Saxagliptin suppresses degradation of type II collagen and aggrecan in primary human chondrocytes: a therapeutic implication in osteoarthritis

Abstract

Osteoarthritis (OA) is a major public health concern for which a reliable non-invasive treatment option has yet to be developed. In the present study, we investigated the effects of saxagliptin, a novel dipeptidyl peptidase IV (DPP-4) inhibitor, on several important aspects of the pathophysiology of OA using primary human chondrocytes. The results of real-time PCR and ELISA analyses show that saxagliptin treatment significantly decreased mRNA and protein expression of three key cartilage degrading enzymes: matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13. The results of western blot confirmed that this decrease in MMP-1, -3, and -13 expression prevented degradation of type II collagen. We also found that saxagliptin significantly inhibited expression of a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-4 and ADAMTS-5, which was reflected by markedly decreased degradation of aggrecan. Inhibition of DPP-4 by saxagliptin also reduced oxidative stress in human primary chondrocytes as evidenced by decreased production of reactive oxygen species (ROS) and increased glutathione (GSH) levels. Additionally, the results of western blot analysis show that the effects of saxagliptin are mediated through the p38/IjBa/NF-jB pathway, which is considered an important treatment target for OA. These findings suggest a potential role for saxagliptin as a novel treatment against OA.

Evaluation of Long-Time Decoction-Detoxicated Hei-Shun-Pian (Processed Aconitum carmichaeli Debeaux Lateral Root With Peel) for Its Acute Toxicity and Therapeutic Effect on Mono-Iodoacetate Induced Osteoarthritis

“…In sections of human osteoarthritic cartilage, Col10 was found around hypertrophic chondrocyte clusters in the deep zone close to tidemark ( He et al., 2019 ). Besides the collagens, aggrecan, known as a cartilage-specific proteoglycan core protein, is another crucial component of cartilage ECM ( Hu et al., 2019 ). In the OA state, aggrecan was significantly degraded in the cartilage, and the expression of aggrecan was inversely related to the OA progression ( Eid et al., 2006 ).…”

Insulin Signaling in Arthritis

“…Exposure to AGEs activated the p38 MAPK signaling pathway and increased the degradation of IkBa, upregulating NF-kB. In OA, saxagliptin was able to affect this pro-inflammatory process (138).…”

Insulin Resistance in Osteoarthritis: Similar Mechanisms to Type 2 Diabetes Mellitus

“…It was also shown to reduce oxidative stress and inhibit p38-dependent activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) [141]. Saxagliptin, a novel dipeptidyl peptidase IV (DPP-4) inhibitor, suppresses the degradation of type II collagen in primary human chondrocytes by decreasing MMP, ADAMTS, and ROS production and increasing glutathione levels mediated by p38/NFkB pathway [142]. Metformin, the most commonly used antidiabetic drug, reduced inflammation, decreased the number of T helper 17 ( 17) cells, and increased the number of regulatory T (Treg) cells in a mouse model of collagen-induced arthritis [143].…”