Conjugation with Methylsulfonylmethane Improves Hyaluronic Acid Anti-Inflammatory Activity in a Hydrogen Peroxide-Exposed Tenocyte Culture In Vitro Model.

Amelia Cataldi,Clarissa Gissi,Marialucia Gallorini,Cristina Antonetti Lamorgese Passeri,Francesco Oliva,Anna Concetta Berardi,Alessia Colosimo,Alessia Ricci

doi:10.3390/ijms21217956

Abstract

Rotator cuff tears (RCTs) and rotator cuff disease (RCD) are important causes of disability in middle-aged individuals affected by nontraumatic shoulder dysfunctions. Our previous studies have demonstrated that four different hyaluronic acid preparations (HAPs), including Artrosulfur® hyaluronic acid (HA) (Alfakjn S.r.l., Garlasco, Italy), may exert a protective effect in human RCT-derived tendon cells undergoing oxidative stress damage. Recently, methylsulfonylmethane (MSM) (Barentz, Paderno Dugnano, Italy) has proven to have anti-inflammatory properties and to cause pain relief in patients affected by tendinopathies. This study aims at evaluating three preparations (Artrosulfur® HA, MSM, and Artrosulfur® MSM + HA) in the recovery from hydrogen peroxide-induced oxidative stress damage in human tenocyte. Cell proliferation, Lactate Dehydrogenase (LDH) release, and inducible nitric oxide synthases (iNOS) and prostaglandin E2 (PGE2) modulation were investigated. In parallel, expression of metalloproteinases 2 (MMP2) and 14 (MMP14) and collagen types I and III were also examined. Results demonstrate that Artrosulfur® MSM + HA improves cell escape from oxidative stress by decreasing cytotoxicity and by reducing iNOS and PGE2 secretion. Furthermore, it differentially modulates MMP2 and MMP14 levels and enhances collagen III expression after 24 h, proteins globally related to rapid acceleration of the extracellular matrix (ECM) remodelling and thus tendon healing. By improving the anti-cytotoxic effect of HA, the supplementation of MSM may represent a feasible strategy to ameliorate cuff tendinopathies.

Highlights

Degenerative nontraumatic rotator cuff tears (RCTs) and rotator cuff disease (RCD) are a common cause of chronic shoulder pain and disability, for which incidence increases with age, starting from the third decade of life, with a maximum epidemiologic peak above the fifth one [1]
The observation revealed that dead round-shaped cells no longer adhering to the culture plate were the most prevalent type in the presence of H2O2 alone, while vital elongated fibroblast-like cells prevailed when MSM and, above all, the two hyaluronic acid preparations (HAPs) were coadministered together with H2O2, After 24 h of treatment, cell proliferation was not totally suppressed in response to 2 mM H2O2 and no substantial change was observed when H2O2 was administered together with one of the three preparations (Figure 2B)
Additional in vivo studies are crucial to prove that the combination of hyaluronic acid (HA) with the antioxidant MSM may improve clinical outcomes of rotator cuff tendinopathies in terms of anti-inflammatory and antioxidant functions

Summary

Introduction

Degenerative nontraumatic rotator cuff tears (RCTs) and rotator cuff disease (RCD) are a common cause of chronic shoulder pain and disability, for which incidence increases with age, starting from the third decade of life, with a maximum epidemiologic peak above the fifth one [1]. Conservative surgery could be a possibility for repairing tendon damages in patients suffering from RCTs and RCD. Among conservative management options, growing evidences indicate that hyaluronic acid (HA) alleviates pain, counteracts the inflammation reaction, and improves function in individuals affected by age-related RCTs [2,3,4,5]. Our group has recently shown that human tendon-derived cells from RCTs promptly respond to different hyaluronic acid preparations (HAPs) in vitro, including Artrosulfur® HA, by enhancing cellular metabolism and by counteracting hydrogen peroxide (H2O2)-induced cytotoxicity and inflammation [6,7,8]. By modulating the hyaluronan receptor CD44 and the Nrf transcription factor-related molecular cascade, this HAP has demonstrated a higher cytoprotective effect in human RCT-derived tendon cells undergoing oxidative stress damage [7,8]

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