Lysyl Oxidase Control of TGF-? in Bone

描述（由申请人提供）：赖氨酰氧化酶（LOX）是一种铜依赖性胺氧化酶，可氧化胶原蛋白和弹性蛋白的肽基赖氨酸/羟基赖氨酸的伯胺，引发一系列缩合反应，形成共价分子内/分子间交联。然而，最近的研究表明，LOX在调节细胞功能中起着关键作用，并且通过尚不清楚的机制。在我们研究骨生物学中胶原修饰酶的过程中，我们获得的数据表明LOX在体外和骨基质中与一种有效的生长因子转化生长因子-<$1（TGF-<$1）相互作用。此外，LOX似乎可能通过其胺氧化酶活性抑制TGF-β 1信号传导。在E18.5 LOX缺失骨中，TGF-β 1信号传导增强，胶原基质紊乱，颅面骨发育受损。因此，我们假设LOX氧化骨中的成熟TGF-β 1并调节其信号传导，这对胶原蛋白的产生/组织和矿化至关重要。为了验证这一假设，我们提出了以下具体目标：1。为了研究LOX介导的TGF-β 1氧化是否发生在骨基质（1a）和体外（1b），2。研究LOX酶在体外（2a）和离体（2b）对TGF-β 1信号传导及其结果（碱性磷酸酶活性、胶原合成/组织化、矿化）的影响。从这项研究中获得的数据可能提供了一个新的机制，TGF-β 1的功能是由一种胺氧化酶，脂氧合酶，及其在骨中的生物学意义的洞察。 公共卫生相关性：本研究将探索赖氨酰氧化酶（一种铜依赖性胺氧化酶）在控制骨中有效生长因子TGF-21功能中的新功能。所获得的数据可能会提供一个新的机制，骨发育和重塑的调节洞察。

DESCRIPTION (provided by applicant): Lysyl oxidase (LOX) is a copper-dependent amine oxidase that oxidizes primary amine of peptidyl lysine/hydroxylysine of collagen and elastin to initiate a series of condensation reactions to form covalent intra/intermolecular cross-linking. However, recent studies have revealed that LOX plays critical roles in regulating cellular functions as well through the mechanisms that are not well understood. During the course of our studies on collagen modifying enzymes in bone biology, we obtained data indicating that LOX interacts with a potent growth factor, transforming growth factor-¿1 (TGF-¿1), in vitro and in bone matrix. In addition, LOX appears to suppress the TGF-¿1 signaling likely through its amine oxidase activity. In the E18.5 LOX-null bone, the TGF-¿1 signaling was enhanced, collagen matrix was disorganized and craniofacial bone development was impaired. Thus, we hypothesized that LOX oxidizes mature TGF-¿1 in bone and regulates its signaling that is critical for collagen production/organization and mineralization. To test this hypothesis, we propose the following specific aims: 1. To investigate if LOX-mediated TGF-¿1 oxidation occurs in bone matrix (1a) and in vitro (1b), 2. To investigate the effect of LOX enzyme on TGF-¿1 signaling and its outcome (alkaline phosphatase activity, collagen synthesis/organization, mineralization) in vitro (2a) and ex vivo (2b). The data obtained from this study may provide an insight into a novel mechanism by which TGF-¿1 function is regulated by an amine oxidase, LOX, and its biological significance in bone. PUBLIC HEALTH RELEVANCE: This study will explore a novel function of lysyl oxidase, a copper-dependent amine oxidase, in controlling the function of a potent growth factor, TGF-21, in bone. The data obtained may provide an insight into a novel mechanism by which bone development and remodeling are regulated.