LOXL2 in Temporomandibular Joint Osteoarthritis



 DESCRIPTION (provided by applicant): Temporomandibular joint (TMJ) osteoarthritis (OA) is a degenerative disease that affects both cartilage and subchondral bone. The prevalence among adults in the United States of is 33% and the female-to-male ratio from 3:1 to 9:1. Our studies showed that lysyl oxidase like-2 (LOXL2) is expressed during regenerative response to fracture healing and is required for chondrocyte development. Preliminary studies showed that LOXL2 expression is increased in clinical TMJ- and knee-OA as a compensatory late-stage anabolic response because its expression upregulated by mediator of OA, it inhibits effects and apoptosis induced by catabolic mediators. Overexpression of LOXL2 increases COL2A1 and SOX9 without activating key catabolic mediators of OA such as MMP13 and ADAMTS5 expression. We hypothesize that LOXL2 is a mediator of anabolic signaling pathways, and could promote anabolic response to prevent or repair Cho/+ TMJ-OA mouse and TMJ-OA patient-derived cells. Specific Aims of the study are: 1) to determine the effect and mechanism of LOXL2 in attenuating human and mouse TMJ-OA and 2) to determine LOXL2 function in prevention/ regeneration of TMJ-OA fibrocartilage in female Cho/+ OA mouse models and patient-derived TMJ- OA cells. The completion of Aim 1 will determine if LOXL2 has a role in the pathogenesis and if early administration of rLOXL2 prevents TMJ-OA in genetic mouse models and patient-derived TMJ-OA cells. Alternatively, we will use surgical TMJ OA mouse models. Thus, the study will evaluate our hypothesis that LOXL2 mediated mechanism in TMJ-OA and LOXL2 induced collagen crosslinking and anabolic response promotes repair in mouse and TMJ-OA. In the future, a LOXL2 inducible transgenic mouse model will be generated to study the effect of inducible LOXL2 expression on TMJ-OA. The long-term goal is to develop LOXL2 as a potential therapeutic protein for clinical application in TMJ OA.