Meta-analysis Integrated With Multi-omics Data Analysis to Elucidate Pathogenic Mechanisms of Age-Related Knee Osteoarthritis in Mice

Abstract

Increased mechanistic insight into the pathogenesis of knee osteoarthritis (KOA) is needed to develop efficacious disease-modifying treatments. Though age-related pathogenic mechanisms are most relevant to the majority of clinically-presenting KOA, the bulk of our mechanistic understanding of KOA has been derived using surgically induced post-traumatic OA (PTOA) models. Here, we took an integrated approach of meta-analysis and multi-omics data analysis to elucidate pathogenic mechanisms of age-related KOA in mice. Protein-level data were integrated with transcriptomic profiling to reveal inflammation, autophagy, and cellular senescence as primary hallmarks of age-related KOA. Importantly, the molecular profiles of cartilage aging were unique from those observed following PTOA, with less than 3% overlap between the two models. At the nexus of the three aging hallmarks, Advanced Glycation End-Product (AGE)/Receptor for AGE emerged as the most statistically robust pathway associated with age-related KOA. This pathway was further supported by analysis of mass spectrometry data. Notably, the change in AGE-RAGE signaling over time was exclusively observed in male mice, suggesting sexual dimorphism in the pathogenesis of age-induced KOA in murine models. Collectively, these findings implicate dysregulation of AGE-RAGE signaling as a sex-dependent driver of age-related KOA.

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity

“…1F ) 18 . A recent systematic review identified elevated inflammation, increased senescence, and impaired autophagy as common denominators associated with aging-induced KOA in mice 19 , all of which are downstream of α-Klotho 20 – 24 . When we accessed archived microarray data (GSE80285) 25 , we found that inhibition of α-Klotho protein significantly activated PI3K/Akt signaling in human primary chondrocytes in vitro (Fig.…”

Osteoarthritis gene therapy in 2022

“…Of the 24 preclinical studies listed in Table 1, 20 were performed in animal models that required surgical destabilization of the joint. While these models are likely to be relevant to posttraumatic OA, their relevance to idiopathic OA, the majority manifestation, is unclear [21]. Likewise, two of the listed studies used MIA, an inhibitor of glycolysis, to induce OA.…”

Network-based cytokine inference implicates Oncostatin M as a driver for inflammation phenotype of knee osteoarthritis

“…One of the most debilitating age-related diseases is osteoarthritis (OA) of the knee joint (KOA), which is characterized by an age-and/or mechanical stress-dependent progressive loss of cartilage integrity [3][4][5] . Age-associated cellular changes in articular cartilage include cell depletion due to various forms of cell death together with dysfunctional intrinsic cellular repair responses to mechanical loading 6 .…”