Abstract

The lysyl oxidase family comprises five members in mammals, lysyl oxidase (LOX) and four lysyl oxidase like proteins (LOXL1-4). They are copper amine oxidases with a highly conserved catalytic domain, a lysine tyrosylquinone cofactor, and a conserved copper-binding site. They catalyze the first step of the covalent cross-linking of the extracellular matrix (ECM) proteins collagens and elastin, which contribute to ECM stiffness and mechanical properties. The role of LOX and LOXL2 in fibrosis, tumorigenesis, and metastasis, including changes in their expression level and their regulation of cell signaling pathways, have been extensively reviewed, and both enzymes have been identified as therapeutic targets. We review here the molecular features and three-dimensional structure/models of LOX and LOXLs, their role in ECM cross-linking, and the regulation of their cross-linking activity by ECM proteins, proteoglycans, and by inhibitors. We also make an overview of the major ECM cross-links, because they are the ultimate molecular readouts of LOX/LOXL activity in tissues. The recent 3D model of LOX, which recapitulates its known structural and biochemical features, will be useful to decipher the molecular mechanisms of LOX interaction with its various substrates, and to design substrate-specific inhibitors, which are potential antifibrotic and antitumor drugs.

Introduction

The lysyl oxidase family comprises five members in mammals, lysyl oxidase (LOX) and four lysyl oxidase-like proteins (LOXL1-4) [1–4]. They are copper amine oxidases with a highly conserved catalytic domain, a lysine tyrosylquinone cofactor (LTQ), and a conserved copper-binding site. They catalyze the oxidative deamination of primary amine groups into reactive aldehydes and follow a ping-pong mechanism (Figure 1) [5,6]. LOX has insoluble extracellular matrix substrates, namely collagens and elastin, and initiates their covalent cross-linking. It also acts on few soluble substrates [2] such as fibroblast growth factor-2 (FGF-2) [7] and transforming growth factor β (TGF-β) [8], and inhibits their signaling. LOX oxidizes the receptor β of the platelet-derived growth factor (PDGF). The inhibition of LOX enzymatic activity and the inactivation of the LOX gene decrease the binding affinity of PDGF receptor-β for PDGF-BB and its maximum binding level and alters its downstream signaling, whereas the addition of LOX enhances the PDGF-BB-mediated chemotaxis of smooth muscle cells [9]. Furthermore, LOX regulates megakaryocyte expansion by PDGF-BB [10].

Enzymatic reaction catalyzed by lysyl oxidase (EC 1.4.3.13) and lysyl oxidase-like enzymes

Figure 1
Enzymatic reaction catalyzed by lysyl oxidase (EC 1.4.3.13) and lysyl oxidase-like enzymes

The ping-pong mechanism has been described by Williamson and Kagan [5], whereas the role of His303 as catalytic base has been identified by Oldfield et al. [49].

Figure 1
Enzymatic reaction catalyzed by lysyl oxidase (EC 1.4.3.13) and lysyl oxidase-like enzymes

The ping-pong mechanism has been described by Williamson and Kagan [5], whereas the role of His303 as catalytic base has been identified by Oldfield et al. [49].

LOX [1] and LOXL2 [11], which are the most studied members of the family, can be internalized by fibroblasts [12] and HaCat skin keratinocytes [13], respectively, and nuclear proteins are substrates of LOX and LOXL2 (reviewed in [14]). LOX interacts with histone H1, which might be one of its substrates [15]. The nuclear expression of LOX is an independent prognostic factor in rectal cancer patients [16]. LOXL2 oxidizes trimethylated lysine 4 in histone H3 [17] and the methylated transcription factor TAF10, which belongs to the TFIID complex. This might disrupt interactions of TAF10 with other members of the complex, and inhibit the ability of the complex to activate transcription [18]. Beside their initiation of extracellular matrix (ECM) covalent cross-linking and the regulation of transcription [14], LOX and LOXLs are involved in development [19], in tissue repair and remodeling [20], glaucoma [21–24], fibrosis [1,25–28], cancer and metastasis [28–35]. LOX and LOXL2, but not LOXL1, LOXL3 and LOXL4 are hypoxia-inducible factor (HIF)-regulated genes [36]. LOXL3 is essential for melanoma cell survival by maintaining genomic stability [37]. In addition, LOX is highly responsive to HIF-2α, which is mediated by two functional hypoxia inducible factor response elements recently identified in the human lysyl oxidase gene promoter [38]. The role of LOX and LOXL2 in regulating cell signaling in the above diseases, and the cellular and tissue readouts of their activities have been recently reviewed. We focus in this review on the molecular features and three-dimensional structure/models of LOX and LOXLs, their role in ECM cross-linking, and the regulation of their cross-linking activity by ECM proteins, proteoglycans and inhibitors, which are potential anti-fibrotic and anti-tumor drugs. We also make an overview of the major ECM cross-links because they are the ultimate molecular readouts of LOX/LOXL activity in tissues.

Domain organization of LOX and LOXLs

Lysyl oxidases exist in mammals but also in other eukaryotes, bacteria and archaea. The expansion of LOX genes during metazoan evolution results in the existence of two subfamilies. The first one comprises LOXL2, LOXL3, and LOXL4, and the second one comprises LOX, LOXL1, and LOXL5 [39]. A sixth member of the LOX family, LOXL5, is not found in mammals but is exclusively in various fish clades [39].

The catalytic domain of the five members of the mammalian LOX family is highly conserved but their N-termini differ (Figure 2). LOX and LOXL1 contain a N-terminal propeptide, whereas the N-terminus of LOXL2, LOXL3, and LOXL4 is made of four scavenger receptor cysteine-rich (SRCR) domains. LOX and LOXL1 are synthesized as preproenzymes and secreted as proenzymes. The cleavage of the propeptide is required for their activation [40,41] as detailed in section 2. A cytokine receptor-like (CRL) domain is located at the C-terminus of all the members of the LOX family including LOXL5 (Figure 2) [39]. It exhibits a C-X9-C-X-W-X34-C-X13-C motif found in the cytokine receptors of class I [42]. No function has been associated with this domain so far.

Domain organization of the members of the LOX family

Figure 2
Domain organization of the members of the LOX family

The major proteolytic processing sites and matrix metalloproteinase cleavage sites are indicated. (Blue: Bone morphogenetic protein-1 (BMP-1) cleavage site, black: metalloproteinase and A disintegrin and metalloproteinase with thrombospondin-motif (ADAMTS) cleavage sites, green: PACE4 cleavage site).

Figure 2
Domain organization of the members of the LOX family

The major proteolytic processing sites and matrix metalloproteinase cleavage sites are indicated. (Blue: Bone morphogenetic protein-1 (BMP-1) cleavage site, black: metalloproteinase and A disintegrin and metalloproteinase with thrombospondin-motif (ADAMTS) cleavage sites, green: PACE4 cleavage site).

The SRCR domains, containing six cysteine residues each, were likely acquired in LOXL2-4 with the appearance of ECM in early metazoans [39]. No common function has been described so far for the SRCR domains [43] although they may be involved in protein–protein interactions but the fourth SRCR domain of LOXL2 regulates the activity of LOXL2 catalytic domain [44]. The absence of this domain did not alter the Km value of LOXL2 when elastin is used at a substrate but induces a significant decrease in kcat value, suggesting that the fourth SRCR domain plays a positive allosteric role [44]. In addition, SRCR domains bear the major deacetylase activity of LOXL3 on the transcription factor Stat3 in nuclei [45]. SRCR domains 1 and 2 are cleaved from LOXL2 as discussed below. Two N-glycosylation sites are present in the second (Asn288) and fourth (Asn455) SRCR domains of human LOXL2 [46]. The glycans attached to the Asn455 residue are comprised of four to seven residues in addition to the trimannose core, and are fucosylated with a third being sialylated [46]. The attachment of glycans to Asn455 is found only in LOXL2 and not in other LOXLs.

The catalytic domains of the five members of the mammalian LOX family share more than 50% of sequence identity [11], and contain a copper binding site (Figure 2). The essential copper ion is incorporated into LOX within the Golgi apparatus. ATP7A is known to be required for transport of copper into the trans-Golgi network and as a result, silencing of ATP7A has been shown to inhibit LOX activity in breast and lung cancer cell lines, resulting in a significant loss of tumor growth and metastatic potential of these cells in mice [47]. The copper ion is coordinated in LOX by three histidine residues H292, H294 and H296. They are essential to the formation of LTQ, which requires copper and oxygen and is required for LOX and LOXL enzymatic activity [48]. The lysine tyrosylquinone cofactor is formed by Lys320 and Tyr355 residues in human LOX, and by Lys653 and Tyr689 residues in human LOXL2 [2,44] The histidine residue 303 has been identified as the catalytic base of LOX [49]. The mutation of this residue induces a partial or total loss of copper incorporation in LOX depending on the mutation and a decrease in or total inhibition of LTQ formation [49]. A calcium ion has been identified in the crystal of a precursor state of human LOXL2 [50]. The calcium coordination site identified in human LOXL2 (Asp549, Leu550, Glu722, Asp724, Asn727, and Asn728) is conserved in human LOX (Asp214, Leu215, Glu388, Asp390, Asn393, and Asn394), and all the residues involved in the coordination of calcium are conserved in LOX through evolution [51] and in LOXL1, LOXL3, and LOXL4.

Proteolytic processing of LOX and LOXLs

Processing of LOX and LOXL1

LOX and LOXL1 are secreted as proenzymes and the cleavage of the propeptide is required for their activation (Figure 2) [40,41]. Bone morphogenetic protein-1 (BMP-1, also known as procollagen C-proteinase), and mammalian tolloids 1 and 2 catalyzes the cleavage of the Gly168–Asp169 bond in human LOX, releasing the mature form of LOX and the propeptide in the extracellular milieu. Another cleavage site has been identified in murine proLOX between Arg192 and Pro193 releasing another isoform of LOX (35 kDa) [52]. This sequence is conserved in human proLOX suggesting that the cleavage could also occur in the human proenzyme. Matrix metalloprotease-2 processes proLOX by catalyzing the cleavage of the Asn156–Leu157 bond [53]. It has been recently shown that prolysyl oxidase is also processed between Asp218 and Tyr219 by the procollagen N-proteinases A disintegrin and metalloproteinase with thrombospondin-motif 2 (ADAMTS2) and ADAMTS14 [54]. The N-terminal part of the isoform of LOX generated by BMP-1 contains several conserved tyrosine residues, which are missing in the isoform processed by ADAMTS2 and 14. Some of these conserved tyrosine residues are O-sulfated and contribute to LOX binding to collagen. Indeed, the LOX isoform generated by ADAMTS2 binds to a lower extent to collagen than the isoform generated by BMP-1 [54]. The functions, if any, of the N-terminal propeptide-like region released upon processing by ADAMTS2 and 14 remain to be determined.

Several ECM proteins regulate the proteolytic activation of proLOX. Fibronectin interacts with proLOX and is critical for its proteolytic activation, which is decreased in fibronectin-null mouse embryonic fibroblasts [55]. The proteolytic activation of proLOX is reduced in fibulin-4 deficient osteoblasts and is rescued by the addition of recombinant fibulin-4 showing that fibulin-4 stimulates proLOX processing [56]. Thrombospondin-1 binds to the helical cross-linking site of collagens and inhibits proLOX processing by BMP-1 [57].

The propeptides of LOX and LOXL1

The propeptide of LOX is required for the exit of proLOX from the endoplasmic reticulum [58]. It is a glycosylated but its glycosylation is not required for the secretion and the processing of prolysyl oxidase. It is only required for optimal enzyme activity of the mature enzyme [58]. It is a bioactive ECM fragment [59,60], which has anti-tumoral [61] and anti-angiogenic properties [62], and stimulates adipogenesis [63]. Its biological functions have been recently reviewed [61]. The propeptide sequence of murine LOX may be cleaved by matrix metalloproteinase-10 between Ser50 and Leu51 (Figure 2) [64], which corresponds to Ser56 and Leu57 residues in human LOX.

We have recently identified 17 new binding partners of the LOX propeptide including the cross-linking enzymes, lysyl oxidase-like 2 and transglutaminase-2, which suggests new functions of the propeptide in ECM cross-linking [59], and tropoelastin. Indeed, the propeptides of LOX and LOXL1 interact with tropoelastin, and are required for LOX/LOXL1 deposition onto elastic fibers [65]. The affinity of the binding of LOX propeptide to tropoelastin is very high (KD = 1.39 nM) [59].

Processing of LOXL2

LOXL2 is processed extracellularly by serine proteases, generating a 65 kDa form lacking the first two SRCR domains (Figure 2) [66]. The cleavage between the second and third SRCR domains occurs between Lys317 and Ala318 residues and is catalyzed by proprotein convertases. Proprotein convertase subtilisin/kexin type 6 (PACE4) is the major protease that processes extracellular LOXL2 [67]. No processing of LOXL2 by BMP-1 was observed, even in the presence of procollagen C-proteinase enhancer 1 [68]. The proteolytic processing of LOXL2 is required for cross-linking collagen IV in the ECM although it does not affect the oxidation of a small, soluble, substrate (1,5-diaminopentane) in vitro [66]. It is thus possible that SRCR1 and 2 domains prevent the interaction of a large substrate such as collagen IV with the enzyme. It has been confirmed that LOXL2 processing is not essential for its amine oxidase activity in vitro with collagen type IV or tropoelastin as substrates but LOXL2 processing doubles the extent of collagen IV cross-linking when the concentration of LOXL2 is ≤10 nM [67].

The removal of the first two SRCR domains does not occur in all LOXLs, and the sequence recognized by PACE4 is unique to LOXL2. Indeed, no processing of LOXL4 has been demonstrated in several cell types and LOXL4 is enzymatically active in vitro even in absence of the SRCR domains [69].

Structures and models of LOX and LOXLs

Circular dichroism analyses have shown that LOX contains 27.5% β-strands [48]. LOXL2 and LOXL3 also give a typical β-sheet spectrum [45,68]. No experimental three-dimensional structure of mammalian LOX is available. The X-ray structure of LOX from Pichia pastoris is a homodimer in which each subunit contains a copper ion with another quinone cofactor, 2,4,5-trihydroxyphenylalanine quinone cofactor (PDB IDs: 1N9E and 1W7C) [70,71]. The only three-dimensional experimental structure available for a member of the LOX mammalian family is the X-ray structure of a glycosylation-deficient mutant of human LOXL2 comprising the catalytic domain and the SRCR3 and 4 domains (Figure 3A) [50]. The SRCR domains 1 and 2 located at the N-terminus are missing. As stated by the authors this structure represents a precursor state of LOXL2, which would require ‘pronounced conformational rearrangements’ to be activated [50]. The shape and low-resolution structure of full-length human LOXL2 have been determined by small-angle X-ray scattering experiments and single-particle electron microscopy [68]. LOXL2 has a rod-like structure with a stalk composed of the SRCR domains (13 nm) and the catalytic domain (4 nm) at its tip [68].

3D structure and models of the human LOX family members

Figure 3
3D structure and models of the human LOX family members

(A) X-ray structure of a dimeric precursor state of LOXL2 lacking the SRCR1 and SRCR2 domains (PDB ID: 5ZE3). (B) 3D model of LOX built by Bhuvanasundar et al. (2014) [73] (helix: red, β-strands: cyan, loop: gray, copper ion: blue sphere), (C) 3D model of LOX built by Vallet et al. [51]. In (A,C) SRCR domains: green, catalytic domain: orange, CRL domain: cyan, calcium ion: green, copper ion: orange, zinc ion: brown). (B,C) Modified from the open-access cited publications.

Figure 3
3D structure and models of the human LOX family members

(A) X-ray structure of a dimeric precursor state of LOXL2 lacking the SRCR1 and SRCR2 domains (PDB ID: 5ZE3). (B) 3D model of LOX built by Bhuvanasundar et al. (2014) [73] (helix: red, β-strands: cyan, loop: gray, copper ion: blue sphere), (C) 3D model of LOX built by Vallet et al. [51]. In (A,C) SRCR domains: green, catalytic domain: orange, CRL domain: cyan, calcium ion: green, copper ion: orange, zinc ion: brown). (B,C) Modified from the open-access cited publications.

Several three-dimensional models of LOX have been generated. Kagan and Ryvkin’s model was built using sequence alignments and secondary structure prediction and contains the copper ion and the LTQ [72]. However, in this model the LTQ is located at 20 Å from the copper ion, which is not consistent with the LTQ redox role during the enzymatic reaction, and no molecular dynamics simulations were run to assess the stability of the model. The other LOX model was built ab initio with the Robetta server and refined with Maestro 9.3 but does not contain the LTQ cofactor (Figure 3B) [73]. A very short dynamic simulation (4 ns), not sufficient to evaluate the stability of the model, was performed and the fluctuations during the trajectory were not reported [73]. None of the above models include the disulfide bridges stabilizing LOX [74]. However, we have recently built a three-dimensional model of LOX by combining different techniques including homology modeling using LOXL2 structure (PDB ID: 5ZE3) as a template, a threading approach and distant homologs (Figure 3C) [51]. The content in secondary structure of the model (9.2% of α-helices and 18.9% of β-strands) is in agreement the values recently reported for active LOX (8.43 and 22%, respectively) [75]. This model, which is not solely based on the inactive structure of LOXL2, is the first one to include the five disulfide bridges stabilizing LOX tertiary structure, the copper ion (and not a zinc ion as in the X-ray structure of LOXL2), and the LTQ cofactor, which is missing in the X-ray structure of LOXL2. In this model, the copper coordination sphere was defined by 2.45 and 4.4 Å distances, in agreement with expected values, and adopted an octahedral geometry. The coordination sphere of the copper ion was defined by the LTQ, and the three histidine residues H292, H294, and H296. Although all these residues were constrained to coordinate the copper ion, the H296 residue did not interact directly with it but stabilized a water molecule involved in the copper coordination sphere [51]. Our model is thus so far the only one so far to recapitulate all known molecular features of human LOX and it is stable during a 1-μs molecular dynamics simulation [51]. The distance between the loops surrounding the catalytic groove fluctuated during the simulations, suggesting that the groove forms a hinge with a variable opening to accommodate the various size of LOX substrates. Furthermore, the 3D structure of the CRL domain is consistent with the X-ray structure of the CRL domain of the human erythropoietin receptor [51].

LOX- and LOXL-mediated cross-linking of collagens and elastin

LOX and LOXLs catalyze the first step of collagen and elastin cross-linking, which contribute to the mechanical properties of ECM and tissues, namely tensile strength of collagen fibrils and elasticity of elastic fibers [76], which depend on tissues and may be altered in diseases. The oxidative deamination of selected lysyl and hydroxylysyl residues catalyzed by LOX and LOXLs in their substrates leads to the formation of allysine or hydroxyallysine residues also known as α-aminoadipic δ-semialdehydes. These reactive aldehydes spontaneously condense with other aldehydes or with ε-amino groups of lysine and hydroxylysine residues to form covalent intra- and inter-molecular cross-links in collagens and elastin, which are bifunctional (reducible cross-links of collagen and elastin), trifunctional (mature collagen cross-links, pyridinolines, pyrroles and arginoline) (Figure 4A) or tetrafunctional (mature elastin cross-links, desmosine, isodesmosine) (Figure 4B). Both pyridinolines and desmosines contain a pyridinium ring (Figure 4). This particular ring, which is also present in advanced glycation endproducts such as glyceraldehyde-derived pyridinium, mediates the interaction of pyridinoline with the receptor of advanced glycation endproducts (RAGE) [77].

Major mature, non-reducible, cross-links of collagens and elastin [82,101] (drawn with Chemspace, https://chem-space.com/)

Figure 4
Major mature, non-reducible, cross-links of collagens and elastin [82,101] (drawn with Chemspace, https://chem-space.com/)

(A) Mature collagen cross-links. (B) Mature elastin cross-links.

Figure 4
Major mature, non-reducible, cross-links of collagens and elastin [82,101] (drawn with Chemspace, https://chem-space.com/)

(A) Mature collagen cross-links. (B) Mature elastin cross-links.

LOX- and LOXL-mediated cross-linking of collagens

LOX activity is essential for collagen fibrillogenesis and for the correct shape of collagen fibrils [78]. LOX- and LOXL-mediated cross-linking contributes to the stiffness and mechanical properties of the ECM and tissues [76]. The covalent cross-linking between telopeptides and triple-helical domains of neighboring collagen molecules stiffen collagen fibrils by resisting intermolecular sliding [79]. LOX-mediated intermolecular cross-linking can occur between different types of collagen such as collagens I and II, I and III, I and V, II and IX and II and XI [80]. Collagens I, III and IV are substrates of LOXL2 in vitro [31,66,81]. LOXL2 initiates the cross-linking of the N-terminus of collagen IV network, the 7S dodecamer, in glomerular basement membrane [31,66].

The lysine and hydroxylysine residues oxidized by LOX in fibril-forming collagens are located in their telopeptides, which are short non-triple helical sequences located at both the N- and C-termini of collagen molecules [82]. Analogs of the N-telopeptide of the α1 chain of collagen I labeled with fluorine 18 are used as substrate-based radiotracers for positron emission tomography imaging of LOX in melanoma [83]. The condensation of two lysine-derived aldehydes forms allysine aldol dimers, which are all intramolecular when formed at the N-terminus, and intramolecular or intermolecular when formed at the C-terminus [84]. The spontaneous condensation of lysine- and hydroxylysine-aldehyde residues generated in the telopeptides with ε-amino groups of helical lysine or hydroxylysine residues leads to the formation of reducible intermolecular cross-links. The lysine residues located in the triple helix of collagens are Lys87 and Lys930 in the α1chain of collagen I and Lys87 and Lys933 in the α2 chain of collagen I. These lysine residues are also targeted by glycation in collagen I [85] and may be glycosylated by the addition of galactose or glucose and galactose [86]. In vitro studies of LOX-mediated cross-linking of collagen fibrils have shown that the amount of bifunctional, reducible, cross-links peaked between 4 and up to 8 h depending on the cross-link [87]. The type of intermolecular cross-links formed in fibrillar collagens depends on the hydroxylation of telopeptide lysine residues, which is catalyzed by lysyl hydroxylase-2 (LH2) and is tissue-specific. Lysine-aldehyde derived cross-links predominate in skin and cornea, and hydroxylysine-aldehyde-derived pathway in bone, cartilage and other skeletal tissues [82]. LH2 induces a switch from the lysine to the hydroxylysine pathway in fibrosis [27,82] and cancer [88,89], and enhances lung cancer metastasis by inducing an increase in the amount of hydroxylysine-derived collagen cross-links, which results in a stiffer tumor stroma [88].

The mature trifunctional collagen cross-links predominating in skeletal tissues are lysyl pyridinoline (or deoxypyridinoline), hydroxylysyl pyridinoline (or pyridinoline) in both cartilage and bone, and lysyl pyrrole and hydroxylysyl pyrrole in mineralizing tissues and (Figure 4) tendons [90,91]. The relative concentrations of pyridinoline and pyrrole may reflect the structural organization of vertebral body trabeculae [91]. Hydroxyhomocitrulline, resulting from collagen carbamylation, is preferentially formed at collagen cross-linking sites and decreases the formation of pyridinoline and deoxypyridinoline in bone and tendon [92]. Another trifunctional mature cross-link, arginoline (Figure 4) is present in mature bovine articular cartilage in equimolar amount with hydroxylysyl pyridinoline [93]. The trifunctional cross-link histidinohydroxylysinonorleucine, identified in human and bovine skin but not in rat or murine skin, has been considered for many years as a mature cross-link of the lysine aldehyde pathway. However, it has been recently shown to be an artefact and not a natural cross-link [94]. Aldol dimers appear thus to be the major stable cross-links formed by N- and C-telopeptides in skin, cornea and certain tendons [94].

Fibromodulin, a small leucine-rich proteoglycan, regulates the extent of fibrillar collagen cross-linking. The lysine residues of the C-telopeptide are more oxidized and the C-telopeptide cross-linking of collagen I is more extensive in the tendon of fibromodulin-deficient mice than in control mice [84]. Fibromodulin binds to collagen fibrils and LOX, which targets the enzyme toward N-telopeptide cross-linking sites in collagen I and II fibrils [95]. Another proteoglycan, the membrane proteoglycan syndecan-4, interacts with collagen and promotes collagen fiber formation via its extracellular domain, which may facilitate LOX-mediated collagen cross-linking [96]. Furthermore, the interaction between periostin and BMP-1 promotes the proteolytic activation of proLOX, and periostin may provide a scaffold for the interaction between proLOX and BMP-1 on a fibronectin matrix [97].

LOX- and LOXL-mediated cross-linking of tropoelastin

LOX-mediated cross-linking of tropoelastin and elastin deposition onto microfibrils are concomitant [98]. Tropoelastin is cross-linked by LOX, LOXL1 [65], and LOXL2 [68,81]. Dehydrolysinonorleucine, resulting from the condensation of one allysine residue and one lysine residue, and allysine aldol formed by the condensation of two allysine residues are the major bifunctional cross-links of elastin. LOXL2 initiates the formation of dehydrolysinonorleucine and desmosine in elastin [68]. The major mature, tetrafunctional, cross-links of elastin are desmosine or isodesmosine (Figure 4). The amount of desmosine of elastic fibers is decreased by ultraviolet radiation [99]. The trifunctional cross-links dehydromerodesmosine and cyclopentenosine have been also identified in elastin together with trace amounts of desmopyridine and isodesmopyridine [100]. Elastin is heterogeneously cross-linked with a high number of intramolecular cross-links, and random cross-linking of tropoelastin results in an unordered elastin network [101]. A comprehensive map of human elastin cross-linking during elastogenesis has been generated, showing that cross-linking occurs within and between tropoelastin molecules in a stochastic manner [102]. Both Lys-Pro and Lys-Ala domains of elastin participate in intra- and inter-domain bifunctional cross-links, whereas Lys-Ala domains are involved in interdomain tetrafunctional cross-links [102].

Methods of LOX- and LOXL-mediated cross-link analysis

The formation of lysyl- and hydroxylysyl-derived aldehydes by oxidative deamination of LOX and LOXL substrates can be detected using O-(biotinylcarbazoylmethyl) hydroxylamine as a probe with a commercially available reagent [103]. It has been used to detect aldehydes generated in collagen by LOXL2 and LOXL3 [103]. The qualitative and quantitative analysis of cross-links in sample hydrolysates by liquid chromatography coupled or not with mass spectrometry (LC–MS/MS) has been recently reviewed [104,105]. LC–MS/MS analysis of elastin peptides generated by various proteases has been used to draft the comprehensive map human elastin cross-linking during elastogenesis [102]. Immunoassays are available for routine analysis of pyridinolines in biological fluids to monitor bone resorption [106]. Pyridinolines are used as markers of bone resorption for the clinical assessment of osteoporosis in postmenopausal women [107], and as biomarkers of osteogenesis imperfecta [108]. Immunoassays for measuring desmosine, an indicator of elastin degradation, are also commercially available.

Recently, several spectroscopy techniques have been developed to measure the amount of collagen cross-links in biological samples. Fourier transform infrared spectroscopy has been applied to the analysis of pyridinoline and deoxypyridinoline in cross-linked peptides [109] and in unstained histological articular cartilage sections in a spatially resolved manner with a possible correlation with histology and histomorphometry parameters of the analyzed region [110]. Raman microspectroscopy has been used to determine the distribution of pyridinoline in mineralized tissues with a spatial resolution of approximately 1 μm, and the correlations with histologic and histomorphometric parameters [111].

Inhibition of LOX and LOXLs

LOX/LOXL2 are therapeutic targets as mentioned above [1,32,112,113] and numerous studies aim at developing specific inhibitors of LOX and LOXL2 as potential drugs [4,114]. β-aminoproprionitrile (β-APN), containing a primary amino group (Figure 5), irreversibly inhibits LOX and LOXLs, although conflicting results have been reported for the inhibition of LOX and LOXL2 [11,114]. It induces the formation of abnormal collagen fibrils with irregular profiles and widely dispersed diameters [78], and its effect on LOX activity and cross-link formation has been evaluated in numerous studies but only a few recent examples are provided below. β-APN improves cardiac function and ventricular collagen and matrix metalloproteinase/tissue inhibitor of metalloproteinase profiles in response to volume overload [115]. It slows down angiogenesis and migration of human endothelial cell in vitro [116], and reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats where LOX is overexpressed [117]. However, if β-APN usually decreases the amount of several collagen and elastin cross-links, it is not always able to restore tissue architecture as shown in a hyperoxia-based mouse model of bronchopulmonary dysplasia associated with aberrant late lung development [118].

Chemical inhibitors of LOX and LOXL2 (drawn with Chemspace, https://chem-space.com/)

Figure 5
Chemical inhibitors of LOX and LOXL2 (drawn with Chemspace, https://chem-space.com/)

CCT365623: (5-((5-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)sulfonyl)thiophen-2-yl)methanamine, PXS-5153A: (Z)-3-(1-(4-amino-2-fluorobut-2-en-1-yl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylbenzenesulfonamide dihydrochloride

Figure 5
Chemical inhibitors of LOX and LOXL2 (drawn with Chemspace, https://chem-space.com/)

CCT365623: (5-((5-(methylsulfonyl)-[1,1′-biphenyl]-3-yl)sulfonyl)thiophen-2-yl)methanamine, PXS-5153A: (Z)-3-(1-(4-amino-2-fluorobut-2-en-1-yl)-2-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-N,N-dimethylbenzenesulfonamide dihydrochloride

Several other inhibitors of LOX and LOXLs have been developed for the treatment of fibrosis and cancer (see [114] for a review). New LOX inhibitors based on an aminomethylenethiophene scaffold have been discovered by high-throughput screening and structure–activity relationship optimization has led to the design of the orally bioavailable LOX inhibitor CCT365623 (Figure 5) with good anti-metastatic properties [119]. PXS-5153A, which contains a sulfonyl group like CCT365623 (Figure 5), is a selective orally active inhibitor of LOXL2/LOXL3, which inhibits LOXL2 in a two‐step process by first binding to the LTQ and subsequent formation of an additional bond [120]. It reduces collagen cross-linking and disease severity in two liver fibrosis models [120]. PXS-S1A inhibiting both LOX and LOXL2 and PXS-S2A, a highly selective inhibitor of LOXL2, inhibited the growth of primary tumors and decreased primary tumor angiogenesis with the dual inhibitor having a greater effect [121]. PXS-S2B, the orally available form of PXS-S2A [121], preserves the glomerular structure and function in diabetic nephropathy where LOXL2 is increased [122]. 4-(aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine derivatives are selective and orally active inhibitors of LOXL2 [123]. Triazole derivatives, inhibiting LOXL2, have been synthesized and their binding to a three-dimensional model of LOXL2 has been evaluated in silico by docking [124]. Derivatives of benzylamines substituted with electron withdrawing groups at the para-position and 2-substituted pyridine-4-ylmethanamines have been tested for their inhibition of LOX and LOXL2. This led to the identification of (2-chloropyridin-4-yl)methanamine as a selective, mostly reversible, inhibitor of LOXL2 over LOX and three amine oxidases [125]. Further potential inhibitors of LOX and LOXL2-4 have been identified through 2D virtual screening from multimillion commercial compound libraries [114].

A specific, noncompetitive allosteric inhibitor of LOXL2, the monoclonal antibody AB0023 targeting the fourth scavenger receptor cysteine-rich domain of human LOXL2, has been developed [126]. This antibody decreases the activation of disease-associated fibroblasts in vivo together with the TGF-β1 amount and signaling in primary and metastatic xenograft models of cancer and in liver and lung fibrosis models [127]. It inhibits the increase in cross-linked collagens in experimental liver fibrosis [128]. However, a humanized variant of AB0023 with equivalent LOXL2 binding and inhibitory properties (immunoglobulin G4-κ) called Simtuzumab (GS 6624) has been shown to be ineffective in patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis [129] and in patients with primary sclerosing cholangitis in a Phase II trial [130]. Other studies using Simtuzumab failed to show significant improvement of fibrosis, and its use in clinics might be compromised [131,132]. Heparin, which inhibits lysyl oxidase activity on collagens with little effect on elastin oxidation, might be used as a LOX inhibitor in idiopathic fibrosis [133].

Another approach to target collagen cross-linking and to develop new anti-fibrotic or anti-cancer treatments is to design cross-links breakers as it has been done for advanced glycation endproducts [134]. The combination of a phototherapeutic agent and natural photosensitizer, hypocrellin B, and of the zeolitic imidazolate framework ZIF8 results in a photosensitizer that decomposes the mature collagen cross-link pyridinoline [135], providing new perspectives for therapeutic inhibition of collagen cross-linking in fibrosis and cancer.

Perspectives

  • Importance of the field: The three-dimensional model recapitulating the known features of LOX will be very useful, with the limitations inherent to 3D models, to decipher the molecular recognition mechanisms involved in the interaction of LOX with its ECM substrates, to design substrate-specific inhibitors of LOX as potential drugs for the treatment of fibrosis and cancer, and to modulate the properties of engineered tissues used as biomaterials in regenerative medicine.

  • Current thinking: Ongoing crystallogenesis experiments should allow us to obtain the X-ray structure of this enzyme to refine the study of these processes at the molecular level. The role of the calcium binding site recently identified in LOX and LOXLs on their enzymatic activity and on the binding of their substrates remains to be determined but it might contribute to tether calcium-binding substrates (e.g., elastin), processing enzymes (e.g., BMP-1), and partners (e.g., thrombospondin-1) to LOX and/or LOXLs. The role of the recently identified interactions between lysyl oxidases and ADAMTS proteins [136] in regulating ECM cross-linking and assembly also warrants further investigations to determine if ADAMTS proteins are LOX substrates, and if and how LOX can regulate their molecular forms. Transglutaminase-2 [137], peroxidasin, which stabilizes the collagen IV network via sulfilimine cross-links [138], and glycation, a non-enzymatic process, also contribute to ECM covalent cross-linking.

  • Future directions: An integrative approach combining all the ECM cross-linking pathways together with transcriptomic and proteomic data regarding the enzymes and substrates involved would be useful to build dynamic, tissue-specific, ECM ‘cross-linkomes’ (i.e., all the covalent cross-links formed in ECM proteins), and to determine the molecular and cellular mechanisms triggering their rewiring in diseases.

Summary

  • LOX and LOXLs catalyze the first step of covalent cross-linking of several collagens and elastin.

  • ECM proteins (fibronectin, fibulin-4 and thrombospondin-1) and proteoglycans (fibromodulin and syndecan-4) regulate LOX processing and/or LOX-mediated collagen cross-linking.

  • The bifunctional cross-links spontaneously form mature tri- or tetra-functional cross-links, stabilizing collagen and elastin supramolecular assemblies and providing ECM stiffness.

  • LOX and LOXL2 are therapeutic targets for the treatment of cancer and fibrosis.

Author Contribution

S.R.B. performs literature searches, drafted the initial and revised versions of the manuscript, and S.D.V. designed the initial and revised figures. Both authors contributed to the final version of the manuscript.

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Funding

This work was supported by the Fondation pour la Recherche Médicale [grant number DBI20141231336 (to S.R.B.)]; the Ligue Nationale contre le Cancer [Comité du Rhône] [grant number 2017-01CI: UCBL (to S.R.B.)]; and the CNRS [AAP Inter-Instituts 2017-Projet LoxIMoRe (to S.R.B.)].

Abbreviations

     
  • ADAMTS

    A disintegrin and metalloproteinase with thrombospondin-motif

  •  
  • β-APN

    β-aminoproprionitrile

  •  
  • BMP-1

    bone morphogenetic protein-1

  •  
  • CRL

    cytokine receptor-like

  •  
  • ECM

    extracellular matrix

  •  
  • HIF

    hypoxia-inducible factor

  •  
  • LC–MS/MS

    liquid chromatography/tandem mass spectrometry

  •  
  • LH2

    lysyl hydroxylase-2

  •  
  • LOX

    lysyl oxidase

  •  
  • LOXL

    lysyl oxidase-like

  •  
  • LTQ

    lysine tyrosylquinone

  •  
  • PDGF

    platelet-derived growth factor

  •  
  • SRCR

    scavenger receptor cysteine-rich

  •  
  • TAF10

    transcription initiation factor TFIID subunit 10

  •  
  • TGF-β

    transforming growth factor-β

References

References
1.
Trackman
P.C.
(
2016
)
Lysyl oxidase isoforms and potential therapeutic opportunities for fibrosis and cancer
.
Expert Opin. Ther. Targets
20
,
935
945
[PubMed]
2.
Trackman
P.C.
(
2016
)
Enzymatic and non-enzymatic functions of the lysyl oxidase family in bone
.
Matrix Biol.
52-54
,
7
18
[PubMed]
3.
Rodriguez-Pascual
F.
and
Rosell-Garcia
T.
(
2018
)
Lysyl oxidases: functions and disorders
.
J. Glaucoma
27
,
S15
S19
[PubMed]
4.
Finney
J.
,
Moon
H.-J.
,
Ronnebaum
T.
,
Lantz
M.
and
Mure
M.
(
2014
)
Human copper-dependent amine oxidases
.
Arch. Biochem. Biophys.
546
,
19
32
[PubMed]
5.
Williamson
P.R.
and
Kagan
H.M.
(
1986
)
Reaction pathway of bovine aortic lysyl oxidase
.
J. Biol. Chem.
261
,
9477
9482
[PubMed]
6.
Shah
M.A.
,
Scaman
C.H.
,
Palcic
M.M.
and
Kagan
H.M.
(
1993
)
Kinetics and stereospecificity of the lysyl oxidase reaction
.
J. Biol. Chem.
268
,
11573
11579
[PubMed]
7.
Li
W.
,
Nugent
M.A.
,
Zhao
Y.
,
Chau
A.N.
,
Li
S.J.
,
Chou
I.-N.
et al. .
(
2003
)
Lysyl oxidase oxidizes basic fibroblast growth factor and inactivates its mitogenic potential
.
J. Cell. Biochem.
88
,
152
164
[PubMed]
8.
Atsawasuwan
P.
,
Mochida
Y.
,
Katafuchi
M.
,
Kaku
M.
,
Fong
K.S.K.
,
Csiszar
K.
et al. .
(
2008
)
Lysyl oxidase binds transforming growth factor-beta and regulates its signaling via amine oxidase activity
.
J. Biol. Chem.
283
,
34229
34240
[PubMed]
9.
Lucero
H.A.
,
Ravid
K.
,
Grimsby
J.L.
,
Rich
C.B.
,
DiCamillo
S.J.
,
Mäki
J.M.
et al. .
(
2008
)
Lysyl oxidase oxidizes cell membrane proteins and enhances the chemotactic response of vascular smooth muscle cells
.
J. Biol. Chem.
283
,
24103
24117
[PubMed]
10.
Eliades
A.
,
Papadantonakis
N.
,
Bhupatiraju
A.
,
Burridge
K.A.
,
Johnston-Cox
H.A.
,
Migliaccio
A.R.
et al. .
(
2011
)
Control of megakaryocyte expansion and bone marrow fibrosis by lysyl oxidase
.
J. Biol. Chem.
286
,
27630
27638
[PubMed]
11.
Moon
H.-J.
,
Finney
J.
,
Ronnebaum
T.
and
Mure
M.
(
2014
)
Human lysyl oxidase-like 2
.
Bioorg. Chem.
57
,
231
241
[PubMed]
12.
Nellaiappan
K.
,
Risitano
A.
,
Liu
G.
,
Nicklas
G.
and
Kagan
H.M.
(
2000
)
Fully processed lysyl oxidase catalyst translocates from the extracellular space into nuclei of aortic smooth-muscle cells
.
J. Cell. Biochem.
79
,
576
582
[PubMed]
13.
Lugassy
J.
,
Zaffryar-Eilot
S.
,
Soueid
S.
,
Mordoviz
A.
,
Smith
V.
,
Kessler
O.
et al. .
(
2012
)
The enzymatic activity of lysyl oxidas-like-2 (LOXL2) is not required for LOXL2-induced inhibition of keratinocyte differentiation
.
J. Biol. Chem.
287
,
3541
3549
[PubMed]
14.
Iturbide
A.
,
García de Herreros
A.
and
Peiró
S.
(
2015
)
A new role for LOX and LOXL2 proteins in transcription regulation
.
FEBS J.
282
,
1768
1773
[PubMed]
15.
Mello
M.L.S.
,
Alvarenga
E.M.
,
Vidal B de
C.
and
Di Donato
A.
(
2011
)
Chromatin supraorganization, mitotic abnormalities and proliferation in cells with increased or down-regulated lox expression: indirect evidence of a LOX-histone H1 interaction in vivo
.
Micron
42
,
8
16
[PubMed]
16.
Liu
N.
,
Cox
T.R.
,
Cui
W.
,
Adell
G.
,
Holmlund
B.
,
Ping
J.
et al. .
(
2017
)
Nuclear expression of lysyl oxidase enzyme is an independent prognostic factor in rectal cancer patients
.
Oncotarget
8
,
60015
60024
[PubMed]
17.
Herranz
N.
,
Dave
N.
,
Millanes-Romero
A.
,
Pascual-Reguant
L.
,
Morey
L.
,
Díaz
V.M.
et al. .
(
2016
)
Lysyl oxidase-like 2 (LOXL2) oxidizes trimethylated lysine 4 in histone H3
.
FEBS J.
283
,
4263
4273
[PubMed]
18.
Iturbide
A.
,
Pascual-Reguant
L.
,
Fargas
L.
,
Cebrià
J.P.
,
Alsina
B.
,
García de Herreros
A.
et al. .
(
2015
)
LOXL2 oxidizes methylated TAF10 and controls TFIID-dependent genes during progenitor differentiation
.
Mol. Cell
58
,
755
766
[PubMed]
19.
Mäki
J.M.
(
2009
)
Lysyl oxidases in mammalian development and certain pathological conditions
.
Histol. Histopathol.
24
,
651
660
[PubMed]
20.
Cai
L.
,
Xiong
X.
,
Kong
X.
and
Xie
J.
(
2017
)
The role of the lysyl oxidases in tissue repair and remodeling: a concise review
.
Tissue Eng. Regen. Med.
14
,
15
30
[PubMed]
21.
Wordinger
R.J.
and
Clark
A.F.
(
2014
)
Lysyl oxidases in the trabecular meshwork
.
J. Glaucoma
23
,
S55
S58
[PubMed]
22.
Wiggs
J.L.
and
Pasquale
L.R.
(
2014
)
Expression and regulation of LOXL1 and elastin-related genes in eyes with exfoliation syndrome
.
J. Glaucoma
23
,
S62
S63
[PubMed]
23.
Zenkel
M.
and
Schlötzer-Schrehardt
U.
(
2014
)
Expression and regulation of LOXL1 and elastin-related genes in eyes with exfoliation syndrome
.
J. Glaucoma
23
,
S48
S50
[PubMed]
24.
Laczko
R.
,
Szauter
K.M.
and
Csiszar
K.
(
2014
)
LOXL1-associated candidate epithelial pathomechanisms in exfoliation glaucoma
.
J. Glaucoma
23
,
S43
S47
[PubMed]
25.
Afratis
N.A.
,
Klepfish
M.
,
Karamanos
N.K.
and
Sagi
I.
(
2018
)
The apparent competitive action of ECM proteases and cross-linking enzymes during fibrosis: applications to drug discovery
.
Adv. Drug Deliv. Rev.
129
,
4
15
[PubMed]
26.
Gjaltema
R.A.F.
and
Bank
R.A.
(
2017
)
Molecular insights into prolyl and lysyl hydroxylation of fibrillar collagens in health and disease
.
Crit. Rev. Biochem. Mol. Biol.
52
,
74
95
[PubMed]
27.
Ricard-Blum
S.
,
Baffet
G.
and
Théret
N.
(
2018
)
Molecular and tissue alterations of collagens in fibrosis
.
Matrix Biol.
68-69
,
122
149
[PubMed]
28.
Li
T.
,
Wu
C.
,
Gao
L.
,
Qin
F.
,
Wei
Q.
and
Yuan
J.
(
2018
)
Lysyl oxidase family members in urological tumorigenesis and fibrosis
.
Oncotarget
9
,
20156
20164
[PubMed]
29.
Perryman
L.
and
Erler
J.T.
(
2014
)
Lysyl oxidase in cancer research
.
Future Oncol.
10
,
1709
1717
[PubMed]
30.
Wu
L.
and
Zhu
Y.
(
2015
)
The function and mechanisms of action of LOXL2 in cancer (Review)
.
Int. J. Mol. Med.
36
,
1200
1204
[PubMed]
31.
Añazco
C.
,
López-Jiménez
A.J.
,
Rafi
M.
,
Vega-Montoto
L.
,
Zhang
M.-Z.
,
Hudson
B.G.
et al. .
(
2016
)
Lysyl oxidase-like-2 cross-links collagen IV of glomerular basement membrane
.
J. Biol. Chem.
291
,
25999
26012
[PubMed]
32.
Cox
T.R.
,
Gartland
A.
and
Erler
J.T.
(
2016
)
Lysyl oxidase, a targetable secreted molecule involved in cancer metastasis
.
Cancer Res.
76
,
188
192
[PubMed]
33.
Wang
T.-H.
,
Hsia
S.-M.
and
Shieh
T.-M.
(
2016
)
Lysyl oxidase and the tumor microenvironment
.
Int. J. Mol. Sci.
18
,
62
34.
Johnston
K.A.
and
Lopez
K.M.
(
2018
)
Lysyl oxidase in cancer inhibition and metastasis
.
Cancer Lett.
417
,
174
181
[PubMed]
35.
Amendola
P.G.
,
Reuten
R.
and
Erler
J.T.
(
2019
)
Interplay between LOX enzymes and integrins in the tumor microenvironment
.
Cancers (Basel)
11
,
pii: E729
[PubMed]
36.
Schietke
R.
,
Warnecke
C.
,
Wacker
I.
,
Schödel
J.
,
Mole
D.R.
,
Campean
V.
et al. .
(
2010
)
The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1
.
J. Biol. Chem.
285
,
6658
6669
[PubMed]
37.
Santamaría
P.G.
,
Floristán
A.
,
Fontanals-Cirera
B.
,
Vázquez-Naharro
A.
,
Santos
V.
,
Morales
S.
et al. .
(
2018
)
Lysyl oxidase-like 3 is required for melanoma cell survival by maintaining genomic stability
.
Cell Death Differ.
25
,
935
950
[PubMed]
38.
Wang
V.
,
Davis
D.A.
and
Yarchoan
R.
(
2017
)
Identification of functional hypoxia inducible factor response elements in the human lysyl oxidase gene promoter
.
Biochem. Biophys. Res. Commun.
490
,
480
485
[PubMed]
39.
Grau-Bové
X.
,
Ruiz-Trillo
I.
and
Rodriguez-Pascual
F.
(
2015
)
Origin and evolution of lysyl oxidases
.
Sci. Rep.
5
,
10568
[PubMed]
40.
Uzel
M.I.
,
Scott
I.C.
,
Babakhanlou-Chase
H.
,
Palamakumbura
A.H.
,
Pappano
W.N.
,
Hong
H.H.
et al. .
(
2001
)
Multiple bone morphogenetic protein 1-related mammalian metalloproteinases process pro-lysyl oxidase at the correct physiological site and control lysyl oxidase activation in mouse embryo fibroblast cultures
.
J. Biol. Chem.
276
,
22537
22543
[PubMed]
41.
Borel
A.
,
Eichenberger
D.
,
Farjanel
J.
,
Kessler
E.
,
Gleyzal
C.
,
Hulmes
D.J.
et al. .
(
2001
)
Lysyl oxidase-like protein from bovine aorta. Isolation and maturation to an active form by bone morphogenetic protein-1
.
J. Biol. Chem.
276
,
48944
48949
42.
Bazan
J.F.
(
1990
)
Structural design and molecular evolution of a cytokine receptor superfamily
.
Proc. Natl. Acad. Sci. U.S.A.
87
,
6934
6938
[PubMed]
43.
Martínez
V.G.
,
Moestrup
S.K.
,
Holmskov
U.
,
Mollenhauer
J.
and
Lozano
F.
(
2011
)
The conserved scavenger receptor cysteine-rich superfamily in therapy and diagnosis
.
Pharmacol. Rev.
63
,
967
1000
[PubMed]
44.
Xu
L.
,
Go
E.P.
,
Finney
J.
,
Moon
H.
,
Lantz
M.
,
Rebecchi
K.
et al. .
(
2013
)
Post-translational modifications of recombinant human lysyl oxidase-like 2 (rhLOXL2) secreted from Drosophila S2 cells
.
J. Biol. Chem.
288
,
5357
5363
[PubMed]
45.
Ma
L.
,
Huang
C.
,
Wang
X.-J.
,
Xin
D.E.
,
Wang
L.
,
Zou
Q.C.
et al. .
(
2017
)
Lysyl oxidase 3 is a dual-specificity enzyme involved in STAT3 deacetylation and deacetylimination modulation
.
Mol. Cell
65
,
296
309
[PubMed]
46.
Go
E.P.
,
Moon
H.-J.
,
Mure
M.
and
Desaire
H.
(
2018
)
Recombinant human Lysyl oxidase-like 2 secreted from human embryonic kidney cells displays complex and acidic glycans at all three N-linked glycosylation sites
.
J. Proteome Res.
17
,
1826
1832
[PubMed]
47.
Shanbhag
V.
,
Jasmer-McDonald
K.
,
Zhu
S.
,
Martin
A.L.
,
Gudekar
N.
,
Khan
A.
et al. .
(
2019
)
ATP7A delivers copper to the lysyl oxidase family of enzymes and promotes tumorigenesis and metastasis
.
Proc. Natl. Acad. Sci. U.S.A.
116
,
6836
6841
[PubMed]
48.
Lopez
K.M.
and
Greenaway
F.T.
(
2011
)
Identification of the copper-binding ligands of lysyl oxidase
.
J. Neural. Transm. (Vienna)
118
,
1101
1109
[PubMed]
49.
Oldfield
R.N.
,
Johnston
K.A.
,
Limones
J.
,
Ghilarducci
C.
and
Lopez
K.M.
(
2018
)
Identification of histidine 303 as the catalytic base of lysyl oxidase via site-directed mutagenesis
.
Protein J.
37
,
47
57
[PubMed]
50.
Zhang
X.
,
Wang
Q.
,
Wu
J.
,
Wang
J.
,
Shi
Y.
and
Liu
M.
(
2018
)
Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in a precursor state
.
Proc. Natl. Acad. Sci. U.S.A.
115
,
3828
3833
[PubMed]
51.
Vallet
S.D.
,
Guéroult
M.
,
Belloy
N.
,
Dauchez
M.
and
Ricard-Blum
S.
(
2019
)
A three-dimensional model of human lysyl oxidase, a cross-linking enzyme
.
ACS Omega
4
,
8495
8505
52.
Atsawasuwan
P.
,
Mochida
Y.
,
Katafuchi
M.
,
Tokutomi
K.
,
Mocanu
V.
,
Parker
C.E.
et al. .
(
2011
)
A novel proteolytic processing of prolysyl oxidase
.
Connect. Tissue Res.
52
,
479
486
[PubMed]
53.
Panchenko
M.V.
,
Stetler-Stevenson
W.G.
,
Trubetskoy
O.V.
,
Gacheru
S.N.
and
Kagan
H.M.
(
1996
)
Metalloproteinase activity secreted by fibrogenic cells in the processing of prolysyl oxidase. Potential role of procollagen C-proteinase
.
J. Biol. Chem.
271
,
7113
7119
[PubMed]
54.
Rosell-García
T.
,
Paradela
A.
,
Bravo
G.
,
Dupont
L.
,
Bekhouche
M.
,
Colige
A.
et al. .
(
2019
)
Differential cleavage of lysyl oxidase by the metalloproteinases BMP1 and ADAMTS2/14 regulates collagen binding through a tyrosine sulfate domain
.
J. Biol. Chem.
294
,
11087
11100
[PubMed]
55.
Fogelgren
B.
,
Polgár
N.
,
Szauter
K.M.
,
Ujfaludi
Z.
,
Laczkó
R.
,
Fong
K.S.K.
et al. .
(
2005
)
Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation
.
J. Biol. Chem.
280
,
24690
24697
[PubMed]
56.
Sasaki
T.
,
Stoop
R.
,
Sakai
T.
,
Hess
A.
,
Deutzmann
R.
,
Schlötzer-Schrehardt
U.
et al. .
(
2016
)
Loss of fibulin-4 results in abnormal collagen fibril assembly in bone, caused by impaired lysyl oxidase processing and collagen cross-linking
.
Matrix Biol.
50
,
53
66
[PubMed]
57.
Rosini
S.
,
Pugh
N.
,
Bonna
A.M.
,
Hulmes
D.J.S.
,
Farndale
R.W.
and
Adams
J.C.
(
2018
)
Thrombospondin-1 promotes matrix homeostasis by interacting with collagen and lysyl oxidase precursors and collagen cross-linking sites
.
Sci. Signal.
11
,
eaar2566
[PubMed]
58.
Grimsby
J.L.
,
Lucero
H.A.
,
Trackman
P.C.
,
Ravid
K.
and
Kagan
H.M.
(
2010
)
Role of lysyl oxidase propeptide in secretion and enzyme activity
.
J. Cell. Biochem.
111
,
1231
1243
[PubMed]
59.
Vallet
S.D.
,
Miele
A.E.
,
Uciechowska-Kaczmarzyk
U.
,
Liwo
A.
,
Duclos
B.
,
Samsonov
S.A.
et al. .
(
2018
)
Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners
.
Sci. Rep.
8
,
11768
[PubMed]
60.
Ricard-Blum
S.
and
Vallet
S.D.
(
2019
)
Fragments generated upon extracellular matrix remodeling: Biological regulators and potential drugs
.
Matrix Biol.
75-76
,
170
189
[PubMed]
61.
Trackman
P.C.
(
2018
)
Functional importance of lysyl oxidase family propeptide regions
.
J. Cell Commun. Signal.
12
,
45
53
[PubMed]
62.
Nareshkumar
R.N.
,
Sulochana
K.N.
and
Coral
K.
(
2018
)
Inhibition of angiogenesis in endothelial cells by Human Lysyl oxidase propeptide
.
Sci. Rep.
8
,
10426
[PubMed]
63.
Griner
J.D.
,
Rogers
C.J.
,
Zhu
M.-J.
and
Du
M.
(
2017
)
Lysyl oxidase propeptide promotes adipogenesis through inhibition of FGF-2 signaling
.
Adipocyte
6
,
12
19
[PubMed]
64.
Schlage
P.
,
Egli
F.E.
,
Nanni
P.
,
Wang
L.W.
,
Kizhakkedathu
J.N.
,
Apte
S.S.
et al. .
(
2014
)
Time-resolved analysis of the matrix metalloproteinase 10 substrate degradome
.
Mol. Cell. Proteomics
13
,
580
593
[PubMed]
65.
Thomassin
L.
,
Werneck
C.C.
,
Broekelmann
T.J.
,
Gleyzal
C.
,
Hornstra
I.K.
,
Mecham
R.P.
et al. .
(
2005
)
The Pro-regions of lysyl oxidase and lysyl oxidase-like 1 are required for deposition onto elastic fibers
.
J. Biol. Chem.
280
,
42848
42855
[PubMed]
66.
López-Jiménez
A.J.
,
Basak
T.
and
Vanacore
R.M.
(
2017
)
Proteolytic processing of lysyl oxidase-like-2 in the extracellular matrix is required for crosslinking of basement membrane collagen IV
.
J. Biol. Chem.
292
,
16970
16982
[PubMed]
67.
Okada
K.
,
Moon
H.-J.
,
Finney
J.
,
Meier
A.
and
Mure
M.
(
2018
)
Extracellular processing of lysyl oxidase-like 2 and its effect on amine oxidase activity
.
Biochemistry
57
,
6973
6983
[PubMed]
68.
Schmelzer
C.E.H.
,
Heinz
A.
,
Troilo
H.
,
Lockhart-Cairns
M.P.
,
Jowitt
T.A.
,
Marchand
M.F.
et al. .
(
2019
)
Lysyl oxidase-like 2 (LOXL2)-mediated cross-linking of tropoelastin
.
FASEB J.
33
,
5468
5481
[PubMed]
69.
Mäki
J.M.
,
Tikkanen
H.
and
Kivirikko
K.I.
(
2001
)
Cloning and characterization of a fifth human lysyl oxidase isoenzyme: the third member of the lysyl oxidase-related subfamily with four scavenger receptor cysteine-rich domains
.
Matrix Biol.
20
,
493
496
[PubMed]
70.
Duff
A.P.
,
Cohen
A.E.
,
Ellis
P.J.
,
Kuchar
J.A.
,
Langley
D.B.
,
Shepard
E.M.
et al. .
(
2003
)
The crystal structure of Pichia pastoris lysyl oxidase
.
Biochemistry
42
,
15148
15157
[PubMed]
71.
Duff
A.P.
,
Cohen
A.E.
,
Ellis
P.J.
,
Hilmer
K.
,
Langley
D.B.
,
Dooley
D.M.
et al. .
(
2006
)
The 1.23 Angstrom structure of Pichia pastoris lysyl oxidase reveals a lysine-lysine cross-link
.
Acta Crystallogr. D Biol. Crystallogr.
62
,
1073
1084
[PubMed]
72.
Kagan
H.M.
and
Ryvkin
F.
(
2011
)
Lysyl oxidase and lysyl oxidase-like enzymes
. In
The Extracellular Matrix: An Overview
(
Mecham
R.P.
, ed.), pp.
303
335
,
Springer Berlin Heidelberg
,
Berlin, Heidelberg
73.
Bhuvanasundar
R.
,
John
A.
,
Sulochana
K.N.
,
Coral
K.
,
Deepa
P.R.
and
Umashankar
V.
(
2014
)
A molecular model of human lysyl Oxidase (LOX) with optimal copper orientation in the catalytic cavity for induced fit docking studies with potential modulators
.
Bioinformation
10
,
406
412
[PubMed]
74.
Chen
X.
and
Greenaway
F.T.
(
2011
)
Identification of the disulfide bonds of lysyl oxidase
.
J. Neural Transm. (Vienna)
118
,
1111
1114
[PubMed]
75.
Bhuvanasundar
R.
,
Ragavachetty
N.N.
,
Singh
N.K.
,
Coral
K.
,
Deepa
P.R.
and
Sulochana
K.N.
(
2019
)
Expression, purification and characterization of a biologically active and thermally stable human lysyl oxidase
.
Indian J. Biochem. Biophys.
56
,
105
116
76.
Avery
N.C.
and
Bailey
A.J.
(
2008
)
Restraining cross-links responsible for the mechanical properties of collagen fibers: natural and artificial
. In
Collagen: Structure and Mechanics
(
Fratzl
P.
, ed.), pp.
81
110
,
Springer Science+Business Media, LLC
,
Berlin, Heidelberg
77.
Murakami
Y.
,
Fujino
T.
,
Kurachi
R.
,
Hasegawa
T.
,
Usui
T.
,
Hayase
F.
et al. .
(
2018
)
Identification of pyridinoline, a collagen crosslink, as a novel intrinsic ligand for the receptor for advanced glycation end-products (RAGE)
.
Biosci. Biotechnol. Biochem.
82
,
1508
1514
[PubMed]
78.
Herchenhan
A.
,
Uhlenbrock
F.
,
Eliasson
P.
,
Weis
M.
,
Eyre
D.
,
Kadler
K.E.
et al. .
(
2015
)
Lysyl oxidase activity is required for ordered collagen fibrillogenesis by tendon cells
.
J. Biol. Chem.
290
,
16440
16450
[PubMed]
79.
Eekhoff
J.D.
,
Fang
F.
and
Lake
S.P.
(
2018
)
Multiscale mechanical effects of native collagen cross-linking in tendon
.
Connect. Tissue Res.
59
,
410
422
[PubMed]
80.
Eyre
D.R.
and
Wu
J.J.
(
2005
)
Collagen cross-links
.
Top. Curr. Chem.
247
,
207
229
81.
Kim
Y.-M.
,
Kim
E.-C.
and
Kim
Y.
(
2011
)
The human lysyl oxidase-like 2 protein functions as an amine oxidase toward collagen and elastin
.
Mol. Biol. Rep.
38
,
145
149
[PubMed]
82.
Yamauchi
M.
and
Sricholpech
M.
(
2012
)
Lysine post-translational modifications of collagen
.
Essays Biochem.
52
,
113
133
[PubMed]
83.
Kuchar
M.
,
Neuber
C.
,
Belter
B.
,
Bergmann
R.
,
Lenk
J.
,
Wodtke
R.
et al. .
(
2018
)
Evaluation of fluorine-18-labeled α1(I)-N-telopeptide analogs as substrate-based radiotracers for PET imaging of melanoma-associated Lysyl oxidase
.
Front. Chem.
6
,
121
[PubMed]
84.
Kalamajski
S.
,
Liu
C.
,
Tillgren
V.
,
Rubin
K.
,
Oldberg
Å
,
Rai
J.
et al. .
(
2014
)
Increased C-telopeptide cross-linking of tendon type I collagen in fibromodulin-deficient mice
.
J. Biol. Chem.
289
,
18873
18879
[PubMed]
85.
Hudson
D.M.
,
Archer
M.
,
King
K.B.
and
Eyre
D.R.
(
2018
)
Glycation of type I collagen selectively targets the same helical domain lysine sites as lysyl oxidase-mediated cross-linking
.
J. Biol. Chem.
293
,
15620
15627
[PubMed]
86.
Terajima
M.
,
Perdivara
I.
,
Sricholpech
M.
,
Deguchi
Y.
,
Pleshko
N.
,
Tomer
K.B.
et al. .
(
2014
)
Glycosylation and cross-linking in bone type I collagen
.
J. Biol. Chem.
289
,
22636
22647
[PubMed]
87.
Siegel
R.C.
(
1976
)
Collagen cross-linking. Synthesis of collagen cross-links in vitro with highly purified lysyl oxidase
.
J. Biol. Chem
251
,
5786
5792
[PubMed]
88.
Chen
Y.
,
Terajima
M.
,
Yang
Y.
,
Sun
L.
,
Ahn
Y.-H.
,
Pankova
D.
et al. .
(
2015
)
Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma
.
J. Clin. Invest.
125
,
1147
1162
[PubMed]
89.
Pankova
D.
,
Chen
Y.
,
Terajima
M.
,
Schliekelman
M.J.
,
Baird
B.N.
,
Fahrenholtz
M.
et al. .
(
2016
)
Cancer-associated fibroblasts induce a collagen cross-link switch in tumor stroma
.
Mol. Cancer Res.
14
,
287
295
[PubMed]
90.
Viguet-Carrin
S.
,
Garnero
P.
and
Delmas
P.D.
(
2006
)
The role of collagen in bone strength
.
Osteoporos. Int.
17
,
319
336
[PubMed]
91.
Eyre
D.R.
,
Weis
M.A.
and
Wu
J.-J.
(
2008
)
Advances in collagen cross-link analysis
.
Methods
45
,
65
74
[PubMed]
92.
Taga
Y.
,
Tanaka
K.
,
Hamada
C.
,
Kusubata
M.
,
Ogawa-Goto
K.
and
Hattori
S.
(
2017
)
Hydroxyhomocitrulline is a collagen-specific carbamylation mark that affects cross-link formation
.
Cell Chem. Biol.
24
,
1276.e3
1284.e3
93.
Eyre
D.R.
,
Weis
M.A.
and
Wu
J.-J.
(
2010
)
Maturation of collagen Ketoimine cross-links by an alternative mechanism to pyridinoline formation in cartilage
.
J. Biol. Chem.
285
,
16675
16682
[PubMed]
94.
Eyre
D.R.
,
Weis
M.
and
Rai
J.
(
2019
)
Analyses of lysine aldehyde cross-linking in collagen reveal that the mature cross-link histidinohydroxylysinonorleucine is an artifact
.
J. Biol. Chem.
294
,
6578
6590
[PubMed]
95.
Kalamajski
S.
,
Bihan
D.
,
Bonna
A.
,
Rubin
K.
and
Farndale
R.W.
(
2016
)
Fibromodulin interacts with collagen cross-linking sites and activates lysyl oxidase
.
J. Biol. Chem.
291
,
7951
7960
[PubMed]
96.
Herum
K.M.
,
Lunde
I.G.
,
Skrbic
B.
,
Louch
W.E.
,
Hasic
A.
,
Boye
S.
et al. .
(
2015
)
Syndecan-4 is a key determinant of collagen cross-linking and passive myocardial stiffness in the pressure-overloaded heart
.
Cardiovasc. Res.
106
,
217
226
[PubMed]
97.
Maruhashi
T.
,
Kii
I.
,
Saito
M.
and
Kudo
A.
(
2010
)
Interaction between periostin and BMP-1 promotes proteolytic activation of lysyl oxidase
.
J. Biol. Chem.
285
,
13294
13303
[PubMed]
98.
Sato
F.
,
Seino-Sudo
R.
,
Okada
M.
,
Sakai
H.
,
Yumoto
T.
and
Wachi
H.
(
2017
)
Lysyl oxidase enhances the deposition of tropoelastin through the catalysis of tropoelastin molecules on the cell surface
.
Biol. Pharm. Bull.
40
,
1646
1653
[PubMed]
99.
Dhital
B.
,
Durlik
P.
,
Rathod
P.
,
Gul-E-Noor
F.
,
Wang
Z.
,
Sun
C.
et al. .
(
2017
)
Ultraviolet radiation reduces desmosine cross-links in elastin
.
Biochem. Biophys. Rep.
10
,
172
177
[PubMed]
100.
Mecham
R.P.
(
2018
)
Elastin in lung development and disease pathogenesis
.
Matrix Biol.
73
,
6
20
[PubMed]
101.
Schräder
C.U.
,
Heinz
A.
,
Majovsky
P.
,
Mayack
B.K.
,
Brinckmann
J.
,
Sippl
W.
et al. .
(
2018
)
Elastin is heterogeneously cross-linked
.
J. Biol. Chem.
293
,
15107
15119
[PubMed]
102.
Hedtke
T.
,
Schräder
C.U.
,
Heinz
A.
,
Hoehenwarter
W.
,
Brinckmann
J.
,
Groth
T.
et al. .
(
2019
)
A comprehensive map of human elastin cross-linking during elastogenesis
.
FEBS J.
[PubMed]
103.
Aumiller
V.
,
Strobel
B.
,
Romeike
M.
,
Schuler
M.
,
Stierstorfer
B.E.
and
Kreuz
S.
(
2017
)
Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis
.
Sci. Rep.
7
,
149
[PubMed]
104.
Yamauchi
M.
,
Taga
Y.
,
Hattori
S.
,
Shiiba
M.
and
Terajima
M.
(
2018
)
Analysis of collagen and elastin cross-links
.
Methods Cell Biol.
143
,
115
132
[PubMed]
105.
Joshi
A.
,
Zahoor
A.
and
Buson
A.
(
2019
)
Measurement of collagen cross-links from tissue samples by mass spectrometry
.
Methods Mol. Biol.
1944
,
79
93
[PubMed]
106.
Shaw
N.
and
Högler
W.
(
2012
)
Biochemical markers of bone metabolism
. In
Pediatric Bone
2nd
edn (
Glorieux
H.F.
,
Pettifor
J.M.
and
Juppner
H.
, eds), pp.
361
381
,
Elsevier Inc.
,
Amsterdam, Netherlands
107.
Kuo
T.-R.
and
Chen
C.-H.
(
2017
)
Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives
.
Biomark. Res.
5
,
18
[PubMed]
108.
Lindert
U.
,
Kraenzlin
M.
,
Campos-Xavier
A.B.
,
Baumgartner
M.R.
,
Bonafé
L.
,
Giunta
C.
et al. .
(
2015
)
Urinary pyridinoline cross-links as biomarkers of osteogenesis imperfecta
.
Orphanet J. Rare Dis.
10
,
104
[PubMed]
109.
Paschalis
E.P.
,
Gamsjaeger
S.
,
Tatakis
D.N.
,
Hassler
N.
,
Robins
S.P.
and
Klaushofer
K.
(
2015
)
Fourier transform Infrared spectroscopic characterization of mineralizing type I collagen enzymatic trivalent cross-links
.
Calcif. Tissue Int.
96
,
18
29
[PubMed]
110.
Rieppo
L.
,
Kokkonen
H.T.
,
Kulmala
K.A.M.
,
Kovanen
V.
,
Lammi
M.J.
,
Töyräs
J.
et al. .
(
2017
)
Infrared microspectroscopic determination of collagen cross-links in articular cartilage
.
J. Biomed. Opt.
22
,
35007
[PubMed]
111.
Gamsjaeger
S.
,
Robins
S.P.
,
Tatakis
D.N.
,
Klaushofer
K.
and
Paschalis
E.P.
(
2017
)
Identification of pyridinoline trivalent collagen cross-links by Raman microspectroscopy
.
Calcif. Tissue Int.
100
,
565
574
[PubMed]
112.
Chen
L.
,
Li
S.
and
Li
W.
(
2018
)
LOX/LOXL in pulmonary fibrosis: potential therapeutic targets
.
J. Drug Target
27
,
1
23
113.
Puente
A.
,
Fortea
J.I.
,
Cabezas
J.
,
Arias Loste
M.T.
,
Iruzubieta
P.
,
Llerena
S.
et al. .
(
2019
)
LOXL2-A new target in antifibrogenic therapy?
Int. J. Mol. Sci.
20
,
E1634
[PubMed]
114.
Hajdú
I.
,
Kardos
J.
,
Major
B.
,
Fabó
G.
,
Lőrincz
Z.
,
Cseh
S.
et al. .
(
2018
)
Inhibition of the LOX enzyme family members with old and new ligands. Selectivity analysis revisited
.
Bioorg. Med. Chem. Lett.
28
,
3113
3118
[PubMed]
115.
El Hajj
E.C.
,
El Hajj
M.C.
,
Ninh
V.K.
and
Gardner
J.D.
(
2018
)
Inhibitor of lysyl oxidase improves cardiac function and the collagen/MMP profile in response to volume overload
.
Am. J. Physiol. Heart Circ. Physiol.
315
,
H463
H473
[PubMed]
116.
Shi
L.
,
Zhang
N.
,
Liu
H.
,
Zhao
L.
,
Liu
J.
,
Wan
J.
et al. .
(
2018
)
Lysyl oxidase inhibition via β-aminoproprionitrile hampers human umbilical vein endothelial cell angiogenesis and migration in vitro
.
Mol. Med. Rep.
17
,
5029
5036
[PubMed]
117.
Miana
M.
,
Galán
M.
,
Martínez-Martínez
E.
,
Varona
S.
,
Jurado-López
R.
,
Bausa-Miranda
B.
et al. .
(
2015
)
The lysyl oxidase inhibitor β-aminopropionitrile reduces body weight gain and improves the metabolic profile in diet-induced obesity in rats
.
Dis. Model Mech.
8
,
543
551
[PubMed]
118.
Mižíková
I.
,
Ruiz-Camp
J.
,
Steenbock
H.
,
Madurga
A.
,
Vadász
I.
,
Herold
S.
et al. .
(
2015
)
Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia
.
Am. J. Physiol. Lung Cell Mol. Physiol.
308
,
L1145
L1158
[PubMed]
119.
Leung
L.
,
Niculescu-Duvaz
D.
,
Smithen
D.
,
Lopes
F.
,
Callens
C.
,
McLeary
R.
et al. .
(
2019
)
Anti-metastatic inhibitors of lysyl oxidase (LOX): design and structure-activity relationships
.
J. Med. Chem.
62
,
5863
5884
120.
Schilter
H.
,
Findlay
A.D.
,
Perryman
L.
,
Yow
T.T.
,
Moses
J.
,
Zahoor
A.
et al. .
(
2019
)
The lysyl oxidase like 2/3 enzymatic inhibitor, PXS-5153A, reduces crosslinks and ameliorates fibrosis
.
J. Cell. Mol. Med.
23
,
1759
1770
[PubMed]
121.
Chang
J.
,
Lucas
M.C.
,
Leonte
L.E.
,
Garcia-Montolio
M.
,
Singh
L.B.
,
Findlay
A.D.
et al. .
(
2017
)
Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer
.
Oncotarget
8
,
26066
26078
[PubMed]
122.
Stangenberg
S.
,
Saad
S.
,
Schilter
H.C.
,
Zaky
A.
,
Gill
A.
,
Pollock
C.A.
et al. .
(
2018
)
Lysyl oxidase-like 2 inhibition ameliorates glomerulosclerosis and albuminuria in diabetic nephropathy
.
Sci. Rep.
8
,
9423
[PubMed]
123.
Rowbottom
M.W.
,
Bain
G.
,
Calderon
I.
,
Lasof
T.
,
Lonergan
D.
,
Lai
A.
et al. .
(
2017
)
Identification of 4-(Aminomethyl)-6-(trifluoromethyl)-2-(phenoxy)pyridine derivatives as potent, selective, and orally efficacious inhibitors of the copper-dependent amine oxidase, lysyl oxidase-like 2 (LOXL2)
.
J. Med. Chem.
60
,
4403
4423
[PubMed]
124.
Muhammad
S.A.
,
Ali
A.
,
Ismail
T.
,
Zafar
R.
,
Ilyas
U.
and
Ahmad
J.
(
2014
)
In silico study of anti-carcinogenic lysyl oxidase-like 2 inhibitors
.
Comput. Biol. Chem.
51
,
71
82
[PubMed]
125.
Hutchinson
J.H.
,
Rowbottom
M.W.
,
Lonergan
D.
,
Darlington
J.
,
Prodanovich
P.
,
King
C.D.
et al. .
(
2017
)
Small molecule lysyl oxidase-like 2 (LOXL2) Inhibitors: the identification of an inhibitor selective for LOXL2 over LOX
.
ACS Med. Chem. Lett.
8
,
423
427
[PubMed]
126.
Rodriguez
H.M.
,
Vaysberg
M.
,
Mikels
A.
,
McCauley
S.
,
Velayo
A.C.
,
Garcia
C.
et al. .
(
2010
)
Modulation of lysyl oxidase-like 2 enzymatic activity by an allosteric antibody inhibitor
.
J. Biol. Chem.
285
,
20964
20974
[PubMed]
127.
Barry-Hamilton
V.
,
Spangler
R.
,
Marshall
D.
,
McCauley
S.
,
Rodriguez
H.M.
,
Oyasu
M.
et al. .
(
2010
)
Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment
.
Nat. Med.
16
,
1009
1017
[PubMed]
128.
Ikenaga
N.
,
Peng
Z.-W.
,
Vaid
K.A.
,
Liu
S.B.
,
Yoshida
S.
,
Sverdlov
D.Y.
et al. .
(
2017
)
Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal
.
Gut
66
,
1697
1708
[PubMed]
129.
Harrison
S.A.
,
Abdelmalek
M.F.
,
Caldwell
S.
,
Shiffman
M.L.
,
Diehl
A.M.
,
Ghalib
R.
et al. .
(
2018
)
Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis
.
Gastroenterology
155
,
1140
1153
[PubMed]
130.
Muir
A.J.
,
Levy
C.
,
Janssen
H.L.A.
,
Montano-Loza
A.J.
,
Shiffman
M.L.
,
Caldwell
S.
et al. .
(
2019
)
Simtuzumab for primary sclerosing cholangitis: phase II study results with insights on the natural history of the disease
.
Hepatology
69
,
684
698
[PubMed]
131.
Altinbas
A.
(
2017
)
A quick overview to the early phase clinical trials of Simtuzumab®: Are we loosing the most promising anti-fibrotic product?
Med. Hypotheses
108
,
159
160
[PubMed]
132.
Fickert
P.
(
2019
)
Is this the last requiem for simtuzumab?
Hepatology
69
,
476
479
[PubMed]
133.
Janssen
R.
(
2017
)
Lysyl oxidase inhibition by heparin in idiopathic pulmonary fibrosis: is there still hope?
Am. J. Respir. Crit. Care Med.
195
,
141
142
[PubMed]
134.
Jud
P.
and
Sourij
H.
(
2019
)
Therapeutic options to reduce advanced glycation end products in patients with diabetes mellitus: a review
.
Diabetes Res. Clin. Pract.
148
,
54
63
[PubMed]
135.
Chen
Y.
,
He
F.
,
Liu
W.
and
Zhang
J.
(
2016
)
Spectroscopic studies on the interaction of pyridinoline cross-linking in type 1 collagen with ZIF8-HB
.
Adv. Exp. Med. Biol.
923
,
63
67
[PubMed]
136.
Aviram
R.
,
Zaffryar-Eilot
S.
,
Hubmacher
D.
,
Grunwald
H.
,
Mäki
J.M.
,
Myllyharju
J.
et al. .
(
2019
)
Interactions between lysyl oxidases and ADAMTS proteins suggest a novel crosstalk between two extracellular matrix families
.
Matrix Biol.
75-76
,
114
125
[PubMed]
137.
Wang
L.
,
Uhlig
P.C.
,
Eikenberry
E.F.
,
Robenek
H.
,
Bruckner
P.
and
Hansen
U.
(
2014
)
Lateral growth limitation of corneal fibrils and their lamellar stacking depend on covalent collagen cross-linking by transglutaminase-2 and lysyl oxidases, respectively
.
J. Biol. Chem.
289
,
921
929
[PubMed]
138.
Bhave
G.
,
Colon
S.
and
Ferrell
N.
(
2017
)
The sulfilimine cross-link of collagen IV contributes to kidney tubular basement membrane stiffness
.
Am. J. Physiol. Renal Physiol.
313
,
F596
F602
[PubMed]