Establishment of an Ex Vivo Inflammatory Osteoarthritis Model With Human Osteochondral Explants.

Kaihu Li,Penghui Zhang,Mauro Alini,Yong Zhu,Zhen Li,Sibylle Grad

doi:10.3389/fbioe.2021.787020

Abstract

Osteoarthritis (OA) is the most common degenerative joint disease without clear pathophysiological mechanism and effective drugs for treatment. Although various animal models exist, the translation of the outcome into clinics remains difficult due to species differences. In this study, an ex vivo inflammatory OA model was induced using different concentrations of interleukin one beta (IL-1β) and tumor necrosis factor α (TNF-α) on explants from the human femoral head. In the inflammatory OA groups, the gene expression levels of cartilage catabolism (matrix metalloproteinase 1 (MMP1), matrix metalloproteinase 3 (MMP3)), and inflammation (interleukin 6 (IL-6), interleukin 8 (IL-8)) markers were significantly upregulated, while the anabolic genes (collagen 2 (COL2), aggrecan (ACAN), and proteoglycan 4 (PRG4)) were downregulated compared to the control group. The release of cytokines (IL-6, IL-8) and nitric oxide (NO) in the conditioned medium was also upregulated in inflammatory OA groups. The Safranin O/Fast Green staining showed loss of proteoglycan in the superficial zone cartilage after cytokine treatment. The results indicated that an ex vivo inflammation and degeneration model was successfully established using osteochondral explants from the human femoral head. This model can be used to elucidate the in-depth mechanism of inflammatory OA and to screen new drugs for OA treatment.

Highlights

Osteoarthritis (OA) is the most common degenerative joint disease, mainly invading knee and hip joints (Martel-Pelletier et al, 2016)
Through encouraging research and development, several potential disease-modifying OA drugs (DMOADs) have been found in experimental OA models based on animal studies (Cai et al, 2021)
Groups stimulated by 1 ng/ml IL-1β and 1 ng/ml TNF-α still showed remarkable changes in anabolic gene (COL2), catabolic gene (MMP3), and inflammatory gene expression (IL-8) on day 7. These results suggested that the combination of 1 ng/ml IL-1β and 1 ng/ml TNF-α was sufficient to induce a certain grade of inflammatory and catabolic effect on human osteochondral explants after 7 days of culture

Summary

Introduction

Osteoarthritis (OA) is the most common degenerative joint disease, mainly invading knee and hip joints (Martel-Pelletier et al, 2016). OA mainly manifests progressive and recurrent joint pain, swelling, and restricted activity causing many years lived with disability (YLDs) (Safiri et al, 2020). The underlying pathophysiologic mechanism has not been fully elucidated due to the heterogeneity of the disease and multiple risk factors like trauma, genetics, gender, and aging (Loeser et al, 2016; He et al, 2020; Coryell et al, 2021). There are no effective disease-modifying OA drugs (DMOADs) approved yet, other than medicines for relieving symptoms (Cai et al, 2021; Oo et al, 2021). To elucidate the pathological mechanism and screen the effectiveness of new drugs, numerous in vitro and in vivo OA models have been developed (Teeple et al, 2013; McCoy, 2015; Johnson et al, 2016). In vitro cell culture models and cytokines, such as interleukin one beta (IL-1β) and tumor

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