Abstract
ObjectiveIn osteoarthritis, chondrocytes tend to acquire a hypertrophic phenotype, which contributes to the modification of the extracellular matrix, resulting in permanent cartilage changes. In mouse chondrocytes, pro-inflammatory macrophages and pro-inflammatory cytokines have been shown to stimulate hypertrophy via the activation of the nuclear factor kappa B (NF-κB) pathway. Whether or not this also occurs in human chondrocytes remains unclear. We therefore aimed to investigate whether hypertrophy-like responses in human cartilage are driven mainly by intrinsic inflammatory signaling or shaped by specific macrophage populations.DesignHuman articular chondrocytes were cultured with pro-inflammatory cytokines or medium conditioned by defined macrophage subsets. Furthermore, the effect of inhibition of NF-κB-dependent gene expression was evaluated using the NF-κB inhibitor SC-514. Hypertrophy was assessed by measuring the transcription level of alkaline phosphatase (ALPL), type X collagen (COL10A1), Indian hedgehog (IHH), and runt-related transcription factor 2 (RUNX2).ResultsThe expression of hypertrophic genes was not promoted in human chondrocytes by pro-inflammatory cytokines neither pro-inflammatory M(IFNγ + TNFα) macrophages. Inhibition of the NF-κB-dependent gene expression did not affect human articular chondrocyte hypertrophy. However, tissue repair M(IL4) macrophages induced hypertrophy by promoting the expression of COL10A1, RUNX2, and IHH.ConclusionIntrinsic inflammatory signaling activation is not involved in the hypertrophic shift observed in human articular chondrocytes cultured in vitro. However, tissue repair macrophages may contribute to the onset of this detrimental phenotype in human osteoarthritic cartilage, given the effect observed in our experimental models.
Highlights
Osteoarthritis (OA) is characterized by progressive loss of articular cartilage, formation of osteophytes, degeneration of the ligaments, and inflammation of the synovium
To study the effect of pro-inflammatory signaling activation on chondrocyte hypertrophy, we used a combination of inflammatory cytokines that are secreted by macrophages, IL1β, TNFα, and IFNγ and used 2 different models, human articular cartilage explants and human articular chondrocytes in alginate
NFκB inhibition did not modify COL10A1, RUNX2, or matrix metalloproteinase-13 (MMP13) expression, indicating that hypertrophy is not affected in osteoarthritic chondrocytes when the main inflammatory pathway is inhibited (Fig. 1D)
Summary
Osteoarthritis (OA) is characterized by progressive loss of articular cartilage, formation of osteophytes, degeneration of the ligaments, and inflammation of the synovium. Even though significant progress has been made in OA research in recent years, advances are still needed to understand the molecular mechanisms of OA in order to develop therapeutic strategies. Articular chondrocytes are responsible for maintaining the balance between catabolic and anabolic processes in the cartilage. In OA, this homeostatic state is lost and chondrocytes acquire an altered phenotype, promoting the degradation of the cartilage and vascularization.[1,2,3] These hypertrophic-like chondrocytes are characterized by the expression of alkaline phosphatase (ALPL), type X collagen (COL10A1), Indian hedgehog (IHH), matrix
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