The Role of the Lysyl Oxidases in Tissue Repair and Remodeling: A Concise Review

Abstract

Tissue injury provokes a series of events containing inflammation, new tissue formation and tissue remodeling which are regulated by the spatially and temporally coordinated organization. It is an evolutionarily conserved, multi-cellular, multi-molecular process via complex signalling network. Tissue injury disorders present grievous clinical problems and are likely to increase since they are generally associated with the prevailing diseases such as diabetes, hypertension and obesity. Although these dynamic responses vary not only for the different types of trauma but also for the different organs, a balancing act between the tissue degradation and tissue synthesis is the same. In this process, the degradation of old extracellular matrix (ECM) elements and new ones' synthesis and deposition play an essential role, especially collagens. Lysyl oxidase (LOX) and four lysyl oxidase-like proteins are a group of enzymes capable of catalyzing cross-linking reaction of collagen and elastin, thus initiating the formation of covalent cross-links that insolubilize ECM proteins. In this way, LOX facilitates ECM stabilization through ECM formation, development, maturation and remodeling. This ability determines its potential role in tissue repair and regeneration. In this review, based on the current in vitro, animal and human in vivo studies which have shown the significant role of the LOXs in tissue repair, e.g., tendon regeneration, ligament healing, cutaneous wound healing, and cartilage remodeling, we focused on the role of the LOXs in inflammation phase, proliferation phase, and tissue remodeling phase of the repair process. By summarizing its healing role, we hope to shed light on the understanding of its potential in tissue repair and provide up to date therapeutic strategies towards related injuries.

Keywords: Cross-link; Lysyl oxidase; Remodeling; Repair; Tissue-engineering.

Fig. 1

The synthesis of activated lysyl oxidases. The output of the process is the removal of the N-terminal signal peptide sequence of human LOX in the endoplasmic reticulum. Then the propeptide domain is N-glycosylated in Golgi and the 50-kDa pro-protein (proLOX) is generated. The proLOX is cleaved by procollagen C-proteinase, mainly bone morphogenic protein-1 (BMP-1), leading to the formation of activated LOX and LOX-propeptide (LOX-PP). In the carboxyl (C)-terminus, the copper binding domain (Cu), the lysyl-tyrosyl quinone (LTQ) residues, and the cytokine receptor-like (CRL) domain are highly conserved in each member of the LOX family

Fig. 2

Formation of stable multivalent cross-links in the ECM. Lysine residues within elastin and collagen are firstly converted into hydroxy-lysine residues by lysyl hydroxylase, then peptidyl lysine and/or hydroxy-lysine residues both serve as the precursors of cross-links and undergo the oxidative deamination catalyzed by the LOX family (LOXs), and unstable aldehydes are generated. The resulting aldehydes then react with neighboring lysine residues or with other peptidyl aldehyde residues spontaneously through Schiff’s base formation or aldol condensation to generate intra- and intermolecular covalent cross-links, leading to the formation of immature dehydroxylysinorleucine (DHLNL) cross-links which are converted into stable pyridinoline (PYR) cross-links, the main type of cross-links in the extracellular matrix (ECM) of cartilage

Fig. 3

Signal transduction initiated by transforming growth factor-β₁ (TGF-β₁). The increase of the lysyl oxidase (LOX) mRNA and activity induced by TGF-β₁ is mediated through the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt), drosophila mothers against decapentaplegic protein 3 (Smad3), and mitogen-activated protein kinases (MAPKs) pathways. The reciprocities among these signalling pathways have been noticed. Akt phosphorylation and the increase in total Akt expression are PI3K-dependent. Moreover, the activation of p38-MAPK is necessary for the induction of TGF-mediated Smad3 signalling. Meanwhile, there is a cross communication between the PI3K and Smad3 signalling pathways in which the inhibition of Smad3 reduces the activation of Akt by TGF-β₁ and that PI3K inhibition reduces the activation of Smad3. In MAPK signalling pathway, TGF-β₁ induces the phosphorylation of p38-MAPK, c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 (ERK1/2). Moreover, TGF-β₁-mediated increase in expression of bone morphogenetic protein-1 (BMP-1) may also activate TGF-β₁ and provide positive feedback to generate more LOX in the formation of the extracellular matrix (ECM). ➀ represents the MAPK pathway; ➁ represents the Smad3 pathway; ➂ represents the PI3K pathway [149, 154, 159, 163]