Lysyl Oxidase (LOX) Family Members: Rationale and Their Potential as Therapeutic Targets for Liver Fibrosis

Abstract

The cross‐linking of structural extracellular matrix (ECM) components, especially fibrillar collagens and elastin, is strongly implicated in fibrosis progression and resistance to fibrosis reversal. Lysyl oxidase family members (LOX and LOXL1 [lysyl oxidase‐like 1], LOXL2 [lysyl oxidase‐like 2], LOXL3 [lysyl oxidase‐like 3], and LOXL4 [lysyl oxidase like 4]) are extracellular copper‐dependent enzymes that play a key role in ECM cross‐linking, but have also other intracellular functions relevant to fibrosis and carcinogenesis. Although the expression of most LOX family members is elevated in experimental liver fibrosis of diverse etiologies, their individual contribution to fibrosis is incompletely understood. Inhibition of the LOX family as a whole and of LOX, LOXL1, and LOXL2 specifically has been shown to suppress fibrosis progression and accelerate its reversal in rodent models of cardiac, renal, pulmonary, and liver fibrosis. Recent disappointing clinical trials with a monoclonal antibody against LOXL2 (simtuzumab) in patients with pulmonary and liver fibrosis dampened enthusiasm for LOX family member inhibition. However, this unexpected negative outcome may be related to the inefficient antibody, rather than to LOXL2, not qualifying as a relevant antifibrotic target. Moreover, LOX family members other than LOXL2 may prove to be attractive therapeutic targets. In this review, we summarize the structural hallmarks, expression patterns, covalent cross‐linking activities, and modes of regulation of LOX family members and discuss the clinical potential of their inhibition to treat fibrosis in general and liver fibrosis in particular.

Single cell RNA sequencing uncovers cellular developmental sequences and novel potential intercellular communications in embryonic kidney

“…Tgfb1 was inferred to regulate alpha crystalline B (Cryab), a stabilizer of the cytoskeleton, integrin beta 1 (Itgb1), a linker for the cytoskeleton to the extracellular matrix, and lysyl oxidase like 2 (Loxl2), a crosslinker of the extracellular matrix. Tgfb1 may therefore contribute to podocytes becoming resistant to mechanical stress caused by urinary flow [31][32][33] . In addition to Tgfb1, which is expressed mainly in macrophages and endothelial cells, neurotrophin 3 (Ntf3), whose expression was enriched in endothelial cells, was inferred to regulate nestin (Nes), a gene encoding the intermediate filaments of podocytes 34 .…”

Lysyl Oxidase (LOX): Functional Contributions to Signaling Pathways

“…It is particularly important to fill these knowledge gaps, as LOX has been shown to be a promising target for therapeutic intervention in cancer [ 3 , 78 , 79 ] and in vascular [ 80 ], myocardial [ 81 , 82 ], peritoneal [ 83 ] liver [ 84 ] and urological disorders [ 85 ], in adipose tissue dysfunction with an inflammatory component [ 86 ] and in inflammation in Crohns’ disease [ 87 ]. In some of these conditions, fibrosis is the pathological endpoint linking aberrant LOX to its ECM cross-linking activity as an attractive target for LOX-inhibitory therapies.…”

Increased SGK1 activity potentiates mineralocorticoid/NaCl-induced hypertension and kidney injury

“…Some genes previously characterized as profibrotic showed lower expression in Tg.sgk1 when compared to WT mice. For instance, Loxl1, a member of the lysyl-oxidase-like family, crosslinks collagen and elastin and has been implicated in fibrogenesis [71]. Similarly, upregulation of Loxl2 may lead to kidney fibrosis in Col4a3 null mice [72].…”