Abstract
The reading of glycan-encoded signals by tissue lectins is considered a major route of the flow of biological information in many (patho)physiological processes. The arising challenge for current research is to proceed from work on a distinct protein to family-wide testing of lectin function. Having previously identified homodimeric galectin-1 and chimera-type galectin-3 as molecular switches in osteoarthritis progression, we here provide proof-of-principle evidence for an intra-network cooperation of galectins with three types of modular architecture. We show that the presence of tandem-repeat-type galectin-8 significantly correlated with cartilage degeneration and that it is secreted by osteoarthritic chondrocytes. Glycan-inhibitable surface binding of galectin-8 to these cells increased gene transcription and the secretion of functional disease markers. The natural variant galectin-8 (F19Y) was less active than the prevalent form. Genome-wide array analysis revealed induction of a pro-degradative/inflammatory gene signature, largely under control of NF-κB signaling. This signature overlapped with respective gene-expression patterns elicited by galectins-1 and -3, but also presented supplementary features. Functional assays with mixtures of galectins that mimic the pathophysiological status unveiled cooperation between the three galectins. Our findings shape the novel concept to consider individual galectins as part of a so far not realized teamwork in osteoarthritis pathogenesis, with relevance beyond this disease.
Highlights
Cell surfaces are characterized by their glycosylation profile like by a molecular fingerprint
Having previously shown a tendency for a higher percentage of Gal-8-positive chondrocytes in Mankin score (MS) ≥ 9 than MS ≤ 4 regions and having reported absence of immunopositivity in specimens of articular cartilage from four osteosarcoma patients, we extended this immunohistochemical analysis by higher patient numbers (15 donors), by including a wide range of degree of cartilage degeneration and by applying a more detailed approach considering the exact MS of all histological sections analyzed
Exemplary illustrations of Safranin O staining of regions with MS 3 and MS 11 as well as immunopositivity for Gal-8 of chondrocytes from three sites at two levels of magnification are presented in Fig. 1a
Summary
Cell surfaces are characterized by their glycosylation profile like by a molecular fingerprint. In the quest to define the molecular switches responsible for initiating the harmful processes that cause serious discomfort and pain, measuring (i) a shift of the sialylation profile of N-glycans in chondrocytes exposed to pro-inflammatory cytokines [13, 14] and (ii) increased tissue reactivity for β-galactosides in regions of severe degeneration [15] has given reason to hypothesize that respective receptors, i.e. adhesion/growth-regulatory galectins (Gals), are involved in OA pathophysiology. Gal-1 [17] and Gal-3 [18] were both revealed to enhance the availability of functional disease markers These data identified an active role of two galectins in driving OA pathogenesis and provided initial insights into the possibility of a concerted action of galectins, a concept of significance beyond this disease. Since we have previously detected Gal-8 in sections of OA cartilage in a systematic galectin profiling [16], answering the question about its pathophysiological role in this disease will put the concept of a functional teamwork within the galectin family to the test in a proof-of-principle manner
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