Perspective (Main Entrance Side) Periostin Deficiency in an Animal Model of Rheumatoid Arthritis S. I Lee, H.Y. Kim, Y. H. Cheon, Y.S. Suh. Internal medicine, Gyeongsang National University Hospital, Jinju, Korea April 2, 2014 APLAR Meeting Rheumatism Center 캠퍼스 진입 축에 주출입구 및 로비 계획으로 높은 인지성 확보 Gyeongsang National University Hospital Disclosures • No relevant financial relationships with commercial interests Gyeongsang National University Hospital Rheumatism Center Introduction • • • • Periostin, also called osteoblast-specific factor 2, is a 90-kDa secreted cell adhesion protein with structural homology to insect cell adhesion molecule fasciclin I. It promotes integrin-dependent cell adhesion and motility and belongs to the superfamily of TGF-β-inducible proteins It is associated with activation of TGF-β and up-regulation of collagen as well as TGF-β-mediated activation of fibroblasts Thus, it has been shown to be an important regulator of bone and tooth formation and maintenance, and of cardiac development and healing. Clinical significances of periostin • • • • • High serum periostin levels are independently associated with increased fracture risk in postmenopausal women (J Clin Endocrinol Metab. 2014) The periostin level reflects disease severity and extrinsic phenotype of adult atopic dermatitis, in which Th2 immune responses are dominant (Br J Dermatol. 2014) Serum periostin was in negative correlation with left ventricular ejection fraction, in positive association with Killip class of AMI patients and higher serum periostin level may be predictive for worse six months disease prognosis (PLoS One. 2014) Urinary periostin is associated with adverse renal profiles and declining of GFR in chronic allograft nephropathy (Transplant Proc. 2014) High periostin is significantly correlated to poor prognosis in patients with esophageal squamous cell carcinoma, non-small cell lung cancer, etc. Conflicting results in allergic airway and skin inflammation. • • • • Periostin-deficient mice decrease eosinophilic inflammation in in allergic lung (Mucosal Immunol 2008) Periostin-deficient mice prevent chronic allergic skin inflammation in response to Th2 cytokines (J Clin Invest 2012) Periostin-deficient mice increase airway hyper-responsiveness and serum IgE levels following allergen challenge associated with a decrease in TGFβ1 and Foxp3 gene expression, suggesting a protective role for periostin through TGF- β -induced Treg differentiation (Clin Exp Allergy 2012) Periostin-deficient mice increase airway hyper-responsiveness and mucus production by goblet cells in an ovalbumin-induced model (J Immunol 2011) However, there are little study to investigate the role of periostin in RA.  Thus, this study was performed to assess the function of periostin in K/BxN serum transfer arthritic mice Synovial fluid periostin (ng/ml) 80 60 40 20 Serum periostin (ng/ml) A RA OA  B  100 80 0 Normal OA RA 60 40 20 0 OA RA P<0.05 Induction of K/BxN serum transfer arthritic mice in PO KO or WT mice WT or PO KO (male, 8-10 weeks old) K/BxN serum 50uL D0 50uL D1 D2 D3 D4 D5 D6 D7 D8 Evaluation Subjects: - Wild type (n=14), PO Knockout (n=15), three independent experiments D9 D10 Sacrifice Mean arthritis scores 9 WT KO 8 7 6  5 4 3 2 1 0 D0 D2 D4 Day after D6 1st D8 Hind paw thickness (mm) A D10 2.6 WT KO 2.5 2.4 2.3  2.2 2.1 2 1.9 D0 D2 D4 Days after immunization D6 1st D8 D10 immunization B WT KO Safranin-O TRAP WT 5 Mean histological scores H/E 4   KO  3 2 1 0 Synovial inflammation Bone erosion Cartilage damage Serum ELISA WT WT KO KO  10 20 15 10 5 0 2.5 2.0 6 4 2 WT WT KO K.O KO 4 3 2 1 0 WT Ankle PCR 5 8 TNF- (pg/ml) IL-1 (pg/ml) 25 6 IL-6 (pg/ml) 30 0 WT KO  WT   1.5  1.0 0.5 0.0 TNFa MMP3 MMP13 IL-6 IL-1b KO TRAP-positive cells 900 KO WT 750 KO  WT   600 450 300 150 0 10 30 RANKL (ng/ml) 50 10 30 RANKL (ng/ml) 50 Conclusion • Our study suggests that periostin contributes to the pathogenesis of inflammatory arthritis and might have a potential protective role in RA. • However, our results are different from a previous report indicating that periostin stimulates migration and invasion of RA-FLSs • In addition, K/BxN serum transfer model has a disadvantage that it cannot reflect the roles of adaptive immune cells such as T cells  Further study using adaptive CIA model will be needed to evaluate precise function of periostin in RA. Thank you for your attention K/BxN arthritic & serum transfer model + KRN TCR TG mice (M>F) (KRN TCR ↑) > 7 wks NOD mice (M<F) (MHCII H2-Ag7) 7-12 wks Day 0 & 2 150ul/injection Collection of serum K/BxN arthritic mice (Anti-GPI Abs) First signs: 4 wks Peak: 8 wks > 5-wk-old males or > 6-wk-old females K/BxN serum transfer arthritic mice First signs: after 2-3 ds Peak: after 8-10 ds Experiments with different doses of K/BxN Serum Jacobs ET et al. Arthritis & Rheum 2004