Lysyl oxidase suppresses the inflammatory response in anterior cruciate ligament fibroblasts and promotes tissue regeneration by targeting myotrophin via the nuclear factor‐kappa B pathway

Abstract

Anterior cruciate ligament (ACL) regeneration is severely affected by the injury‐induced overexpression of matrix metalloproteinases (MMPs) and downregulation of lysyl oxidase (LOX). Previous studies have focused on how the expression of MMPs and downregulation of LOX are physiologically balanced at injured sites for regenerating the ACL tissue, but the role of LOX in regulating cellular functions has not been investigated yet. Herein, we conducted an in vitro cellular experiment and unexpectedly found that exogenous LOX inhibited the expression of MMPs and inflammatory factors and recovered the cell growth; thus, LOX strongly inhibited the tumor necrosis factor‐alpha (TNF‐α)‐induced inflammatory responses. In an in vivo animal model, LOX supplementation suppressed the expression of TNF‐α in injured ACLs and promoted the recovery of the damaged tissues. RNA‐sequencing‐identified differentially expressed genes (DEGs) were highly enriched in the nuclear factor‐kappa B (NF‐κB), chemokine, cytokine‐cytokine receptor interaction, Toll‐like receptor, and TNF signaling pathways. Immunofluorescence tracing was employed to localise the exogenous LOX in the cell nucleus; the exogenous LOX indirectly suggests that it has other biological roles apart from the cross‐linking of the extracellular matrix. Protein–protein interaction network analysis revealed the anti‐inflammatory effect of LOX was alleviated by silencing the myotrophin (MTPN) expression, suggesting that LOX might interact with MTPN and regulate inflammation. Finally, this study suggests that LOX can inhibit the inflammatory response of ACL fibroblasts (ACLfs) and promote the recovery of the damaged ACL tissue through the MTPN‐mediated NF‐κB signaling pathway.

Tenascin‐C regulates migration of SOX10 tendon stem cells via integrin‐α9 for promoting patellar tendon remodeling

“…In animal experiments, TNC induced the recruitment of STSCs to the injured area, significantly accelerating the early repair of tendon tissue, clearly apparent from the accumulation of type I collagen and the restoration of the structure of the tissue. 22 However, excessive secretion of type I collagen in the late stages of tissue repair is not appropriate for the functional regeneration of tendon tissue. Excessive fibrosis caused by type I collagen would cause a repaired tendon to have poor mechanical strength, resulting in failure of the regenerated tendon.…”

A new strategy for osteoarthritis therapy: Inhibition of glycolysis

“…Amino acid metabolism is thought to be involved in the pathogenesis of OA ( Li et al, 2016b ), and a variety of amino acids are abnormally expressed in OA chondrocytes ( Mickiewicz et al, 2015 ; Zheng et al, 2017 ). Unlike most tissues, articular cartilage has no blood vessels, nerves, or lymphatic vessels and is composed mainly of extracellular matrix (ECM) and chondrocytes ( Wang et al, 2020b ). ECM mainly consists of water, collagen, and proteoglycans ( Sophia Fox et al, 2009 ).…”

“…Studies have shown that the primary energy source of chondrocytes is glycolysis ( Lane et al, 2015 ), and disorders of glycolytic metabolism can lead to chondrocyte hypertrophy and extracellular matrix degradation, promoting OA development ( Kudelko et al, 2016 ). Generally, in healthy joints, chondrocytes are in metabolic balance ( Wang et al, 2020b ). In OA joints or inflammatory environments, chondrocytes undergo metabolic reprogramming, enhancing the glycolytic pathway.…”

Apoptosis Activation and Autophagy Inhibition of Chondrocytes by Leptin by the Upregulation of LOXL3 in Osteoarthritis Pathogenesis

“…In the previous research, it has been proposed that the pathogenesis of osteoarthritis is connected with the deformation of joints which occurs because of the vitiated cartilage. Although, multiple studies with deep research also demonstrate the crucial character of inflammatory reaction in the pathogenesis of osteoarthritis [6,7]. TNF-α is the main inflammatory element of cartilage deformation in osteoarthritis.…”