IN OSTEOARTHRITIS Research Articles

Adipokines leptin, adiponectin and resistin and their associations to MMPS, IL-6, COMP and radiographic severity of OA

s / Osteoarthritis and Cartilage 24 (2016) S63eS534 S78 118 ADIPOKINES LEPTIN, ADIPONECTIN AND RESISTIN AND THEIR ASSOCIATIONS TO MMPS, IL-6, COMP AND RADIOGRAPHIC SEVERITY OF OA A. Koskinen-Kolasa y, K. Vuolteenaho y, T. Moilanen z, E. Moilanen y. y The Immunopharmacology Res. Group, Univ. of Tampere Sch. of Med. and Tampere Univ. Hosp., Tampere, Finland; zCoxa Hosp. for Joint Replacement, Tampere, Finland Purpose: Obesity and metabolic syndrome (MetS) are associated with an increased risk of osteoarthritis (OA). Obesity has been claimed to contribute to the development of OA by increasing the load on weightbearing joints. However, this appears to be an over-simplification, since obesity is also linked to OA in the hand and finger joints. Adipocytes, the cells in the adipose tissue, secrete adipokines, which were first found to regulate energy metabolism and appetite. Today we know that adipokines are also produced by many other tissues and cells including joint tissues and that they are involved in the inflammatory responses. We report here the levels of leptin, adiponectin and resistin measured in plasma, synovial fluid and cartilage samples obtained from 100 OA patients as well as their associations to MMPs, IL-6, COMP and radiographic severity of OA. Methods: Cartilage samples, synovial fluid and blood samples, as well as clinical data, were collected from 100 OA patients [BMI 29.7 (8.3) kg/m2, Adipokine levels in plasma, synovial fluid and cartilage culture supernatant and correlations to BMI All (n1⁄4 100) Females (n1⁄4 62) Males (n1⁄4 38) p (F vs M) Median IQR Median IQR Median IQR P-leptin (ng/ml) Correlation to BMI 19.8 r1⁄4 0.67 22.4 p 30 kg/m2; non-obese, BMI < 30 kg/m2), and it was found to correlate with the MMPs only in obese patients (MMP-1: r1⁄4 0.49, p1⁄4 0.001, MMP-3: r1⁄4 0.48, p1⁄4 0.001). Of note, no correlation between BMI and MMPs was found. In cartilage culture media adiponectin correlated positively with the levels of MMP-1, MMP-3, MMP-13 and IL-6 (Table 2). Resistin levels in cartilage culture media correlated with MMP-1 and MMP-13 (Table 2). Associations with radiographic findings and biomarkers of OA In males plasma and cartilage culture media adiponectin was found to be the highest in the patients with the most severe radiographic findings. Plasma adiponectin correlated positively also with circulating biomarkers COMP (r1⁄4 0.55, p1⁄4 0.001) and MMP-3 (r1⁄4 0.34, p1⁄4 0.046) in males. There were no significant differences in leptin levels between radiographic subgroups whereas SF-resistin in females was higher in the group of radiographically most severe OA. Conclusions: These results support the idea that adipokines link obesity to OA, and hold promise as biomarkers and targets for diseasemodifying drugs in OA. 119 YKL-40 IS ASSOCIATED WITH INFLAMMATION AND MMPS IN OSTEOARTHRITIS T. V€ a€ an€ anen y, M. H€ am€al€ainen y, A. Koskinen y, E.-L. Paukkeri y, T. Moilanen yz, E. Moilanen y, K. Vuolteenaho y. y The Immunopharmacology Res. Group, Univ. of Tampere Sch. of Med. and Tampere Univ. Hosp., Tampere, Finland; zCoxa Hosp. for Joint Replacement, Tampere, Finland Purpose: YKL-40 is associated with inflammation and tissue injury in diseases such as asthma and rheumatoid arthritis. It has been shown to be produced by macrophages and some tissue cells as well as by cancer cells. Increased circulating YKL-40 levels have been reported in patients with osteoarthritis (OA). However, the role of YKL-40 in OA joints remains largely unknown. In the present study, we investigated the levels of YKL-40 in simultaneously collected plasma, synovial fluid (SF) and cartilage samples from OA patients undergoing knee replacement

Effects of fibroblast growth factor-2 and its receptor antagonists in osteoarthritis

s / Osteoarthritis and Cartilage 23 (2015) A82eA416 A269 Conclusions: Alkaline phosphatase, BMP-2, and type X collagen production are all characteristic of hypertrophic chondrocytes and may contribute to excess mineralization in OA joints. Taken together, our data suggest that high glucose conditions favor a change towards the hypertrophic phenotype. Ample evidence supports a similar change in human that is characteristic of OA chondrocytes. Our findings are in agreement with the recent clinical studies demonstrating accelerated OA progression in patients with diabetes. The limitations of this study are 1) the hyperglycemic mice were slightly heavier than controls which may add mechanical effects (adipose levels were not measured), and 2) higher noise-to-signal background was present with the type X collagen antibody. These are balanced by the strengths of this study which include 1) animals were verified hyperglycemic prior to DMM, and 2) phenotypic change was tested in two model systems (in vivo rodent and in vitro large mammal). In summary, this study suggests the hypothesis that accelerated hypertrophy of articular chondrocytes is a result of hyperglycemia and may contribute to the progression of OA as previously seen in patients with diabetes. 418 EFFECTS OF FIBROBLAST GROWTH FACTOR-2 AND ITS RECEPTOR ANTAGONISTS IN OSTEOARTHRITIS E. Nummenmaa yz, M. Hamalainen yz, T. Moilanen yx, K. Vuolteenaho yz, E. Moilanen yz. y The Immunopharmacology Res. Group, Univ. of Tampere Sch. of Med., Tampere, Finland; z Tampere Univ. Hosp., Tampere, Finland; xCoxa Hosp. for Joint Replacement, Tampere,

High density mineralised protrusions from the tidemark into hyaline cartilage in human joints

High density mineralised protrusions from the tidemark into hyaline cartilage in human joints

An aggrecan 32-mer fragment generated in osteoarthritis directly excites nociceptive neurons

cartilage (Figure 2). A customized cartilage fixation device was used to measure integration strength (Figure 3). The test proceeded through the full depth of the tissue, and the maximum force recorded was divided by the area of integration to determine the integration strength. Good adhesion with surrounding cartilage was confirmed by push-out tests, which gave interfacial strength values of 158 þ/82 kPa for SDF-1treated defects (Figure 3) All 4 material property measurements (maximum and equilibrium stress, Young's modulus, and maximum force) were similar in neocartilage than in native cartilage (Table 1). Conclusions: We have developed a cartilage repair strategy that exploits the regenerative potential of endogenous chondrogenic progenitor cells. The matrix formed by these cells is similar in composition to native cartilage and strongly adheres to surrounding tissues. In addition, neocartilage is functional, and has mechanical properties comparable with native cartilage. Future studies are needed to for optimization when translated to in vivo system. 29 AN AGGRECAN 32-MER FRAGMENT GENERATED IN OSTEOARTHRITIS DIRECTLY EXCITES NOCICEPTIVE NEURONS R.E. Miller y, R.J. Miller z, A. Belmadani z, S.B. Golub x, A.J. Fosang x, A.-M. Malfait y. yRush Univ. Med. Ctr., Chicago, IL, United States; zNorthwestern Univ., Chicago, IL, United States; xUniv. of Melbourne, Parkville, Australia

A role for CC-chemokine receptor 7 (CCR7) in a murine model of osteoarthritis: Impact on joint structure and function

A role for CC-chemokine receptor 7 (CCR7) in a murine model of osteoarthritis: Impact on joint structure and function

Granulocyte population in synovial fluid varies in patients after anterior cruciate ligament reconstruction and positivily correlates with the protein levels of a proinflammatory cytokine, il-1 beta

Granulocyte population in synovial fluid varies in patients after anterior cruciate ligament reconstruction and positivily correlates with the protein levels of a proinflammatory cytokine, il-1 beta

Galectin fingerprinting in oa cartilage

Galectin fingerprinting in oa cartilage

Periodontitis disease as a model of inflammation and bone remodelling to study osteoarthritis drug effects. Results from a pilot study in OA patients treated with chondroitin sulfate

Periodontitis disease as a model of inflammation and bone remodelling to study osteoarthritis drug effects. Results from a pilot study in OA patients treated with chondroitin sulfate

OSX-CRE directed ablation of site-1 protease in mice results in kyphosis and scoliosis

OSX-CRE directed ablation of site-1 protease in mice results in kyphosis and scoliosis

The association of comorbid conditions with patient reported outcomes in osteoarthritis

The association of comorbid conditions with patient reported outcomes in osteoarthritis

Be it resolved: plain radiography or MRI – which is better in assessing outcome in clinical trials?

Be it resolved: plain radiography or MRI – which is better in assessing outcome in clinical trials?

Comparison of radiographic hip joint space in weight bearing and supine X-rays in patients with hip pathology

Comparison of radiographic hip joint space in weight bearing and supine X-rays in patients with hip pathology

TGFβ1 increases oxidative stress in human osteoarthritis articular chondrocytes through mechanisms involving NOX4

TGFβ1 increases oxidative stress in human osteoarthritis articular chondrocytes through mechanisms involving NOX4

Exploratory biomarker analysis reveals a genetic epistatic interaction in interleukin 1 receptor antagonist (IL1RN) gene associated to cartilage volume growth measured by MRI in response to sprifermin therapy in patients with knee radiographic osteoarthritis

Exploratory biomarker analysis reveals a genetic epistatic interaction in interleukin 1 receptor antagonist (IL1RN) gene associated to cartilage volume growth measured by MRI in response to sprifermin therapy in patients with knee radiographic osteoarthritis

Deciphering the role of 75kDa SirT1 fragment in osteoarthritis

s / Osteoarthritis and Cartilage 21 (2013) S9–S62 S49 Fig. Molecular networks generated from the genes differentially expressed by age. The molecular networks generated from genes differentially expressed in meniscus by age (top: up-regulated genes; bottom: down-regulated genes) using GRANITE. The colors are based on the database from which the network is extracted. ellipse 1⁄4 protein; square 1⁄4 transcription factor 79 DECIPHERING THE ROLE OF 75KDA SIRT1 FRAGMENT IN OSTEOARTHRITIS M. Dvir-Ginzberg y, H. Oppenheimer y, H. Meir y, O. Gabay z, K. Zaal z, C. Sanchez x, A. Haze k, L. Kandel k, M. Leibergall k. yHebrew Univ. of Jerusalem, Jerusalem, Israel; zNIAMS, NIH, MD, USA; xHebrew Univ. of Jerusalem, University of Liege, Liege, Belgium; kHebrew Univ. of JerusalemHadassah Med. Center, Jerusalem, Israel Objective: SirT1 is a nuclear NAD-dependent deacetylase associated with cellmetabolismand survival. In joints, recent evidence shows that it regulates cartilage homeostasis and is involved in the inflammatory phase of osteoarthritis (OA). It is widely held that the inflammatory cytokines tumor necrosis factor alpha (TNFa), and interleukin 1b (IL-1b) may elicit chondrocyte death associated with the deterioration of articular cartilage (AC) in OA. Exposing human chondrocytes to both cytokines leads to cathepsin B-mediated cleavage of the nuclear full-length SirT1 (FLSirT1; 110kDa) to generate a stable but enzymatically inactive 75kDa fragment of SirT1 (75SirT1). Here we aim to elucidate the biological andbiochemical role of 75kDa SirT1 fragment in-vivo and in-vitro Methods: Using immunoblot analyses we aimed to detect cathepsin B, FLSirT1 and/or 75SirT1 in OA and normal human chondrocytes. Confocal imaging of SirT1 was used tomonitor its subcellular trafficking following TNFa stimulation of human chondrocytes. Coimmunofluorescent staining for cathepsin B, mitochondrial cytochrome oxidase subunit IV and lysosome-associated membrane protein 1 together with SirT1was performed. Human chondrocytes were tested for apoptosis by fluorescence-activated cell sorter analysis and immunoblotting for caspases 3 and 8. Human chondrocyte mitochondrial extracts were obtained and analyzed for 75SirT1-cytochrome C association. In-vivo assays of heterozygous haploinsufficient (SirT1+/-) and wildtype (WT; SirT1+/+) 129/J mice aged 1 or 9 months were systematically compared for musculoskeletal features, scored for osteoarthritis (OA) severity, and monitored for chondrocyte apoptosis in articular cartilage. Protein extracts from articular chondrocytes were isolated and immunoblotted for SirT1 and active caspase 3. Results: Confocal imaging, immunoprecipitation assays and immunoblot analyses following TNFa challenge of human chondrocytes exhibited that 75SirT1 was generated and exported to the cytoplasm wherein it colocalized with the mitochondrial membrane and associates with cytochrome C. Additionally, levels of cathepsin B and 75SirT1 were elevated in OA versus normal chondrocytes. Subjecting human chondrocytes to TNFa and a cathepsin B inhibitor (ALLN), enhanced levels of apoptotic cell and cleaved caspase 3. Immunoblot assays comparing medial tibial plateau articular cartilage (MTP-AC) of heterozygous haploinsufficient (SirT1+/-) and wild-type (WT; SirT1+/+) 129/J mice revealed reduced levels of FLSirT1 in both strains at 9 months compared to their 1 month equivalent. WT 9-monthold strains presented the 75SirT1 fragments in immunoblot assays, whereas age-matched SirT1+/-mice possessed undetected 75SirT1 levels. Interestingly, 9 month-old SirT1+/mice exhibited increased OA severity andaugmented levels of apoptosis comparedwithage-matchedWTmice. Conclusion: Despite 75SirT1 being enzymatically impaired our results show that it is relatively stable and participates in promoting chondrocyte survival following exposure to proinflammatory cytokines or during articular cartilage maturation. 80 ASYMPTOMATIC INDIVIDUALS WITH RADIOGRAPHIC EVIDENCE OF KNEE OSTEOARTHRITIS WALK WITH DIFFERENT KNEE MECHANICS PATTERNS THAN SYMPTOMATIC INDIVIDUALS WITH THE SAME RADIOGRAPHIC EVIDENCE J.L. Astephen Wilson, G. Hatfield, W.D. Stanish, C.L. HubleyKozey. Dalhousie Univ., Halifax, NS, Canada

Secreted 14-3-3ε: discovery by proteomics of a novel biomarker and/or therapeutical target in osteoarthritis

Secreted 14-3-3ε: discovery by proteomics of a novel biomarker and/or therapeutical target in osteoarthritis

The role of primary cilia in cartilage health and disease

The role of primary cilia in cartilage health and disease

Strontium ranelate increases the number of patients with improvement in osteoarthritis symptoms compared to placebo in the SEKOIA study

s / Osteoarthritis and Cartilage 21 (2013) S63–S312 S143 Conclusions: In 2 years of follow up substantial numbers of participants with complaints due to early OA could be diagnosed according to clinical or radiographic ACR criteria with either hip or knee OA after two years of follow up. Specific factors associated with this progression found in the hip group: morning stiffness of the hip, pain medication use, and Heberden's nodes. In the knee group Heberden's nodes were associated with the diagnosis of knee OA. 264 STRONTIUM RANELATE INCREASES THE NUMBER OF PATIENTS WITH IMPROVEMENT IN OSTEOARTHRITIS SYMPTOMS COMPARED TO PLACEBO IN THE SEKOIA STUDY O. Bruyere y, P. Richette z, N. Bellamy x, J. Brown k, R. Chapurlat {, X.-J. Chevalier , E. Czerwinski yy, J.-P. Devogelaer zz, L. March xx, Placebo (N 1⁄4 472) n (%) SrRan 2 g (N 1⁄4 454) n (%) Difference relative to placebo [95% CI] p-value

Characterization of cell metabolic changes in osteoarthritic labrum cells

Characterization of cell metabolic changes in osteoarthritic labrum cells

The Correlation of Body Mass Index, Plasma C-Telopeptidase, and Synovial Fluid Leptin in Osteoarthritis, Before and After Exercise: A Study in Explaining Role of Leptin and Exercise in Osteoarthritis With Obesity and Osteoporosis

s 499 dysplasia for the past 25 years. He did not have any prior history of effusions. The occurrence of recurring effusions with a history of recent use of zoledronic acid points to a diagnosis of this being a rare medication side-effect. A detailed search of literature shows that a few cases have been reported to the FDA after use of zoledronic acid but none have been published. Dyspnea is a listed side effect occurring in 22-27% patients but the etiology is not elucidated. This case highlights the importance of having a high index of clinical suspicion to make a diagnosis of drug induced lung disease. This is especially the case for newer drugs with which we do not have long term data and experience. As the clinical indications for bisphosphonate use continues to expand, it is important for clinicians to prevent, recognize, and manage any possible complications effectively and expeditiously. It also raises awareness to be vigilant for the possibility of a pleural effusion after the use of zoledronic acid as dyspnea is a frequently reported complication. 137 Prevention and Treatment: Osteoporosis Subset BMD Level Odds Ratio (95% CI) All Osteopenia (n 5 8841) T-score -1.5 to -2.4 1.55 (1.38-1.73) Osteoporosis (n55732) T-score -2.5 1.15 (0.99-1.34) Subset NOT on medication at DXA date Osteopenia (n55501) T-score -1.5 to -2.4 1.68 (1.35-2.09) Osteoporosis (n 5 2108) T-score -2.5 1.27 (1.02-1.58) and Other Conditions THE CORRELATION OF BODY MASS INDEX, PLASMA C-TELOPEPTIDASE, AND SYNOVIAL FLUID LEPTIN IN OSTEOARTHRITIS, BEFORE AND AFTER EXERCISE: A STUDY IN EXPLAINING ROLE OF LEPTIN AND EXERCISE IN OSTEOARTHRITIS WITH OBESITY AND