Glycated Collagen Stimulates Differentiation of Gingival Myofibroblasts

Abstract

Background: Glucose‐derived metabolites may alter the structure and biologic properties of important proteins in periodontium, such as collagens. As a consequence, it is possible that collagen‐binding cells may change their phenotypic traits. Although the glucose‐derived product methylglyoxal (MGO) has been detected in periodontal lesions, the precise effect of collagen glycation on gingival connective tissue biology is not fully understood. The present study evaluates whether collagen glycation by MGO may affect phenotypic properties and remodeling capacity of human gingival fibroblasts (HGFs). Methods: Primary cultures of HGFs were grown on Type I collagen matrices previously treated with MGO. Cell cultures were tested for cell viability, apoptosis, α‐smooth muscle actin (SMA), fibronectin (FN) production, and collagen remodeling. Mechanical properties and morphology of MGO‐treated collagen gels were evaluated using rheometry and atomic force microscopy. Statistical analysis was performed by Kruskal‐Wallis and Mann‐Whitney U tests. Results: MGO‐treated collagen did not affect cell viability or apoptosis. In addition, MGO did not induce significant changes in morphology or mechanical properties of the collagen matrix. However, MGO‐treated collagen stimulated an increase in the myofibroblast marker α‐SMA, production and assembly of FN, and contraction of collagen matrices. Moreover, use of a triple‐helical peptide that reconstitutes the collagen‐binding domain for integrins GFOGER reverted the assembly of FN induced by MGO‐treated collagen. Conclusions: The present study shows that collagen glycation by MGO stimulates differentiation of myofibroblasts and production and assembly of FN. These responses may alter the homeostatic balance and wound‐healing response of gingival connective tissues affected by diabetes mellitus or aging.

Evaluation of the nephrotoxicity and safety of low-dose aristolochic acid, extending to the use of Xixin (Asurum), by determination of methylglyoxal and D-lactate

“…In agreement with these observations, severe renal injury and interstitial fibrosis were detected at day 70. As previously described, accumulation of methylglyoxal is harmful and aggravates fibrosis in a variety of pathologies [33][34][35].…”

“…The potential mechanisms include activation of transient receptor potential ankyrin 1 (TRPA1) [35], promotion of the cell cycle [35], differentiation of fibroblasts [33][34][35][36], induction of the epithelial-mesenchymal transition (EMT) via the TGF-β/Snail axis [34], and inhibition of the binding step of collagen phagocytosis [37]. Moreover, Kottmann et al proposed that lactic acid may activate TGF-β and lead to accumulation of hypoxia-inducible factor 1-α (HIF-1α)-which promotes myofibroblast differentiation-in idiopathic pulmonary fibrosis [38].…”

Diabetes alters the involvement of myofibroblasts during periodontal wound healing

“…Diverse factors may contribute to myofibroblastic differentiation in pathological conditions including increasing levels of tissue stiffness, prolonged activation of TGF‐β1, and an altered interaction between macrophages and fibroblastic populations (Pakshir & Hinz, 2018). Our group has recently described that a characteristic trait of diabetes as collagen glycation (Gautieri et al, 2017) by the glucose‐derived product methylglyoxal (MGO) may stimulate the differentiation of gingival myofibroblasts (Retamal et al, 2017). Interestingly, MGO‐glycated collagen may also stimulate Smad3 phosphorylation in cardiac fibroblasts (Talior‐Volodarsky et al, 2015).…”

Role of Fibroblast Populations in Periodontal Wound Healing and Tissue Remodeling

“…Magnification bar = 40 μm. Images in this figure represent reanalysis of previously published data in Retamal et al., 2017.…”