Characterizing heterogeneity in the response of synovial mesenchymal progenitor cells to synovial macrophages in normal individuals and patients with osteoarthritis

Akash Fichadiya, Karri L Bertram, Guomin Ren, Robin M Yates, Roman J Krawetz

Resident macrophages in OA synovial tissue contribute to synovitis through pro-inflammatory mediators driving cartilage loss. What remains unknown is how these macrophages interact with synovial mesenchymal progenitor cells (sMPCs) in the joint. sMPCs have the potential to undergo chondrogenesis, but for yet unknown reasons, this ability is decreased in OA patients. In this study, we sought to identify if alteration of macrophage activity regulates the chondrogenic capacity of sMPCs. An explant model was developed using human synovium obtained from normal individuals and OA patients. These explants were subjected to macrophage depletion and/or cytokine stimulation in order to regulate/deplete the residing macrophage population. Supernatant was collected following a 12-day treatment phase and subjected to inflammatory secretome analysis. sMPCs from the explants were subsequently placed under 21-day chondrogenic differentiation and levels of type II collagen (Col2a), Aggrecan (Acan), and Sox9 gene expression was quantified. Inflammatory secretome analysis from OA patients revealed the presence of pro-inflammatory analytes following pro- and anti-inflammatory cytokine stimulation and/or macrophage depletion. Additionally, chondrogenic differentiation of sMPCs was heterogeneously impacted across all OA patients following pro-/anti-inflammatory cytokine stimulation and/or macrophage depletion. Tissue resident synovial macrophages can regulate the chondrogenic differentiation of sMPCs after cytokine stimulation in a patient specific manner. The secretion profile of OA synovium was also responsive to cytokine stimulation and/or macrophage depletion as observed by the largely pro-inflammatory milieu upregulated following cytokine stimulation.