Abstract
Background and ObjectiveThe potential benefit of using hyaluronan (HA) in reconstructive periodontal surgery is still a matter of debate. The aim of the present study was to evaluate the effects of two HA formulations on human oral fibroblasts involved in soft tissue wound healing/regeneration.Material and MethodsMetabolic, proliferative and migratory abilities of primary human palatal and gingival fibroblasts were examined upon HA treatment. To uncover the mechanisms whereby HA influences cellular behavior, wound healing‐related gene expression and activation of signaling kinases were analyzed by qRT‐PCR and immunoblotting, respectively.ResultsThe investigated HA formulations maintained the viability of oral fibroblasts and increased their proliferative and migratory abilities. They enhanced expression of genes encoding type III collagen and transforming growth factor‐β3, characteristic of scarless wound healing. The HAs upregulated the expression of genes encoding pro‐proliferative, pro‐migratory, and pro‐inflammatory factors, with only a moderate effect on the latter in gingival fibroblasts. In palatal but not gingival fibroblasts, an indirect effect of HA on the expression of matrix metalloproteinases 2 and 3 was detected, potentially exerted through induction of pro‐inflammatory cytokines. Finally, our data pointed on Akt, Erk1/2 and p38 as the signaling molecules whereby the HAs exert their effects on oral fibroblasts.ConclusionBoth investigated HA formulations are biocompatible and enhance the proliferative, migratory and wound healing properties of cell types involved in soft tissue wound healing following regenerative periodontal surgery. Our data further suggest that in gingival tissues, the HAs are not likely to impair the healing process by prolonging inflammation or causing excessive MMP expression at the repair site.
Highlights
Hyaluronan (HA) is a naturally occurring non-sulfated glycosaminoglycan involved in maintaining extracellular matrix (ECM) resilience and tissue hydration
The wound healing process involves a number of events rigorously controlled by matrix metalloproteinases (MMPs) and growth factors including transforming growth factor-β1 (TGF-β1), platelet- derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2), and epidermal growth factor (EGF).[15]
To investigate the mechanism behind the differential induction of MMP2 and MMP3 by HA in HPF vs HGF cells, we treated oral fibroblasts with recombinant pro-inflammatory cytokines and examined the effect on MMP expression. qRT-PCR analyses revealed that increasing concentrations (5 and 10 ng/mL) of IL-1α, IL-1β, or tumor necrosis factor-α (TNF-α) applied to HPF or HGF cells had no effect on the expression of MMP1 and MMP8 mRNA levels (Figure 5A and B) but caused a significant and dose-dependent increase in MMP2 and MMP3 mRNAs (Figure 5C and D) compared to their levels in untreated cells
Summary
Hyaluronan (HA) is a naturally occurring non-sulfated glycosaminoglycan involved in maintaining extracellular matrix (ECM) resilience and tissue hydration. The wound healing process involves a number of events rigorously controlled by matrix metalloproteinases (MMPs) and growth factors including transforming growth factor-β1 (TGF-β1), platelet- derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2), and epidermal growth factor (EGF).[15] MMPs degrade ECM components and elicit a pro-inflammatory response, promoting cell migration during wound remodeling.[16] PDGF induces cellular responses throughout all phases of the repair process.[17] TGF-β1 has been recognized as a key regulator of collagen expression.[18] FGF-2 plays a role in re-epithelialization, angiogenesis, and granulation tissue formation and contributes to matrix synthesis and remodeling, which are critical for the wound healing process.[19] EGF is a potent stimulator of epithelialization, angiogenesis, fibroblast proliferation, and survival.[20]. The goal of the present study was to investigate the in vitro effects of two commercially available HA preparations of non-animal origin planned to be used in reconstructive periodontal surgery. We hypothesized that HA stimulates the wound healing potential of oral fibroblasts in vitro and would contribute to soft tissue healing/ regeneration following reconstructive periodontal surgery
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