Functionalized Nanogels with Endothelin-1 and Bradykinin Receptor Antagonist Peptides Decrease Inflammatory and Cartilage Degradation Markers of Osteoarthritis in a Horse Organoid Model of Cartilage

Abstract

Osteoarthritis (OA) is a degenerative and heterogeneous disease that affects all types of joint structures. Current clinical treatments are only symptomatic and do not manage the degenerative process in animals or humans. One of the new orthobiological treatment strategies being developed to treat OA is the use of drug delivery systems (DDS) to release bioactive molecules over a long period of time directly into the joint to limit inflammation, control pain, and reduce cartilage degradation. Two vasoactive peptides, endothelin-1 and bradykinin, play important roles in OA pathogenesis. In this study, we investigated the effects of two functionalized nanogels as DDS. We assessed the effect of chitosan functionalized with a type A endothelin receptor antagonist (BQ-123-CHI) and/or hyaluronic acid functionalized with a type B1 bradykinin receptor antagonist (R-954-HA). The biocompatibility of these nanogels, alone or in combination, was first validated on equine articular chondrocytes cultured under different oxic conditions. Further, in an OA equine organoid model via induction with interleukin-1 beta (IL-1β), a combination of BQ-123-CHI and R-954-HA (BR5) triggered the greatest decrease in inflammatory and catabolic markers. In basal and OA conditions, BQ-123-CHI alone or in equimolar combinations with R-954-HA had weak pro-anabolic effects on collagens synthesis. These new nanogels, as part of a composite DDS, show promising attributes for treating OA.

Effect of pro-inflammatory cytokine priming and storage temperature of the mesenchymal stromal cell (MSC) secretome on equine articular chondrocytes

“…Additionally, media conditioned from MSCs primed with IL-1β triggered a significant increase in MMP1 and MMP13 mRNA levels and HtrA1 protein amounts, which could be attributed to the increase in the concentration of pro-inflammatory molecules observed in the CM. IL-1β is one of the major pro-inflammatory cytokines involved in OA pathogenesis and its potential to increase MMP1 and MMP13 levels in eAC cultures has already been demonstrated (Bourdon et al, 2021;Cullier et al, 2022). However, the same studies have shown that the addition of IL-1β to eACs tended to be associated with decreased levels of HTRA1, which was not observed in our experiments.…”

Blinded, Randomized Tolerance Study of a Biologically Enhanced Nanogel with Endothelin-1 and Bradykinin Receptor Antagonist Peptides via Intra-Articular Injection for Osteoarthritis Treatment in Horses

“…However, before assessing its clinical e cacy, its safety must be validated. The biocompatibility of the abovementioned functionalized nanogels has already been validated in a previous in vitro study in which nanogels showed no cytotoxic effects but rather sustained metabolic activity and proliferation of equine articular chondrocytes (19).…”

“…They were produced in aseptic conditions to ensure sterile, pyrogenfree nanogels of speci c physicochemical characteristics. A similar formulation was previously investigated in vitro (19) and was proven to be biocompatible with no cytotoxic effect and bene ce metabolic activity and proliferation of equine chondrocytes (19).…”

“…In vivo studies in a rat model of OA showed that type A endothelin receptor antagonist (BQ-123) and type B1 bradykinin receptor antagonist (R-954) decreased cartilage degradation and nociception (14). In vitro studies on an equine cartilage organoid model of OA revealed that the combination of chitosan functionalized with a type A endothelin receptor antagonist (BQ-123-CHI) and hyaluronic acid functionalized with a type B1 bradykinin receptor antagonist (R-954-HA) induced a decrease in in ammatory and catabolic markers (19). These results reinforce the potential therapeutic value of this type of functionalized nanogels in the management of chronic joint disorders involving painful and in ammatory components.…”

Women’s contribution to stem cell research for osteoarthritis: an opinion paper

“…Tissue engineering studies conducted since the emergence of ACT in 1994 by Brittberg ( Brittberg et al, 1994 ) led to the development of suitable biological substitutes and refinement of organotypic models by the group of M. Demoor* ( Demoor et al, 2014 ). These mini-tissues/organoids have been incorporated in some translational research studies by the same group* ( Desancé et al, 2018 ; Cullier et al, 2022 ) to develop cell-based and cell-free orthobiological therapeutic approaches. Therefore, some in vitro studies have been transposed from humans ( Legendre et al, 2013 ; Gómez-Leduc et al, 2016 ; Gómez-Leduc et al, 2017 ; Legendre et al, 2017 ) to horses ( Desancé et al, 2018 ) again by this group* to demonstrate the therapeutic potential of chondrocytes and stem cells for cartilage engineering in both species and to have the possibility to carry out preparatory work in horses before transposing it to humans.…”