Senescent Tissue-Resident Mesenchymal Stromal Cells Are an Internal Source of Inflammation in Human Osteoarthritic Cartilage

Human osteoarthritic cartilage contains not only chondrocytes (OACs), but also mesenchymal stromal cells (OA-MSCs), whose abundance increases during osteoarthritis (OA). However, it is not clear how OA-MSC contributes to OA pathogenesis. Here, we show that aging OA-MSC plays an important role in cell senescence, fibrosis, and inflammation in cartilage. Protein array analysis indicates that OA-MSC expresses pro-inflammatory senescence associated secretory phenotype (SASP) including IL-1β, IL-6, IL-8, and CXCL1, 5, and 6, which play key roles in OA pathogenesis. OAC is a main recipient of the inflammatory signals by expressing receptors of cytokines. RNAseq analysis indicates that the transition from normal cartilage stromal cells (NCSCs) to OA-MSC during aging results in activation of SASP gene expression. This cell transition process can be recapitulated by a serial passage of primary OAC in cell culture comprising (1) OAC dedifferentiation into NCSC-like cells, and (2) its subsequent senescence into pro-inflammatory OA-MSC. While OAC dedifferentiation is mediated by transcriptional repression of chondrogenic gene expression, OA-MSC senescence is mediated by transcriptional activation of SASP gene expression. We postulate that, through replication-driven OAC dedifferentiation and mesenchymal stromal cell (MSC) senescence, OA-MSC becomes an internal source of sterile inflammation in human cartilage joint.