Investigation of Cytokine Changes in Osteoarthritic Knee Joint Tissues in Response to Hyperacute Serum Treatment

Dorottya Kardos, Bence Marschall, Melinda Simon, István Hornyák, Adél Hinsenkamp, Olga Kuten, Zsuzsanna Gyevnár, Gábor Erdélyi, Tamás Bárdos, Tamás Mirkó Paukovits, Krisztián Magos, György Béres, Kálmán Szenthe, Ferenc Bánáti, Susan Szathmary, Stefan Nehrer, Zsombor Lacza, Dorottya Kardos, Bence Marschall, Melinda Simon, István Hornyák, Adél Hinsenkamp, Olga Kuten, Zsuzsanna Gyevnár, Gábor Erdélyi, Tamás Bárdos, Tamás Mirkó Paukovits, Krisztián Magos, György Béres, Kálmán Szenthe, Ferenc Bánáti, Susan Szathmary, Stefan Nehrer, Zsombor Lacza

Abstract

One option to fight joint degradation and inflammation in osteoarthritis is the injection of activated blood products into the synovial space. It has been demonstrated that hyperacute serum is the most proliferative among plasma products, so we investigated how the cytokine milieu of osteoarthritic knee joint reacts to hyperacute serum treatment in vitro. Cartilage, subchondral bone, and synovial membrane explanted from osteoarthritic knees were stimulated by interleukin-1 beta (IL-1β) and the concentration of 39 biomarkers was measured in the co-culture supernatant after hyperacute serum treatment. The IL-1β stimulation triggered a strong inflammatory response and enhanced the concentrations of matrix metalloproteinase 3 and 13 (MMP-3 and MMP-13), while hyperacute serum treatment reduced inflammation by decreasing the concentrations of IL-1β, tumor necrosis factor alpha (TNF-α), interleukin-6 receptor alpha (IL-6Rα), and by increasing the level of interleukin-1 antagonist (IL-1RA) Cell viability increased by day 5 in the presence of hyperacute serum. The level of MMPs-1, 2, and 9 were higher on day 3, but did not increase further until day 5. The concentrations of collagen 1 alpha 1 (COL1A1) and osteonectin were increased and receptor activator of nuclear factor kappa-B ligand (RANKL) was reduced in response to hyperacute serum. We concluded that hyperacute serum treatment induces cell proliferation of osteoarthritic joint tissues and affects the cytokine milieu towards a less inflamed state.

Keywords: bone remodeling; hyperacute serum; inflammatory cytokines; knee osteoarthritis; matrix metalloproteases.

Conflict of interest statement

Z.L. owns stock in OrthoSera GmbH, a startup company developing the hyperacute serum technology towards clinical application.

Figures

Figure 1
Figure 1
Pathogenesis of osteoarthritis, including the progression of the osteoarthritis (OA) positive feedback loop, including synovial inflammation and tissue degradation. Inflammatory proteins produced mainly by chondrocytes, synovial fibroblasts, and macrophages induce the excess production of tissue-degrading enzymes, such as matrix metalloproteinases. Products of cartilage breakdown are phagocytosed by the synovial cells triggering the release of even more proinflammatory proteins.
Figure 2
Figure 2
Design of the experiment. Our in vitro knee tissue co-culture model was built from the three main tissue types (i.e., synovial membrane, subchondral bone, and hyaline cartilage), which play roles in the pathogenesis of OA. The structure of the model allows similar communication pathways as it happens in vitro. (A) After building the model, tissues were stimulated by IL-1β for 2 days or cultured without IL-1β as a negative control. Medium was exchanged in the IL-1β-stimulated cultures and tissues were treated with 10% hyperacute serum for 5 days. We used human serum albumin with a matched albumin content as a negative control for 5 days (B).
Figure 3
Figure 3
Cytokine pattern comparison. The measured 39 cytokines were present both in vivo and in vitro in a similar distribution. The highest concentrations were measured in the case of cluster of differentiation 163 (CD163), osteonectin, and matrix metalloproteinase-2 (MMP-2) both in vitro and in vivo (A). After transforming the dataset, we found a very strong correlation between the cytokine content of the in vitro and in vivo samples: nsynovial fluid = 19, nsupernatant = 12 (B).
Figure 4
Figure 4
Cell viability in bone, cartilage, and synovial membrane. Hyperacute serum treatment had a positive effect on the cell viability of cartilage, bone, and synovial membrane tissues during a 5 days long culture period, n = 12. The significance level was p < 0.05, where * means that the p-value was between 0.05 and 0.01, ** means that the p-value was between 0.01 and 0.001, and *** means that p-value was lower than 0.001.
Figure 5
Figure 5
Main osteoarthritic inflammatory cytokines detected in the tissue culture supernatant. IL-1β, IL-6Rα, TNF-α, IL-8, and IL-15 significantly increased in response to IL-1β stimulation. A significant decrease was observed in the concentration of IL-1β and IL-6Rα under the influence of hyperacute serum treatment on day 5. The pattern of TNF-α, IL-2, -12, -17, and -18 was the same; however, changes did not reach the significance level, n = 12. The significance level was p < 0.05, where * means that the p-value was between 0.05 and 0.01, ** means that p-value was between 0.01 and 0.001, and *** means that the p-value was lower than 0.001 (A). The correlations of cytokine changes are presented in heatmap tables. Between day 0 and day 5, the correlations were strong between IL-17, IL-12, and TNF- α, as well as between IL-8, IL-18, and TNF-α, while very strong correlations were found between IL-2 and IL-6Rα, IL-8, IL-12, IL-15, IL-17A, IL-18, TNF-α, n = 12 (B).
Figure 6
Figure 6
Inflammatory chemokines detected in the tissue culture supernatant. Chemokine CC ligand 1 (CCL-1), CCL-2, and chemokine C-X-C ligand 1 (CXCL-10) increased significantly after IL-1β stimulation, and the level of CCL-5 and CXCL-10 increased even further in response to hyperacute serum, n = 12. The significance level was p < 0.05, where * means that the p-value was between 0.05 and 0.01, ** means that the p-value was between 0.01 and 0.001, and *** means that the p-value was lower than 0.001 (A). The correlations of chemokine changes are presented in heatmap tables. Between day 0 and day 5, strong correlations were present between CCL-5 and CCL-1, factalkine and CCL-2, CCL-3, CCL-5, and CXCL-10, while strong reverse correlations were found between CXCL-10 and fractalkine, CCL-5 and CCL-3, and fractalkine and CCL-5, n = 12 (B).
Figure 7
Figure 7
Anti-inflammatory cytokines detected in the tissue culture supernatant. IL-1β triggered an anti-inflammatory response evidenced by elevated interleukin-1 antagonist (IL-1RA), interleukin-4 receptor alpha (IL-4Rα), and IL-13 levels. IL-1RA significantly increased to day 3 in response to hyperacute serum treatment, but decreased until day 5, n = 12 (A). The significance level was p < 0.05, where * means that the p-value was between 0.05 and 0.01, ** means that p-value was between 0.01 and 0.001, and *** means that the p-value was lower than 0.001. The correlations of cytokine changes are presented in heatmap tables. Very strong correlations were found among all three anti-inflammatory cytokines (B).
Figure 8
Figure 8
Biomarkers of tissue remodeling detected in tissue culture supernatant. IL-1β affected only MMP-3 and -13, while the concentrations of MMP-1, -2, and -9 increased significantly in response to hyperacute serum treatment (A). The significance level was p < 0.05, where * means that the p-value was between 0.05 and 0.01, ** means that the p-value was between 0.01 and 0.001, and *** means that the p-value was lower than 0.001, n = 12. The correlations of cytokine changes are presented in heatmap tables. A very strong correlation was found between MMP-2 and MMP-13, while reverse strong correlations were found between aggrecan and MMP-1 and MMP-13 (B). Osteonectin was also significantly elevated in response to hyperacute serum treatment. Similar changes were observed in collagen type I alpha I secretion, while receptor activator of nuclear factor kappa-B ligand (RANKL) continuously decreased in response to the hyperacute serum treatment (C). The significance level was p < 0.05, where * means that the p-value was between 0.05 and 0.01, ** means that p-value was between 0.01 and 0.001, and *** means that the p-value was lower than 0.001, n = 12. The correlation of cytokine changes between osteonectin and collagen 1 alpha 1 (COL1A1) was very strong, while reverse strong correlations were found between osteonectin, COL1A1, and RANKL, n = 12 (D).
Figure 8
Figure 8
Biomarkers of tissue remodeling detected in tissue culture supernatant. IL-1β affected only MMP-3 and -13, while the concentrations of MMP-1, -2, and -9 increased significantly in response to hyperacute serum treatment (A). The significance level was p < 0.05, where * means that the p-value was between 0.05 and 0.01, ** means that the p-value was between 0.01 and 0.001, and *** means that the p-value was lower than 0.001, n = 12. The correlations of cytokine changes are presented in heatmap tables. A very strong correlation was found between MMP-2 and MMP-13, while reverse strong correlations were found between aggrecan and MMP-1 and MMP-13 (B). Osteonectin was also significantly elevated in response to hyperacute serum treatment. Similar changes were observed in collagen type I alpha I secretion, while receptor activator of nuclear factor kappa-B ligand (RANKL) continuously decreased in response to the hyperacute serum treatment (C). The significance level was p < 0.05, where * means that the p-value was between 0.05 and 0.01, ** means that p-value was between 0.01 and 0.001, and *** means that the p-value was lower than 0.001, n = 12. The correlation of cytokine changes between osteonectin and collagen 1 alpha 1 (COL1A1) was very strong, while reverse strong correlations were found between osteonectin, COL1A1, and RANKL, n = 12 (D).
Figure 9
Figure 9
The effect of IL-1β stimulation and hyperacute serum treatment on osteoarthritic knee tissues. (A) IL-1β stimulation enhanced the level of inflammatory cytokines such as TNF-α, IL-6Rα, IL-8, IL-15, CCL-1, CCL-2, and CXCL-10 in an osteoarthritic tissue co-culture model, while the level of MMP-3 and MMP-13 also increased. (B) Hyperacute serum treatment reduced IL-1β, TNF-α, IL-6Rα, IL-12, and RANKL, while it increased the number of cells in all the three tissue types, MMP-1, -2, and -9, osteonectin, and COL1A1. The concentration of IL-1RA increased after adding hyperacute serum, but it also decreased at the end of the culture period.

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