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.
Temporomandibular Osteoarthritis (OA) is the most the common disease affecting the jaw. We have identified a new function of protein lysyl oxidase like-2 (LOXL2) critical for cartilage development. Our goal is to use LOXL2 to prevent or repair TMJ OA using genetic mouse model and patient derived cells. This study will provide basic understanding of treating TMJ-OA in experimental animal models with LOXL2 protein, which is responsible for collagen networking and anabolic response in chondrocytes. This study can be exploited further for future clinical applications.
| Kartha, Vinay K; Alamoud, Khalid A; Sadykov, Khikmet et al. (2018) Functional and genomic analyses reveal therapeutic potential of targeting ?-catenin/CBP activity in head and neck cancer. Genome Med 10:54 |
| Bais, Manish V; Goldring, Mary B (2017) LOXL2 as a protective in osteoarthritis cartilage. Aging (Albany NY) 9:2024-2025 |
| Bais, Manish V (2017) Targeting oral cancer epigenome via LSD1. Aging (Albany NY) 9:2455-2456 |
| Alshenibr, Weam; Tashkandi, Mustafa M; Alsaqer, Saqer F et al. (2017) Anabolic role of lysyl oxidase like-2 in cartilage of knee and temporomandibular joints with osteoarthritis. Arthritis Res Ther 19:179 |
| Alsaqer, Saqer F; Tashkandi, Mustafa M; Kartha, Vinay K et al. (2017) Inhibition of LSD1 epigenetically attenuates oral cancer growth and metastasis. Oncotarget 8:73372-73386 |
