Effect of inhibiting MMP13 and ADAMTS5 by intra-articular injection of small interfering RNA in a surgically induced osteoarthritis model of mice

Abstract

Matrix metalloproteinase 13 (MMP13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) are thought to play critical roles in cartilage degradation at the early phase of osteoarthritis (OA). The aim of this study is to examine the effect of chemically modified Mmp13 or Adamts5 small interfering RNA (siRNA), alone or in combination, in a mouse OA model. OA pathology was surgically induced in 9-week-old male C57/BL6 mice (n = 64) via destabilization of the medial meniscus (DMM). We used chemically modified siRNA (Accell siRNAs®) for Mmp13 and Adamts5, as well as a non-targeting control and evaluated their combined and individual effects after injection in the DMM model. The control group (n = 16) was injected with non-targeting siRNA and the normal group (n = 16) did not undergo any surgical induction or intra-articular injection. Histological assessment of the articular cartilage was conducted at 4 and 8 weeks post-DMM surgery to evaluate OA progression. Significant improvement in the histological score was observed at 8 weeks after DMM in all three siRNA-treated groups compared to the control siRNA-injected group. The score of the combined group was significantly lower than that of the Adamts5 siRNA-only group. No significant differences were noted between the Mmp13 siRNA-only group and the combined group. Combined intra-articular injection of Mmp13 and Adamts5 siRNA resulted in almost the same inhibitory effects as Mmp13 siRNA alone on cartilage degradation at the early phase of OA.

Oral administration of N-acetyl cysteine prevents osteoarthritis development and progression in a rat model

“…ECM degradation, which characterizes osteoarthritis, is promoted by several protein-degrading enzymes, including matrix metalloproteinases (MMPs), particularly MMP3 and MMP13 7–10 , and members of the a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family such as ADAMTS4 and ADAMTS5 11–16 . Hypoxia inducible factor 2 (HIF2) also reportedly acts as an upstream regulator of osteoarthritis inducible factors 17–19 .…”

Interleukin‑1β‑mediated suppression of microRNA‑27a‑3p activity in human cartilage via MAPK and NF‑κB pathways: A potential mechanism of osteoarthritis pathogenesis

“…Disruptions in extracellular matrix (ECM) homeostasis are key events in the pathogenesis of OA (25) and ADAMTS5 has a key role in ECM homeostasis due to its capacity to degrade a wide range of ECM components (26). The current study demonstrated that the expression of miR-27a-3p was significantly lower in OA cartilage compared with normal cartilage, while the overexpression of miR-27a-3p in human chondrocytes inhibited ADAMTS5 expression.…”

The N-Acetyl Phenylalanine Glucosamine Derivative Attenuates the Inflammatory/Catabolic Environment in a Chondrocyte-Synoviocyte Co-Culture System

“…A relevant effect of NAPA is the modulation of ADAMTS5, the foremost cartilage ECM-degrading enzyme responsible for aggrecan removal in the early phase of the disease 56 . This pivotal role is confirmed by the effectiveness of inhibiting OA progression by a treatment of this catabolic enzyme by small interfering RNA 56 .…”

“…A relevant effect of NAPA is the modulation of ADAMTS5, the foremost cartilage ECM-degrading enzyme responsible for aggrecan removal in the early phase of the disease 56 . This pivotal role is confirmed by the effectiveness of inhibiting OA progression by a treatment of this catabolic enzyme by small interfering RNA 56 . Notably, ADAMTS5 is an OA drug target validated with the DMM model 31 , and indeed, its antibody-mediated neutralization has proven able to inhibit OA progression in a DMM model 57 .…”