Human Osteochondral Explants: Reliable Biomimetic Models to Investigate Disease Mechanisms and Develop Personalized Treatments for Osteoarthritis
Open Access
- 20 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Rheumatology and Therapy
- Vol. 8 (1), 499-515
- https://doi.org/10.1007/s40744-021-00287-y
Abstract
Introduction Likely due to ignored heterogeneity in disease pathophysiology, osteoarthritis (OA) has become the most common disabling joint disease, without effective disease-modifying treatment causing a large social and economic burden. In this study we set out to explore responses of aged human osteochondral explants upon different OA-related perturbing triggers (inflammation, hypertrophy and mechanical stress) for future tailored biomimetic human models. Methods Human osteochondral explants were treated with IL-1β (10 ng/ml) or triiodothyronine (T3; 10 nM) or received 65% strains of mechanical stress (65% MS). Changes in chondrocyte signalling were determined by expression levels of nine genes involved in catabolism, anabolism and hypertrophy. Breakdown of cartilage was measured by sulphated glycosaminoglycans (sGAGs) release, scoring histological changes (Mankin score) and mechanical properties of cartilage. Results All three perturbations (IL-1β, T3 and 65% MS) resulted in upregulation of the catabolic genes MMP13 and EPAS1. IL-1β abolished COL2A1 and ACAN gene expression and increased cartilage degeneration, reflected by increased Mankin scores and sGAGs released. Treatment with T3 resulted in a high and significant upregulation of the hypertrophic markers COL1A1, COL10A1 and ALPL. However, 65% MS increased sGAG release and detrimentally altered mechanical properties of cartilage. Conclusion We present consistent and specific output on three different triggers of OA. Perturbation with the pro-inflammatory IL-1β mainly induced catabolic chondrocyte signalling and cartilage breakdown, while T3 initiated expression of hypertrophic and mineralization markers. Mechanical stress at a strain of 65% induced catabolic chondrocyte signalling and changed cartilage matrix integrity. The major strength of our ex vivo models was that they considered aged, preserved, human cartilage of a heterogeneous OA patient population. As a result, the explants may reflect a reliable biomimetic model prone to OA onset allowing for development of different treatment modalities.Keywords
Funding Information
- ReumaNederland (DAF-15-4-401)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (91816631/528)
This publication has 49 references indexed in Scilit:
- Identification of stable normalization genes for quantitative real-time PCR in porcine articular cartilageJournal of Animal Science and Biotechnology, 2012
- Changes in chondrocyte gene expression following in vitro impaction of porcine articular cartilage in an impact injury modelJournal of Orthopaedic Research, 2012
- Biomechanical factors in osteoarthritisBest Practice & Research Clinical Rheumatology, 2011
- Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disordersArthritis Research & Therapy, 2010
- Regulation of autophagy in human and murine cartilage: Hypoxia‐inducible factor 2 suppresses chondrocyte autophagyArthritis & Rheumatism, 2009
- Functional characterization of hypertrophy in chondrogenesis of human mesenchymal stem cellsArthritis & Rheumatism, 2008
- Analysis of the Relationship between Peak Stress and Proteoglycan Loss following Injurious Compression of Human Post-mortem Knee and Ankle CartilageBiomechanics and Modeling in Mechanobiology, 2006
- Proteoglycan degradation after injurious compression of bovine and human articular cartilage in vitro: Interaction with exogenous cytokinesArthritis & Rheumatism, 2003
- IL-1β Induces the Degradation of Equine Articular Cartilage by a Mechanism That Is Not Mediated by Nitric OxideBiochemical and Biophysical Research Communications, 1997
- The increased synthesis of inducible nitric oxide inhibits IL-1ra synthesis by human articular chondrocytes: possible role in osteoarthritic cartilage degradationOsteoarthritis and Cartilage, 1996