of MMPs like collagenase-3 and MT1-MMP during bone formation. We have found that all-trans retinoic acid (RA), which usually downregulates MMPs, strongly induces collagenase-3 expression in cultures of embryonic metatarsal cartilage rudiments and in chondrocytic cells. This effect is dose and time dependent, requires the de novo synthesis of proteins, and is mediated by RAR-RXR heterodimers. Analysis of the signal transduction mechanisms underlying the upregulating effect of RA on collagenase-3 expression demonstrated that this factor acts through a signaling pathway involving p38 mitogen-activated protein kinase. RA treatment of chondrocytic cells also induces the production of MT1-MMP, a membrane-bound metalloproteinase essential for skeletal formation, which participates in a proteolytic cascade with collagenase-3. The production of these MMPs is concomitant with the development of an RA-induced differentiation program characterized by formation of a mineralized bone matrix, downregulation of chondrocyte markers like type II collagen, and upregulation of osteoblastic markers such as osteocalcin. These effects are attenuated in metatarsal rudiments in which RA induces the invasion of perichondrial osteogenic cells from the perichondrium into the cartilage rudiment. RA treatment also resulted in the upregulation of Cbfa1, a transcription factor responsible for collagenase-3 and osteocalcin induction in osteoblastic cells. The dynamics of Cbfa1, MMPs, and osteocalcin expression is consistent with the fact that these genes could be part of a regulatory cascade initiated by RA and leading to the induction of Cbfa1, which in turn would upregulate the expression of some of their target genes like collagenase-3 and osteocalcin.
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影响因子：
4.8
作者：
CONNOLLY, TJ;CLOHISY, JC;QUINN, CO
通讯作者：
QUINN, CO
影响因子：
4.8
作者：
Desai, SH;Niles, RM
通讯作者：
Niles, RM
Osf2/Cbfa1：成骨细胞分化的转录激活因子
影响因子：
64.5
作者：
Ducy, P;Zhang, R;Karsenty, G
通讯作者：
Karsenty, G
影响因子：
4.8
作者：
De Luca, F;Uyeda, JA;Baron, J
通讯作者：
Baron, J
影响因子：
64.5
作者：
Komori, T;Yagi, H;Kishimoto, T
通讯作者：
Kishimoto, T