Purpose: Despite its many health benefits, moderate exercise can induce joint discomfort when done infrequently or too intensely even in individuals with healthy joints. This study was designed to evaluate whether NEM (R) (natural eggshell membrane) would reduce exercise-induced cartilage turnover or alleviate joint pain or stiffness, either directly following exercise or 12 hours post exercise, versus placebo. Patients and methods: Sixty healthy, postmenopausal women were randomly assigned to receive either oral NEM 500 mg (n=30) or placebo (n=30) once daily for two consecutive weeks while performing an exercise regimen (50-100 steps per leg) on alternating days. The primary endpoint was any statistically significant reduction in exercise-induced cartilage turnover via the biomarker C-terminal cross-linked telopeptide of type-II collagen (CTX-II) versus placebo, evaluated at 1 and 2 weeks of treatment. Secondary endpoints were any reductions in either exercise-induced joint pain or stiffness versus placebo, evaluated daily via participant questionnaire. The clinical assessment was performed on the per protocol population. Results: NEM produced a significant absolute treatment effect (TEabs) versus placebo for CTX-II after both 1 week (TEabs - 17.2%, P=0.002) and 2 weeks of exercise (TEabs - 9.9%, P=0.042). Immediate pain was not significantly different; however, rapid treatment responses were observed for immediate stiffness (Day 7) and recovery pain (Day 8) and recovery stiffness (Day 4). No serious adverse events occurred and the treatment was reported to be well tolerated by study participants. Conclusion: NEM rapidly improved recovery from exercise-induced joint pain (Day 8) and stiffness (Day 4) and reduced discomfort immediately following exercise (stiffness, Day 7). Moreover, a substantial chondroprotective effect was demonstrated via a decrease in the cartilage degradation biomarker CTX-II.

Les objectifs de ce travail étaient l’évaluation de stades précoces et tardifs de l’arthrose grâce à une étude histologique et biologique de l’arthrose sur un modèle de rupture de ligament croisé crânial chez le lapin (RLCC) et l’évaluation de l’effet de l’âge sur l’évolution de la maladie. L’étude biologique a été réalisée par le dosage sérique d’un marqueur de la dégradation du collagène de type II, le CTX-II, jusqu’à 20 semaines post-chirurgie. Chez les animaux adultes, les concentrations du CTX-II étaient influencées par la chirurgie et par le développement de la pathologie. Chez les jeunes animaux, les niveaux de CTX-II étaient plus élevés en début d’étude et diminuaient au cours du temps. Chez ce groupe d'animaux, les taux de CTX-II n’étaient pas modifiés par l’intervention chirurgicale. L’étude histologique a été réalisée avec une analyse histomorphologique du cartilage et des analyses histomorphométriques du cartilage et de l’os sous-chondral. L’évaluation histologique a permis d’observer des changements liés à l’arthrose chez tous les animaux opérés. Les altérations au niveau du cartilage étaient plus sévères chez les animaux adultes que chez les jeunes, ces derniers présentant une meilleure capacité de compensation à l’instabilité articulaire. Il a été démontré que l’analyse de la plaque osseuse sous-chondrale a permis de distinguer les animaux opérés des animaux non-opérés dans les 2 groupes d’âge, mais les surfaces articulaires affectées n’étaient pas toujours les mêmes. En conclusion, ce travail suggère l’intérêt du CTX-II dans l’évaluation de l’arthrose, mais aussi la pertinence d’effectuer plusieurs temps d’analyse pour mieux connaître l’évolution de la maladie. Les analyses histologiques ont permis de mettre en évidence des changements au niveau du cartilage et de l’os sous-chondral. Les différences observées entre les lapins adultes et les jeunes remettent en question l'utilisation d’animaux trop jeunes dans les études portant sur l’arthrose / The goals of this work were the evaluation of early and late stages of osteoarthritis through a histological and biological study of osteoarthritis using a rabbit model of the anterior cruciate ligament transaction (ACLT) and the evaluation of the effect of age on the evolution of the disease. Biological study was performed with longitudinal analysis of serum level of CTX-II, a marker a type II collagen degradation. In adult animals, serum concentration of CTX-II was influenced by the ACLT surgery and varied with time. In the young rabbits, the serum levels of CTX-II were more elevated at the beginning of study and decrease after. In this animal group, the rates of CTX-II were not influenced by surgical operation. Histological study was accomplished with both histomorphological analysis of the cartilage and with histomorphometric study of both cartilage and sub-chondral bone. Histological evaluation showed osteoarthritis changes in all operated animals. Changes of the cartilage appeared more severe in the adult group compared to the young rabbits, suggesting that these last have a better compensation capacity during articular instability. Bony changes allowed to differentiate operated animals from the unoperated, but the affected articular surfaces were not always the same. In conclusion, this study suggest the interest of the CTX-II biomarker in the evaluation of osteoarthritis, but also the pertinence to perform several time points of analysis to know better the disease evolution. The histological analysis allowed to put in an obvious place changes at the levels of the cartilage and of the sub-chondral bone. Difference noticed between the adult animals and the young rabbits offers a new look for the use of too young animals in osteoarthritis studies

Introduction: Le principal objectif de cette étude est de mesurer l’effet du GDF-5 sur l’homéostasie du cartilage. Le GDF-5 est un gène de susceptibilité de l’OA faisant partie de la famille des BMPs et qui favorise la synthèse du cartilage. Le but de notre étude a été de déterminer l’effet du GDF-5 sur le métabolisme catabolique ainsi que sur l’équilibre global des chondrocytes, principalement au niveau de l’Aggrécan. Méthode : Des chondrocytes arthrosiques canins et humains OA ont été exposés au GDF-5. L’expression des ARNm et des protéines a été analysée afin d’évaluer la production de l’Aggrécan et le ratio Col-II/Col-I au niveau des facteurs anaboliques et du phénotype. Pour le catabolisme, l’expression et l’activité des aggrécanases ADAMTS-4 et ADAMTS-5 ont été mesurées. Les épitopes NITEGE et CTX-II ont aussi été quantifiés dans le liquide synovial canin après des injections intraarticulaires de GDF-5. Résultats : Le GDF-5 provoque une augmentation de l’activité cellulaire des chondrocytes canins et humains. Pour les ARNm et l’expression protéique, le GDF-5 augmente l’expression de l’Aggrécan alors que les facteurs cataboliques le diminuent. Le phénotype reste inchangé en présence du produit, sauf à haute dose où on augmente le ColI. L’activité des aggrécanases diminue puisque l’épitope NITEGE diminue alors que le CTX-II augmente dans l’articulation. Conclusion : En somme, les facteurs anaboliques du cartilage sont favorisés, alors que les facteurs cataboliques sont diminués par le GDF-5. Cette action double permet d’illustrer l’effet du GDF-5, le classant comme un potentiel médicament modifiant la maladie de l’OA qui mérite d’être étudiée. / Purpose: The objective of this study is to assess the effect of GDF-5 on cartilage homeostasis. GDF-5 is a susceptibility gene for OA and member of the BMP super family. Studies have shown that it can increase expression of anabolic factors in chondrocytes. Therefore, our study indentifies how GDF-5 influences this metabolism and the global homeostasis of chondrocytes, aiming mainly towards Aggrecan. Methods : Osteoarthritic (OA) chondrocytes from canine and human models were exposed to GDF-5. Protein expressions, along with mRNA expression were assessed in order to investigate Aggrecan production and the ratio of Col-II/Col-I, for the anabolic phenotype markers. The aggrecanases ADAMTS-4 and ADAMTS-5 and their global activity were assed for the catabolic factors. The NITEGE and CTX-II epitope were also measured in synovial fluid of Pond-Nuki dogs that received intraarticular GDF-5 injections. Results : GDF-5 increases chondrocyte cellular activity, in our canine and human models. Both mRNA and protein expression of the chondrocytes Aggrecan were increased and the aggrecanases expression and activity were decreased. Collagen ratio did not show a phenotype, except et high dosage where the Col-I production is induced. Aggrecanase activity was lowered while CTX-II was increased. Conclusion : In conclusion, the anabolic cellular activity of OA chondrocytes increases while the catabolic factors decrease in presence of GDF-5. This double action illustrates the global effect of GDF-5, identifying it as a potential disease modifying factor of OA that should be further investigated.

Introduction: Le principal objectif de cette étude est de mesurer l’effet du GDF-5 sur l’homéostasie du cartilage. Le GDF-5 est un gène de susceptibilité de l’OA faisant partie de la famille des BMPs et qui favorise la synthèse du cartilage. Le but de notre étude a été de déterminer l’effet du GDF-5 sur le métabolisme catabolique ainsi que sur l’équilibre global des chondrocytes, principalement au niveau de l’Aggrécan. Méthode : Des chondrocytes arthrosiques canins et humains OA ont été exposés au GDF-5. L’expression des ARNm et des protéines a été analysée afin d’évaluer la production de l’Aggrécan et le ratio Col-II/Col-I au niveau des facteurs anaboliques et du phénotype. Pour le catabolisme, l’expression et l’activité des aggrécanases ADAMTS-4 et ADAMTS-5 ont été mesurées. Les épitopes NITEGE et CTX-II ont aussi été quantifiés dans le liquide synovial canin après des injections intraarticulaires de GDF-5. Résultats : Le GDF-5 provoque une augmentation de l’activité cellulaire des chondrocytes canins et humains. Pour les ARNm et l’expression protéique, le GDF-5 augmente l’expression de l’Aggrécan alors que les facteurs cataboliques le diminuent. Le phénotype reste inchangé en présence du produit, sauf à haute dose où on augmente le ColI. L’activité des aggrécanases diminue puisque l’épitope NITEGE diminue alors que le CTX-II augmente dans l’articulation. Conclusion : En somme, les facteurs anaboliques du cartilage sont favorisés, alors que les facteurs cataboliques sont diminués par le GDF-5. Cette action double permet d’illustrer l’effet du GDF-5, le classant comme un potentiel médicament modifiant la maladie de l’OA qui mérite d’être étudiée. / Purpose: The objective of this study is to assess the effect of GDF-5 on cartilage homeostasis. GDF-5 is a susceptibility gene for OA and member of the BMP super family. Studies have shown that it can increase expression of anabolic factors in chondrocytes. Therefore, our study indentifies how GDF-5 influences this metabolism and the global homeostasis of chondrocytes, aiming mainly towards Aggrecan. Methods : Osteoarthritic (OA) chondrocytes from canine and human models were exposed to GDF-5. Protein expressions, along with mRNA expression were assessed in order to investigate Aggrecan production and the ratio of Col-II/Col-I, for the anabolic phenotype markers. The aggrecanases ADAMTS-4 and ADAMTS-5 and their global activity were assed for the catabolic factors. The NITEGE and CTX-II epitope were also measured in synovial fluid of Pond-Nuki dogs that received intraarticular GDF-5 injections. Results : GDF-5 increases chondrocyte cellular activity, in our canine and human models. Both mRNA and protein expression of the chondrocytes Aggrecan were increased and the aggrecanases expression and activity were decreased. Collagen ratio did not show a phenotype, except et high dosage where the Col-I production is induced. Aggrecanase activity was lowered while CTX-II was increased. Conclusion : In conclusion, the anabolic cellular activity of OA chondrocytes increases while the catabolic factors decrease in presence of GDF-5. This double action illustrates the global effect of GDF-5, identifying it as a potential disease modifying factor of OA that should be further investigated.

Objective: Anterior cruciate ligament (ACL) injuries are increasing in adolescents and increase the risk for early-onset knee osteoarthritis (OA). Biomarkers can be a non-invasive measure to assess physiological properties following knee injury or trauma. The objective of this thesis was to i) perform a systematic review to determine the most studied biomarkers of knee healing following ACL reconstruction (ACLR), and age of these patients, and ii) explore the feasibility of measuring these biomarkers in adolescents with ACL injuries. Design: Studies were included if i) participants underwent ACLR, and ii) at least one biomarker of healing was measured. Participant age, sample(s) collected, and biomarker(s) studied were recorded. Interleukin-6 (IL-6), c-terminal crosslinking telopeptide of type II collagen (CTX-II) and procollagen type II collagen propeptide (PIICP) were then measured using ELISA in adolescents prior to ACLR in urine (u) and synovial fluid (sf). Spearman’s Rho (rs) coefficients were calculated to determine the association between uCTX-II/sfCTX-II, and uIL-6/sfIL-6. A ratio of PIICP: CTX-II was calculated to represent the ratio of cartilage synthesis to degradation. Results: The review produced six studies evaluating healing following ACLR. IL-6 and CTX-II were the most studied (3/6 studies), and only one study included adolescents (age 19.6±4.5). Due to multiple undetectable biomarker levels, we could only report rs for uCTX-II/sfCTX-II (rs = -.200, p-value = .800, n=4). We also reported a ratio for sfPIICP: sfCTX-II (23.06 ±19.23). Conclusion: Exploring biomarkers in adolescents was motivated by their unique physiology due to puberty, and this was the first study to do so. The findings from this pilot study indicate that further analysis is required to determine optimal sample preparation. This will allow for reliable results while studying the feasibility of these biomarkers during ACLR recovery. This insight can ensure more informed decision making by clinicians clearing patients for return-to-activity.