Lysyl Oxidase Control of TGF-? in Bone

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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.