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Integrin α1β1 protects against signs of post-traumatic osteoarthritis in the female murine knee partially via regulation of epidermal growth factor receptor.

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Presentation on theme: "Integrin α1β1 protects against signs of post-traumatic osteoarthritis in the female murine knee partially via regulation of epidermal growth factor receptor."— Presentation transcript:

1 Integrin α1β1 protects against signs of post-traumatic osteoarthritis in the female murine knee partially via regulation of epidermal growth factor receptor signalling  S.Y. Shin, A. Pozzi, S.K. Boyd, A.L. Clark  Osteoarthritis and Cartilage  Volume 24, Issue 10, Pages (October 2016) DOI: /j.joca Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

2 Fig. 1 Representative microCT images of left knees from male and female integrin α1-null and WT mice at 2 and 12 weeks PS that underwent either DMM or sham surgery. Mice in the 12 weeks PS group were administered erlotinib (12E) or vehicle12 daily. A, B, D, F, G, I, K, L, N, P, Q, S Cortical bone at the femoral condyles and tibial plateaus is rendered transparent to show the analysed trabecular regions. Trabecular bone is shaded blue, subchondral bone pink, and ossified menisci green. C, E, H, J, M, O, R, T Frontal cross-section taken in the middle of femoral condyle/tibial plateau contact region shaded with a thickness map with thicker regions shaded with hot colours located further right of the spectrum scale. Note the medial displacement of medial meniscus in DMM joints (A, B, D, K, L, N), larger medial meniscus and cMCL at 12 weeks PS in DMM knees (B, L) with this effect lessened with erlotinib treatment in female (D) but worsened in male mice (N), and thicker subchondral bone in DMM (C, E, M, O) compared to sham (H, J, R, T) joints. Osteoarthritis and Cartilage  , DOI: ( /j.joca ) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

3 Fig. 2 Subchondral bone remodelling in knees of integrin α1-null and WT mice at 2, 4, 8, and 12 weeks post DMM or sham surgery as a function of (A, B) sex and bone or (C, D) sex and compartment. The contralateral knees (contra) of DMM mice served as a naïve control. Mice in the 12 week group were administered erlotinib (12E) or vehicle12 daily. Data points represent mean n ≥ 9 with 95% confidence interval. a Different from 2, 4, and 12E weeks PS equivalent (P < 0.01). b Different from all time points PS equivalent (P < 0.05). c Different from 2 and 12E weeks PS equivalent (P < 0.05). d Different from 2 and 4 weeks PS equivalent (P < 0.01). e Different from 12 weeks PS (P < 0.05). f Different from 2, 4, and 8 weeks PS (P < 0.05). * Different from time-matched counterpart(s) (P < 0.05). Note increased thickness with DMM in both femur (A) and tibia (B) but only in the medial compartment (C), with this diminished in erlotinib treated females but not males (A–C). Osteoarthritis and Cartilage  , DOI: ( /j.joca ) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

4 Fig. 3 Meniscal bone remodelling in knees of integrin α1-null and WT mice at 2, 4, 8, and 12 weeks post DMM or sham surgery as a function of (A, B) site and sex or (C) compartment. The contralateral knees (contra) of DMM mice served as a naïve control. Mice in the 12 week group were administered erlotinib (12E) or vehicle12 daily. Data points represent mean (A, B n ≥ 9, C n ≥ 19), with 95% confidence interval. a Different from all time points equivalent (P < 0.05). b Different from 2 and 4 weeks PS equivalent (P < 0.01). * Different from time-matched counterpart(s) (P < 0.05). Note (A, B) the increase in meniscal bone volume with DMM in both anterior and posterior sites but (C) only in the medial compartment and (A, B) the reduction of this with erlotinib treatment in females but not males. Osteoarthritis and Cartilage  , DOI: ( /j.joca ) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

5 Fig. 4 Trabecular bone remodelling in knees of integrin α1-null and WT mice at 2, 4, 8, and 12 weeks PS as a function of sex, compartment and bone. Mice in the 12 week group were administered erlotinib (12E) or vehicle12 daily. Data points represent mean (n ≥ 19) with 95% confidence interval. a Different from 2 weeks PS equivalent (P < 0.05). b Different from all other points (P < 0.01). c Different from 8 weeks PS equivalent (P < 0.05). d Different from all other points except 8 weeks PS equivalent (P < 0.01). e Different from 2 and 12E weeks PS equivalent (P < 0.05). f Different from 12 and 12E PS equivalent. * Different from time-matched counterpart(s) (P < 0.05). Note the significant effect of erlotinib in females but not males on all parameters and a delayed response in males compared to females in some femoral parameters. Osteoarthritis and Cartilage  , DOI: ( /j.joca ) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

6 Fig. 5 Representative frontal histology images of left knees from male and female integrin α1-null and WT mice at 2, 4, 8 or 12 weeks PS. Knees underwent either DMM or sham surgery and mice in the 12 weeks PS group were administered erlotinib (12E) or vehicle12 daily. Sections were stained with haematoxylin, fast green, and safranin-O. Scale bar represents 500 μm. Note the thinner and more fibrillated cartilage in the medial compartment (arrows) beginning at 4 weeks PS in male integrin α1-null and WT DMM knees with this effect delayed until 8 weeks PS in female integrin α1-null mice and 12 weeks PS in female WT mice. Erlotinib treatment alleviated cartilage damage in both male and female integrin α1-null but not WT mice. Osteoarthritis and Cartilage  , DOI: ( /j.joca ) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

7 Fig. 6 Summed histology OA score (out of 48) of knees of WT and integrin α1-null mice at 2, 4, 8, and 12 weeks post DMM or sham surgery as a function of sex, genotype, and region. Mice in the 12 week group were administered erlotinib (12E) or vehicle12 daily. MFC Medial Femoral Condyle. MFC Medial Femoral Condyle. MTP Medial tibial plateau. LFC Lateral femoral condyle. LTP Lateral tibial plateau. Data points represent mean (n ≥ 4). 95% confidence intervals are provided in Supplementary Table 2. a Different from 2 and 4 weeks PS equivalent (P < 0.05). b Different from 2, 12, and 12E weeks PS equivalent (P < 0.01). c Different from 2, 4, and 12E weeks PS equivalent (P < 0.05). d Different from all points of equivalent region except 12E (P < 0.01). e Different from all points of equivalent region (P < 0.05). * Different from time-matched medial compartment (P < 0.05). Note the significant effect of DMM in the medial compartment, the erlotinib effect in integrin αl-null but not WT mice, and a delayed response in females compared to males and in WT females compared to integrin α1-null females. Osteoarthritis and Cartilage  , DOI: ( /j.joca ) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

8 Fig. 7 Percent of chondrocytes from male integrin α1-null and WT mice immuno-stained positively for phosphorylated (A) Smad1/5/8 (pSmad1/5/8) or (B) Smad2/3 (pSmad2/3) at 2, 4, 8, and 12 weeks PS. Data points represent mean (n = 3) with 95% confidence interval. a Different from all points of equivalent genotype (P < 0.05). b Different from 2 weeks PS equivalent (P < 0.05). c Different from time-matched counterpart (P < 0.05). d Different from all points (P < 0.05). Note the reduced staining of pSmad1/5/8 at 12 compared to 2 weeks PS in both genotypes and the higher staining of pSmad2/3 at 8 compared to 2 weeks PS, only in WT cartilage. Osteoarthritis and Cartilage  , DOI: ( /j.joca ) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions


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