The impact of early intra-articular administration of interleukin-1 receptor antagonist on lubricin metabolism and cartilage degeneration in an anterior.

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The impact of early intra-articular administration of interleukin-1 receptor antagonist on lubricin metabolism and cartilage degeneration in an anterior cruciate ligament transection model K.A. Elsaid, L. Zhang, Z. Shaman, C. Patel, T.A. Schmidt, G.D. Jay Osteoarthritis and Cartilage Volume 23, Issue 1, Pages 114-121 (January 2015) DOI: 10.1016/j.joca.2014.09.006 Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Quantitative lubricin gene expression in articular cartilage, lubricin cartilage immunostaining and SF lavage lubricin concentrations following ACLT and intra-articular treatment with PBS or IL-1 ra at 3 and 5 weeks following ACLT. (A) Relative lubricin cartilage expression in control and ACLT joints compared to contra-alteral joints and normalized to glyceraldehyde-3-phosphare dehydrogenase (GAPDH) and received intra-articular injections of PBS or IL-1 ra. Individual data points are presented and the median value is highlighted with an “X”. *Indicates that lubricin cartilage expression in control joints was significantly higher compared to 3-week and 5-week ACLT treated with PBS or IL-1 ra (P < 0.001). **Indicates that lubricin cartilage expression in 3 week ACLT joints treated with IL-1 ra was significantly higher compared with 3 and 5 week ACLT joints treated with PBS (P = 0.002), (P = 0.001). ***Indicates that lubricin cartilage expression in 5 week ACLT joints treated with IL-1 ra was significantly higher compared with 5 week ACLT joints treated with PBS (P = 0.001). (B) mAb 9G3 immunostaining for lubricin from (A) control, (B) 3-week ACLT joints treated with PBS, (C) 3-week ACLT joints treated with IL-1 ra, (D) 5-week ACLT joints treated with PBS, and (E) 5-week ACLT joints treated with IL-1 ra. Arrows point to intense lubricin staining on the surface of articular cartilage and in superficial zone chondrocytes compared to 3 and 5 week ACLT joints treated with PBS. Scale = 50 μm. (C) Urea-adjusted lubricin SF lavage concentrations in control, 5-week ACLT animals following treatment with PBS or IL-1 ra (n = 6 in each group). Individual data points are presented and the median value is highlighted with an “X”. *Indicates that lubricin SF lavage concentrations in control animals were significantly higher compared with 5-week ACLT joints treated with PBS (P < 0.001). **Indicates that lubricin SF lavage concentrations in 5-week ACLT animals treated with IL-1 ra was significantly higher compared with 5-week ACLT animals treated with PBS (P = 0.005). Osteoarthritis and Cartilage 2015 23, 114-121DOI: (10.1016/j.joca.2014.09.006) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Impact of IL-1 ra treatment on cartilage and synovial histopathologies and uCTXII release following ACLT in the rat. (A) Representative Safranin-O (top panel) stained cartilage and H&E (bottom panel) stained synovium from control animals and animals that underwent ACLT followed by intra-articular injection of PBS on days 1, 3, 5 and 7 (PBS) or IL-1 ra (IL-1 ra). The arrow points to synovial thickening and infiltration of inflammatory cells in the PBS-treated group. Scale = 50 μm. (B) Modified OARSI scores of control (n = 5), PBS-treated ACLT animals (n = 9) and IL-1 ra-treated ACLT animals (n = 9). Individual data points are presented and the median value is highlighted with an “X”. *Indicates that OARSI scores of the PBS group were significantly higher than OARSI scores of control or the IL-1 ra groups (P < 0.001). (C) Synovial histopathology scores of control (n = 5), PBS-treated ACLT animals (n = 9) and IL-1 ra-treated ACLT animals (n = 9). Individual data points are presented and the median value is highlighted with an “X”. *Indicates that synovial histopathology scores of PBS-treated ACLT animals were significantly higher than control and IL-1 ra-treated ACLT animals (P < 0.001). **Indicates that synovial histopathology scores of IL-1 ra-treated ACLT animals were significantly higher than control animals (P < 0.001). (D) uCTXII levels, adjusted to urinary creatinine in urines collected over a 24 h period in control animals (n = 5) or at 5 weeks post-ACLT treatment with PBS (n = 10) or IL-1 ra (n = 13). Individual data points are presented and the median value is highlighted with an “X”. *Indicates that uCTXII levels in PBS-treated ACLT animals were significantly higher than uCTXII levels in control or IL-1 ra treated ACLT animals (P < 0.001). Osteoarthritis and Cartilage 2015 23, 114-121DOI: (10.1016/j.joca.2014.09.006) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 Impact of treatment with rhPRG4 and IL-1 ra alone and in combination on chondrocyte apoptosis, lubricin and MMP-13 immunostaining following ACLT and a single intra-articular treatment with IL-1 ra (75 mg/ml; 40 μl), rhPRG4 (200 μg/ml; 40 μl) or IL-1 ra + rhPRG4 (75 mg/ml–200 μg/ml; 40 μl). (A) Representative cleaved caspase-3 (top panel), lubricin (middle panel) and MMP-13 (bottom panel) immunostained articular cartilage from controls and animals that underwent ACLT followed by intra-articular treatment with PBS (PBS), IL-1 ra (IL-1 ra), recombinant lubricin (rhPRG4) and a combination of IL-1 ra and rhPRG4 (IL-1 ra + LUB). Scale = 50 μm. (B) Semi-quantitative analysis of percentage of cleaved caspase-3 positive chondrocytes in controls (n = 5) and ACLT animals treated with PBS, IL-1 ra, rhPRG4 or IL-1 ra + rhPRG4 (n = 6 in each group). Individual data points are presented and the median value is highlighted with an “X”. *Indicates that percentage caspase-3 positive cells in the PBS-treated animals was significantly higher than percentage caspase-3 positive cells in controls (P < 0.001), IL-1 ra (P = 0.003), rhPRG4 (P = 0.001) and IL-1 ra + rhPRG4 (P < 0.001). **Indicates that percentage caspase-3 positive cells in the IL-1 ra-treated animals was significantly higher than percentage caspase-3 positive cells in controls (P < 0.001) and IL-1 ra + rhPRG4 (P = 0.039). Osteoarthritis and Cartilage 2015 23, 114-121DOI: (10.1016/j.joca.2014.09.006) Copyright © 2014 Osteoarthritis Research Society International Terms and Conditions