Chimeric galectin-3 and collagens: Biomarkers and potential therapeutic targets in fibroproliferative diseases

Abstract

Fibrosis, stiffening and scarring of an organ/tissue due to genetic abnormalities, environmental factors, infection, and/or injury, is responsible for > 40% of all deaths in the industrialized world, and to date, there is no cure for it despite extensive research and numerous clinical trials. Several biomarkers have been identified, but no effective therapeutic targets are available. Human galectin-3 is a chimeric gene product formed by the fusion of the internal domain of the collagen alpha gene [N-terminal domain (ND)] at the 5'-end of galectin-1 [C-terminal domain (CRD)] that appeared during evolution together with vertebrates. Due to the overlapping structural similarities between collagen and galectin-3 and their shared susceptibility to cleavage by matrix metalloproteases to generate circulating collagen-like peptides, this review will discuss present knowledge on the role of collagen and galectin-3 as biomarkers of fibrosis. We will also highlight the need for transformative approaches targeting both the ND and CRD domains of galectin-3, since glycoconjugate binding by the CRD is triggered by ND-mediated oligomerization and the therapies targeted only at the CRD have so far achieved limited success.

Keywords: biomarkers; collagens; fibroproliferative diseases; galectin-3; hepatic fibrosis; myocardial fibrosis; pulmonary fibrosis.

Figure 1

Schematic presentation of wound healing and fibrosis: (A) Cell death resulting from tissue injury results in recruitment of inflammatory cells through the damaged epithelium. These cells secrete proteases, degrade basement membrane, and release the components into circulation. Galectin-3 and TGF-β secreted by macrophages activate the resting fibroblasts into myofibroblasts, which secrete fresh basement membrane resulting in wound healing. The synthetic and degradative processes are in balance. (B) Constant and repetitive injury induces damage to the deeper interstitial layer and results in overproduction of the basement membrane components in an unorganized way leading to fibrosis. Secretion of IL-4 and IL-13 by inflammatory cells activates alternative macrophages, activated macrophages secrete increased galectin-3 and overexpress its cell surface receptor CD98. Galectin-3 and CD98 binding stabilizes CD98 and activates PI3K via an association with phosphorylated FAK and β-1 integrin. A galectin-3 feedback loop drives alternative macrophage activation. (Adapted from Genovese and Karsdal, 2016, Expert Review of Proteomics, 13 (2), 213–225).

Figure 2

Fibroproliferative diseases: Various organs develop fibrotic scars as a result of constant tissue damage and insults. FSGS, focal segmental glomerlosclerosis; NASH, nonalcoholic steatohepatitis; AMD, age-related macular degeneration; COPD, chronic obstructive pulmonary disease. (Adapted from Karsdal et al, 2014 Alimentary Pharmacology and Therapeutics, 40: 233–249)

Figure 3

Molecular structure of galectin-1(top left) and galectin-3 (top right). Lower panel: cleaved galectin-3 N-terminal and C-terminal. Visualization and analysis was done by YASARA model software.