Abstract
Mechanical injury to the articular cartilage is a key risk factor in joint damage and predisposition to osteoarthritis. Integrative multi-omics approaches provide a valuable tool to understand tissue behavior in response to mechanical injury insult and help to identify key pathways linking injury to tissue damage. Global or untargeted metabolomics provides a comprehensive characterization of the metabolite content of biological samples. In this study, we aimed to identify the metabolic signature of cartilage tissue post injury. We employed an integrative analysis of transcriptomics and global metabolomics of murine epiphyseal hip cartilage before and after injury. Transcriptomics analysis showed a significant enrichment of gene sets involved in regulation of metabolic processes including carbon metabolism, biosynthesis of amino acids, and steroid biosynthesis. Integrative analysis of enriched genes with putatively identified metabolite features post injury showed a significant enrichment for carbohydrate metabolism (glycolysis, galactose, and glycosylate metabolism and pentose phosphate pathway) and amino acid metabolism (arginine biosynthesis and tyrosine, glycine, serine, threonine, and arginine and proline metabolism). We then performed a cross analysis of global metabolomics profiles of murine and porcine ex vivo cartilage injury models. The top commonly modulated metabolic pathways post injury included arginine and proline metabolism, arginine biosynthesis, glycolysis/gluconeogenesis, and vitamin B6 metabolic pathways. These results highlight the significant modulation of metabolic responses following mechanical injury to articular cartilage. Further investigation of these pathways would provide new insights into the role of the early metabolic state of articular cartilage post injury in promoting tissue damage and its link to disease progression of osteoarthritis.
Highlights
Cartilage is a unique connective tissue with only one cell type – the chondrocytes – embedded in a rough matrix rich in collagen II fibers and proteoglycan contents
Mechanical injury is a cause of articular cartilage damage and is the main risk factor in the development of osteoarthritis; a degenerative disease affecting the synovial joints which is characterised by deterioration of the articular cartilage
We extended the analysis further to include an ex vivo porcine cartilage injury model to compare and validate the metabolomics data obtained from the murine injury model
Summary
Cartilage is a unique connective tissue with only one cell type – the chondrocytes – embedded in a rough matrix rich in collagen II fibers and proteoglycan contents. Cartilage collagen fibers are oriented and highly cross-linked, which aids the efficient joint articulation and provides the matrix with high tensile properties (Palmoski et al, 1979; Vanwanseele et al, 2002). Articular cartilage chondrocytes are highly mechanosensitive cells they rarely divide in healthy cartilage tissue and may appear quiescent (Soder et al, 2002; Tesche and Miosge, 2004; Kvist et al, 2008). Mechanical injury is a cause of articular cartilage damage and is the main risk factor in the development of osteoarthritis; a degenerative disease affecting the synovial joints which is characterised by deterioration of the articular cartilage (reviewed in Lohmander et al, 2007; Thomas et al, 2017). There is still no disease-modifying medical therapy for OA, which creates a major socioeconomic burden in the population (Hunter and Bierma-Zeinstra, 2019)
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