Lactoferricin enhances BMP7-stimulated anabolic pathways in intervertebral disc cells.
Lactoferricin enhances BMP7-stimulated anabolic pathways in intervertebral disc cells.
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DOI：
10.1016/j.gene.2013.04.003
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发表时间：
2013-07-25
期刊：
影响因子：
3.5
通讯作者：
Im HJ
中科院分区：
文献类型：
--
作者：
Ellman MB;Kim J;An HS;Chen D;Kc R;Li X;Xiao G;Yan D;Suh J;van Wijnen AJ;Wang JH;Kim SG;Im HJ
骨形态发生蛋白-7(BMP7)是一种广泛存在于椎间基质和细胞内稳态的合成和抗分解生长因子。同样，乳铁素B(LFcinB)最近被证明在体外培养的牛椎间盘细胞中具有促合成代谢、抗分解代谢、抗氧化和/或抗炎作用。在这项研究中，我们研究了多肽疗法与LFcinB和BMP7联合使用对间盘(IVD)基质修复的潜在好处，并了解这些因素控制的细胞和信号机制。观察BMP7和LFcinB单独及联合作用对牛髓核(NP)细胞蛋白多糖(PG)的积累和合成以及基质蛋白Aggrecan和转录因子SOX-9表达的影响。我们还分析了BMP拮抗剂noggin在IVD组织中的作用，并检测了LFcinB刺激后的作用。为了了解LFcinB与BMP7协同作用的分子机制，我们研究了ERK-SP1轴作为下游细胞内信号调节因子参与BMP7和LFcinB介导的活动。在藻酸盐中培养的牛NP细胞与LFcinB和BMP7协同作用促进PG的合成和积累，部分是通过上调aggrecan基因的表达。LFcinB通过以下途径激活Sp1和SMAD信号通路：(1)SMAD 1/5/8的磷酸化；(2)下调SMAD抑制因子[即骨形态发生蛋白受体拮抗剂noggin(BMP受体拮抗剂)和SMAD6(抑制性SMAD)]；(3)上调Smad4(通用共SMAD)。这些数据表明，抑制LFcinB的noggin可以消除BMP7的负反馈，从而最大化BMP7的生物学活性，最终将椎间盘细胞的动态平衡转变为促合成代谢状态。我们认为，使用BMP7和LFcinB的联合生长因子治疗对椎间盘退变可能是有益的。
Bone-morphogenetic protein-7 (BMP7) is a well-known anabolic and anti-catabolic growth factor on intervertebral (IVD) matrix and cell homeostasis. Similarly, lactoferricin B (LfcinB) has recently been shown to have pro-anabolic, anti-catabolic, anti-oxidative and/or anti-inflammatory effects in bovine disc cells in vitro. In this study, we investigated the potential benefits of using combined peptide therapy with LfcinB and BMP7 for intervertebral disc (IVD) matrix repair and to understand cellular and signaling mechanisms controlled by these factors. We studied the effects of BMP7 and LfcinB as individual treatments and combined therapy on bovine nucleus pulposus (NP) cells by assessing proteoglycan (PG) accumulation and synthesis, and the expression of matrix protein aggrecan and transcription factor SOX-9. We also analyzed the role of noggin, a BMP antagonist, in IVD tissue and examined its effect after stimulation with LfcinB. To understand the molecular mechanisms by which LfcinB synergizes with BMP7, we investigated the ERK-SP1 axis as a downstream intracellular signaling regulator involved in BMP7 and LfcinB-mediated activities. Treatment of bovine NP cells cultured in alginate with LfcinB plus BMP7 synergistically stimulates PG synthesis and accumulation in part by upregulation of aggrecan gene expression. The synergism results from LfcinB-mediated activation of Sp1 and SMAD signaling pathways by (i) phosphorylation of SMAD 1/5/8; (ii) downregulation of SMAD inhibitory factors [i.e., noggin (BMP receptor antagonist) and SMAD6 (inhibitory SMAD)]; and (iii) upregulation of SMAD4 (universal co-SMAD). These data indicate that LfcinB-suppression of noggin may eliminate the negative feedback of BMP7, thereby maximizing biological activity of BMP7 and ultimately shifting homeostasis to a pro-anabolic state in disc cells. We propose that combination growth factor therapy using BMP7 and LfcinB may be beneficial for treatment of disc degeneration.
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影响因子：
4.9
作者：
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通讯作者：
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