Galectin-3 Induces a Pro-degradative/inflammatory Gene Signature in Human Chondrocytes, Teaming Up with Galectin-1 in Osteoarthritis Pathogenesis

Abstract

Inflammatory chemo- and cytokines and matrix-degrading proteases underlie the progression of osteoarthritis (OA). Aiming to define upstream regulators for these disease markers, we pursued initial evidence for an upregulation of members of the adhesion/growth-regulatory galectin family. Immunohistochemical localization of galectin-3 (Gal-3) in sections of human cartilage with increasing levels of degeneration revealed a linear correlation reaching a chondrocyte positivity of 60%. Presence in situ was cytoplasmic, the lectin was secreted from OA chondrocytes in culture and binding of Gal-3 yielded lactose-inhibitable surface staining. Exposure of cells to the lectin led to enhanced gene expression and secretion of functional disease markers. Genome-wide transcriptomic analysis broadened this result to reveal a pro-degradative/inflammatory gene signature under the control of NF-κB. Fittingly, targeting this route of activation by inhibitors impaired the unfavourable response to Gal-3 binding, as also seen by shortening the lectin’s collagen-like repeat region. Gal-3’s activation profile overlaps with that of homodimeric galectin-1 (Gal-1) and also has distinctive (supplementing) features. Tested at subsaturating concentrations in a mixture, we found cooperation between the two galectins, apparently able to team up to promote OA pathogenesis. In summary, our results suggest that a network of endogenous lectins is relevant for initiating this process cascade.

Effects of intra‐articular hyaluronic acid associated to Chitlac (arty‐duo®) in a rat knee osteoarthritis model

“…To our knowledge galectins have never been tested in in vivo OA DMM models and in studies on OA treatment. Several studies reported that Galectin‐1 was associated with cartilage degeneration in OA patients’ explants and with an in vitro up‐regulation of several enzymes involved in matrix degradation . In our study, immunohistochemical analyses highlighted that, both ARTY‐DUO® and HA injections down‐regulated Galectin‐1 expression.…”

“…In addition, we focused on the evaluation of galectins, members of the animal lectin family that bind to the β‐galactoside‐containing carbohydrate moieties of glycoconjugates. In the past few years they have been demonstrated to play a significant role in OA . To our knowledge galectins have never been tested in in vivo OA DMM models and in studies on OA treatment.…”

Galectins‐1 and ‐3 in Human Intervertebral Disc Degeneration: Non‐Uniform Distribution Profiles and Activation of Disease Markers Involving NF‐κB by Galectin‐1

“…Recombinant proteins, AlexaFluor‐labeled galectins, and non‐crossreactive antibody preparations against Gal‐1 or −3 were prepared and applied as previously described in detail …”

“…Being hereby guided to look at tissue degeneration in osteoarthritis, we previously found that an emerging group of elicitors of functional disease markers in cartilage degeneration belongs to the class of endogenous lectins. In particular, we recently revealed the upregulation of distinct endogenous galectins in osteoarthritic cartilage and their involvement in triggering a pro‐degradative/‐inflammatory microenvironment via expression of nuclear factor‐kB (NF‐kB)‐regulated gene expression profiles . Mechanistically, tissue lectins “read” cellular signals encoded by glycans and translate their information into molecular activities .…”

MedUni Wien Researcher of the Month April 2017

“…Die Glykobiologie beschreibt im Wesentlichen die Struktur und Funktion von Glykanen (Zuckerketten), welche durch Interaktion mit zuckerbindenden Proteinen (z. B. Galektinen) ein breites Spektrum biologischer Prozesse beeinflussen können [10,11].…”