Lysyl oxidase like-2 anabolic role in TMJ and knee osteoarthritis

Abstract

INTRODUCTION: Osteoarthritis (OA) is the most common chronic degenerative joint disease that leads to damage and disability of the joints. Several studies mentioned the association between inflammatory process and clinical changes. However, there is no drug approved yet to cure the disease and to regenerate the tissues. Lysyl Oxidase-Like-2 (LOXL2) could be a potential candidate as shown in our previous studies. We showed that LOXL2 is elevated during fracture healing and critical regulator of chondrogenesis. Recently, we showed that LOXL2 is shown to be anabolic to human OA cartilage. The goal of this study is to determine the protective effect of LOXL2 in temporomandibular (TMJ) and knee joint OA and to evaluate if LOXL2 attenuates the adverse effects induced by IL-1β in chondrocytes and osteoblasts. MATERIALS AND METHODS: To evaluate the anti-catabolic effect of LOXL2 in vitro, ATDC5 and MC3T3 cells have been transduced with Adv-RFP-LOXL2 and treated with IL-1β. The protective effect of LOXL2 in vivo was evaluated by systemic injection of adenovirus LOXL2 in a chondrodysplasia mouse model (Cho/+) and intra-articular MIA injection in LOXL2 in transgenic mice followed by an analysis of TMJ and knee joints structural and functional analysis. RESULTS: LOXL2 protects from adverse effects induced by IL-1β in ATDC5 and MC3T3 cells by inhibiting the phospho-NF-κB signaling pathway independent of LOXL2 enzymatic activity. Also, LOXL2 increased the mRNA expression of Aggrecan and SOX9 and decreased the level of ADAMTS5, MMP13 and RANKL induced by IL-1β. LOXL2 promotes the mRNA level of ACAN and SOX9 in Cho/+ in TMJ and knee joints. Moreover, IHC analysis showed that ACAN expression is increased and MMP13 decreased in TMJ and knee tissues. LOXL2 overexpressed mice injected with MIA covered more distances and spent more time on the treadmill than wild-type littermates in a treadmill test. IHC analysis showed more ACAN and less MMP13 staining in the LOXL2 overexpressed group than the control one. CONCLUSION: LOXL2 was shown to attenuate adverse effects induced by IL-1β in chondrocytes and osteoblasts. LOXL2 has a protective and anabolic role in TMJ and knee joints affected by OA. Further, LOXL2 was shown to have a protective function during OA-related disability