Expression of Osteoarthritis Marker YKL-39 is Stimulated by Transforming Growth Factor Beta (TGF-beta) and IL-4 in Differentiating Macrophages

YKL-39 is a Glyco_18 domain containing chitinase-like protein which is currently recognized as a biomarker for the activation of chondrocytes and the progress of the osteoarthritis in human. YKL-39 was identified as an abundantly secreted protein in primary culture of human articular chondrocytes. Two biological activities of YKL-39 might contribute to the disease progression. One is the induction of autoimmune response and second is the participation in tissue remodeling. Other mammalian chitinase-like proteins including chitotriosidase, SI-CLP, YKL-40 and YM1 are expressed by macrophages in various pathological conditions. In contrast, YKL-39 was never reported to be produced by macrophages. We used in vitro model of human monocyte-derived macrophage differentiation to analyse regulation of YKL-39 expression. Expression of YKL-39 was examined by real-time RT-PCR. CD14+ MACS sorted human monocytes differentiated for 6 days under different stimulations including IFNγ, IL-4, dexamethasone and TGF-β. We found that both IL-4 and TGF-β have weak stimulatory effect on YKL-39 expression in all donors tested (3.2 ± 1.7 fold, p = 0.006 and 6.3 ± 3.1 fold, p = 0.014 respectively). However the combination of IL-4 and TGF-β had strong stimulatory effect on the expression of YKL-39 in all analysed individual macrophage cultures (34 ± 36 fold, p = 0.05). IFN-γ did not show statistically significant effect of YKL-39 mRNA expression. Presence of dexamethasone almost completely abolished the stimulatory effects of IL-4 and TGF-β. In summary, we show here for the first time, that human cells of monocyte origin are able to produce YKL-39. Maturation of monocyte derived macrophages in the presence of Th2 cytokine IL-4 and TGF-β leads to the strong activation of YKL-39 expression. Thus elevated levels of YKL-39 observed during chronic inflammations can not be attributed solely to the activity of chondrocytes. In perspective, YKL-39 might serve as a useful biomarker to detect macrophage-specific response in pathologies like tumour, atherosclerosis and Alzheimer disease.