Proteolysis of latent transforming growth factor-β (TGF-β)-binding protein-1 by osteoclasts -: A cellular mechanism for release of TGF-β from bone matrix
Proteolysis of latent transforming growth factor-β (TGF-β)-binding protein-1 by osteoclasts -: A cellular mechanism for release of TGF-β from bone matrix
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DOI：
10.1074/jbc.m111663200
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发表时间：
2002-06-14
影响因子：
4.8
通讯作者：
Bonewald, LF
中科院分区：
文献类型：
--
作者：
Dallas, SL;Rosser, JL;Bonewald, LF
生长因子与细胞外基质（ECM）的结合可能是调节其活性的关键途径。我们已经表明，骨ECM中转化生长因子-β（TGF-β）储存的主要机制是通过其与潜伏性TGF-β结合蛋白-1（LTBP 1）的结合。虽然已经报道了LTBP 1的蛋白水解裂解，但仍不清楚这是否代表释放基质结合的TGF-β的生理机制。在这里，我们研究了LTBP 1在细胞介导的TGF-β从骨ECM释放中的作用。我们首先表征了由原代成骨细胞产生的潜伏性TGF-β的可溶性和ECM结合形式。接下来，我们检测了骨吸收细胞释放ECM结合的TGF-β。分离的禽类破骨细胞和兔骨髓来源的破骨细胞通过LTBP 1裂解释放骨基质结合的TGF-β。1，25-二羟基维生素D增强的LTBP 1切割，导致释放90%的ECM结合的LTBP 1。相反，成骨细胞不能裂解LTBP 1或从骨ECM释放TGF-β。丝氨酸蛋白酶和金属蛋白酶（MMP）抑制剂抑制鸟类破骨细胞LTBP 1的切割。使用纯化的蛋白酶的研究表明，纤溶酶，弹性蛋白酶，MMP 2和MMP 9能够切割LTBP 1产生125-165-kDa的片段。这些研究确定LTBP 1作为一种新的基质金属蛋白酶的底物，并提供了第一个证明，LTBP 1蛋白水解可能是一种生理机制，释放TGF-β的ECM结合的商店，潜在的第一步，在该途径中，基质结合的TGF-β被赋予活性。
The binding of growth factors to the extracellular matrix (ECM) may be a key pathway for regulation of their activity. We have shown that a major mechanism for storage of transforming growth factor-beta (TGF-beta) in bone ECM is via its association with latent TGF-beta-binding protein-1 (LTBP1). Although proteolytic cleavage of LTBP1 has been reported, it remains unclear whether this represents a physiological mechanism for release of matrix-bound TGF-beta. Here we examined the role of LTBP1 in cell-mediated release of TGF-beta from bone ECM. We first characterized the soluble and ECM-bound forms of latent TGF-beta produced by primary osteoblasts. Next, we examined release of ECM-bound TGF-beta by bone resorbing cells. Isolated avian osteoclasts and rabbit bone marrow-derived osteoclasts released bone matrix-bound TGF-beta via LTBP1 cleavage. 1,25-Dihydroxyvitamin D. enhanced LTBP1 cleavage, resulting in release of 90%, of the ECM-bound LTBP1. In contrast, osteoblasts failed to cleave LTBP1 or release TGF-beta from bone ECM. Cleavage of LTBP1 by avian osteoclasts was inhibited by serine protease and metalloproteinase (MMP) inhibitors. Studies using purified proteases showed that plasmin, elastase, MMP2, and MMP9 were able to cleave LTBP1 to produce 125-165-kDa fragments. These studies identify LTBP1 as a novel substrate for MMPs and provide the first demonstration that LTBP1 proteolysis may be a physiological mechanism for release of TGF-beta from ECM-bound stores, potentially the first step in the pathway by which matrix-bound TGF-beta is rendered active.