Comparison of Clinical Efficacy and Mechanical Characteristics of Two Knee Distraction Devices With Relevance for Clinical Practice.

OBJECTIVE: Distraction treatment for severe osteoarthritis below the age of 65 successfully postpones arthroplasty. Most patients have been treated with a general external fixator or a device specifically intended for knee distraction. This study compares clinical efficacy of both devices in retrospect and their mechanical characteristics. DESIGN: Clinical efficacy 2 years posttreatment was compared using retrospective data from patients with severe knee osteoarthritis treated with knee distraction; 63 with the Dynamic Monotube (Stryker GmbH, Switzerland) and 65 with the KneeReviver (ArthroSave BV, the Netherlands). Changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, stiffness, and function, general well-being (SF-36), cartilage thickness by radiographic joint space widening, and adverse events during treatment were assessed. Axial stiffness of clinically feasible configurations was assessed by bench testing for the Dynamic Monotube triax system and the KneeReviver. RESULTS: No differences were observed in clinical efficacy, nor in mechanical characteristics and adverse events between the two devices. Although with large variation, both showed a clinically relevant improvement. In mechanical testing, contact between articular surfaces was observed for both devices at physiological loading. Stiffness of applied configurations strongly varied and primarily depended on bone pin length. CONCLUSIONS: Patients treated with a general intended-use device or a distraction-specific device both experienced clinical and structural efficacy although with significant variation between patients. The latter may be the result of varying mechanical characteristics resulting from differences in clinical configurations of the devices and actual loading. The exact role of full/partial mechanical unloading of the joint during distraction treatment remains unclear.

Can gait patterns be explained by joint structure in people with and without radiographic knee osteoarthritis? Data from the IMI-APPROACH cohort.

OBJECTIVE: To determine the association between joint structure and gait in patients with knee osteoarthritis (OA). METHODS: IMI-APPROACH recruited 297 clinical knee OA patients. Gait data was collected (GaitSmart®) and OA-related joint measures determined from knee radiographs (KIDA) and MRIs (qMRI/MOAKS). Patients were divided into those with/without radiographic OA (ROA). Principal component analyses (PCA) were performed on gait parameters; linear regression models were used to evaluate whether image-based structural and demographic parameters were associated with gait principal components. RESULTS: Two hundred seventy-one patients (age median 68.0, BMI 27.0, 77% female) could be analyzed; 149 (55%) had ROA. PCA identified two components: upper leg (primarily walking speed, stride duration, hip range of motion [ROM], thigh ROM) and lower leg (calf ROM, knee ROM in swing and stance phases). Increased age, BMI, and radiographic subchondral bone density (sclerosis), decreased radiographic varus angle deviation, and female sex were statistically significantly associated with worse lower leg gait (i.e. reduced ROM) in patients without ROA (R2 = 0.24); in ROA patients, increased BMI, radiographic osteophytes, MRI meniscal extrusion and female sex showed significantly worse lower leg gait (R2 = 0.18). Higher BMI was significantly associated with reduced upper leg function for non-ROA patients (R2 = 0.05); ROA patients with male sex, higher BMI and less MRI synovitis showed significantly worse upper leg gait (R2 = 0.12). CONCLUSION: Structural OA pathology was significantly associated with gait in patients with clinical knee OA, though BMI may be more important. While associations were not strong, these results provide a significant association between OA symptoms (gait) and joint structure.

The catabolic-to-anabolic shift seen in the canine osteoarthritic cartilage treated with knee joint distraction occurs after the distraction period.

Background: Cartilage regenerative mechanisms initiated by knee joint distraction (KJD) remain elusive. Animal experiments that are representative for the human osteoarthritic situation and investigate the effects of KJD at consecutive time points could be helpful in this respect but are lacking. This study investigated the effects of KJD on the osteoarthritic joint of dogs on two consecutive timepoints. Methods: Osteoarthritis was bilaterally induced for 10 weeks in 12 dogs using the groove model. Subsequently, KJD was applied to the right hindlimb for 8 weeks. The cartilage, subchondral bone and synovial membrane were investigated directly after KJD treatment, and after 10 weeks of follow-up after KJD treatment. Macroscopic and microscopic joint tissue alterations were investigated using the OARSI grading system. Additionally, proteoglycan content and synthesis of the cartilage were assessed biochemically. RT-qPCR analysis was used to explore involved signaling pathways. Results: Directly after KJD proteoglycan and collagen type II content were reduced accompanied by decreased proteoglycan synthesis. After 10 weeks of follow-up, proteoglycan and collagen type II content were partly restored and proteoglycan synthesis increased. RT-qPCR analysis of the cartilage suggests involvement of the TGF-ß and Notch signalling pathways. Additionally, increased subchondral bone remodelling was found at 10 weeks of follow-up. Conclusion: While the catabolic environment in the cartilage is still present directly after KJD, at 10 weeks of follow-up a switch towards a more anabolic joint environment was observed. Further investigation of this timepoint and the pathways involved might elucidate the regenerative mechanisms behind KJD. The Translational Potential of this Article: Further elucidation of the regenerative mechanisms behind KJD could improve the existing KJD treatment. Furthermore, these findings could provide input for the discovery or improvement of other joint regenerative treatment strategies.

Synovial membrane-derived mesenchymal progenitor cells from osteoarthritic joints in dogs possess lower chondrogenic-, and higher osteogenic capacity compared to normal joints.

BACKGROUND: Synovial membrane-derived mesenchymal progenitor cells (SM-MPCs) are a promising candidate for the cell-based treatment of osteoarthritis (OA) considering their in vitro and in vivo capacity for cartilage repair. However, the OA environment may adversely impact their regenerative capacity. There are no studies for canine (c)SM-MPCs that compare normal to OA SM-MPCs, even though dogs are considered a relevant animal model for OA. Therefore, this study compared cSM-MPCs from normal and OA synovial membrane tissue to elucidate the effect of the OA environment on MPC numbers, indicated by CD marker profile and colony-forming unit (CFU) capacity, and the impact of the OA niche on tri-lineage differentiation. METHODS: Normal and OA synovial membrane were collected from the knee joints of healthy dogs and dogs with rupture of the cruciate ligaments. The synovium was assessed by histopathological OARSI scoring and by RT-qPCR for inflammation/synovitis-related markers. The presence of cSM-MPCs in the native tissue was further characterized with flow cytometry, RT-qPCR, and immunohistochemistry, using the MPC markers; CD90, CD73, CD44, CD271, and CD34. Furthermore, cells isolated upon enzymatic digestion were characterized by CFU capacity, and a population doublings assay. cSM-MPCs were selected based on plastic adherence, expanded to passage 2, and evaluated for the expression of MPC-related surface markers and tri-lineage differentiation capacity. RESULTS: Synovial tissue collected from the OA joints had a significantly higher OARSI score compared to normal joints, and significantly upregulated inflammation/synovitis markers S100A8/9, IL6, IL8, and CCL2. Both normal and OA synovial membrane contained cells displaying MPC properties, including a fibroblast-like morphology, CFU capacity, and maintained MPC marker expression over time during expansion. However, OA cSM-MPCs were unable to differentiate towards the chondrogenic lineage and had low adipogenic capacity in contrast to normal cSM-MPCs, whereas they possessed a higher osteogenic capacity. Furthermore, the OA synovial membrane contained significantly lower percentages of CD90+, CD44+, CD34+, and CD271+ cells. CONCLUSIONS: The OA environment had adverse effects on the regenerative potential of cSM-MPCs, corroborated by decreased CFU, population doubling, and chondrogenic capacity compared to normal cSM-MPCs. OA cSM-MPCs may be a less optimal candidate for the cell-based treatment of OA than normal cSM-MPCs.

The fear for adverse bleeding and cardiovascular events in hemophilia patients using (non-)selective non-steroidal anti-inflammatory drugs: A systematic review reporting on safety.

(Non-)selective non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used for musculoskeletal related pain. These cheap and easily accessible drugs may be of great value for hemophilia patients in developing countries and countries with a high rate of opioid poisoning, but also in developed countries due to potential joint protective effects. However, fear for adverse bleeding and cardiovascular events during the use of these drugs restrains prescription within this population. To give a complete overview of all publications reporting on safety, a systematic search till March 2021 was performed. All studies were reviewed and critically appraised and this resulted in 19 studies eligible for inclusion. Most studies with (non-)selective NSAIDs showed no evident risk for relevant adverse bleeding or cardiovascular events. However, some studies had a high risk of bias and studies reporting on cardiovascular events were limited. Future studies with longitudinal follow-up in well-defined large patient populations, including older patients, focusing on both adverse bleeding and cardiovascular events are required to confirm the alleged safe use.

The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review.

OBJECTIVE: A fusion protein of interleukin-4 and interleukin-10 (IL4-10 FP) was developed as a disease-modifying osteoarthritis drug (DMOAD), and chondroprotection, anti-inflammation, and analgesia have been suggested. To better understand the mechanisms behind its potential as DMOAD, this systematic narrative review aims to assess the potential of IL-4, IL-10 and the combination of IL-4 and IL-10 for the treatment of osteoarthritis. It describes the chondroprotective, anti-inflammatory, and analgesic effects of IL-4, IL-10, and IL4-10 FP. DESIGN: PubMed and Embase were searched for publications that were published from 1990 until May 21, 2021 (moment of search). Key search terms were: Osteoarthritis, Interleukin-4, and Interleukin-10. This yielded 2,479 hits, of which 43 were included in this review. RESULTS: IL-4 and IL-10 showed mainly protective effects on osteoarthritic cartilage in vitro and in vivo, as did IL4-10 FP. Both cytokines showed anti-inflammatory effects, but also proinflammatory effects. Only in vitro IL4-10 FP showed purely anti-inflammatory effects, indicating that proinflammatory effects of one cytokine can be counteracted by the other when given as a combination. Only a few studies investigated the analgesic effects of IL-4, IL-10 or IL4-10 FP. In vitro, IL-4 and IL4-10 FP were able to decrease pain mediators. In vivo, IL-4, IL-10, and IL4-10 FP were able to reduce pain. CONCLUSIONS: In conclusion, this review describes overlapping, but also different modes of action for the DMOAD effects of IL-4 and IL-10, giving an explanation for the synergistic effects found when applied as combination, as is the case for IL4-10 FP.

Subchondral bone changes after joint distraction treatment for end stage knee osteoarthritis.

OBJECTIVE: Increased subchondral cortical bone plate thickness and trabecular bone density are characteristic of knee osteoarthritis (OA). Knee joint distraction (KJD) is a joint-preserving knee OA treatment where the joint is temporarily unloaded. It has previously shown clinical improvement and cartilage regeneration, indicating reversal of OA-related changes. The purpose of this research was to explore 3D subchondral bone changes after KJD treatment using CT imaging. DESIGN: Twenty patients were treated with KJD and included to undergo knee CT imaging before, one, and two years after treatment. Tibia and femur segmentation and registration to canonical surfaces were performed semi-automatically. Cortical bone thickness and trabecular bone density were determined using an automated algorithm. Statistical parametric mapping (SPM) with two-tailed F-tests was used to analyze whole-joint changes. RESULTS: Data was available of 16 patients. Subchondral cortical bone plate thickness and trabecular bone density were higher in the weight-bearing region of the most affected compartment (MAC; mostly medial). Especially the MAC showed a decrease in thickness and density in the first year after treatment, which was sustained towards the second year. CONCLUSIONS: KJD treatment results in bone changes that include thinning of the subchondral cortical bone plate and decrease of subchondral trabecular bone density in the first two years after treatment, potentially indicating a partial normalization of subchondral bone.

Performance of knee image digital analysis of radiographs of patients with end-stage knee osteoarthritis.

OBJECTIVE: Knee Image Digital Analysis (KIDA) is standardized radiographic analysis software for measuring osteoarthritis (OA) characteristics. It was validated in mild OA, but used for severe OA as well. The current goal was to evaluate the performance of KIDA in severe OA. DESIGN: Of 103 patients, standardized radiographs were performed before and one and 2 years after treatment for severe OA. All radiographs were evaluated on subchondral bone density, joint space width (JSW), osteophytes, eminence height, and joint angle, twice within years by the same observer. Part of the radiographs were randomly selected for reevaluation twice within 1 month and evaluation by another observer. The intraclass correlation coefficient (ICC), smallest detectable difference (SDD) and coefficient of variation (CV) were calculated; the SDD and CV were compared to those in mild OA. The relation of severity with KIDA parameters and with observer differences was calculated with linear regression. RESULTS: Intra-observer ICCs were higher in the 98 severe radiographs reanalyzed within 1 month (all >0.8) than the 293 reanalyzed within years (all >0.5; most >0.8) and than inter-observer ICCs (all >0.7). SDDs and CVs were smaller when reanalyzed within a month and comparable to those in mild OA. Some parameters showed bias between readings. Severity showed significant relation with osteophytes and JSW parameters, and with the observer variation in these parameters (all P < 0.04). CONCLUSIONS: KIDA is a well-performing tool also for severe OA. In order to decrease variability and SDDs, images should be analyzed in a limited time frame and randomized order.

IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model.

OBJECTIVE: Ideally, disease-modifying osteoarthritis (OA) drugs (DMOAD) should combine chondroprotective, anti-inflammatory, and analgesic effects in a single molecule. A fusion protein of interleukin-4 (IL-4) and IL-10 (IL4-10 FP) possesses these combined effects. In this study, the DMOAD activity of rat IL4-10 FP (rIL4-10 FP) was tested in a rat model of surgically induced OA under metabolic dysregulation. DESIGN: rIL4-10 FP was produced with HEK293F cells. Bioactivity of purified rIL4-10 FP was determined in a whole blood assay. Male Wistar rats (n = 20) were fed a high-fat diet (HFD) to induce metabolic dysregulation. After 12 weeks, OA was induced according to the Groove model. Two weeks after OA induction, rats were randomly divided into 2 groups and treated with 10 weekly, intra-articular injections of either rIL4-10 FP (n = 10) or phosphate buffered saline (PBS; n = 10). Possible antibody formation was evaluated using ELISA, cartilage degeneration and synovial inflammation were evaluated by histology and mechanical allodynia was evaluated using the von Frey test. RESULTS: Intra-articular injections with rIL4-10 FP significantly reduced cartilage degeneration (P = 0.042) and decreased mechanical allodynia (P < 0.001) compared with PBS. Only mild synovial inflammation was found (nonsignificant), limiting detection of putative anti-inflammatory effects. Multiple injections of rIL4-10 FP did not induce antibodies against rIL4-10 FP. CONCLUSION: rIL4-10 FP showed chondroprotective and analgesic activity in a rat OA model with moderate cartilage damage, mild synovial inflammation, and pain. Future studies will need to address whether less frequent intra-articular injections, for example, with formulations with increased residence time, would also lead to DMOAD activity.

Biochemical marker research in hemophilic arthropathy: A systematic review.

Hemophilic arthropathy (HA) causes major morbidity. Breakthrough therapies reduce the bleeding frequency tremendously, but well-defined joint outcome assessments with a focus on early changes and subclinical damage are lacking. Biomarkers reflecting joint tissue turnover/inflammation might be useful to predict invalidating arthropathy. This systematic review summarized and categorized publications on blood/urinary biomarkers in HA to provide leads for implementation. A PubMed/EMBASE search was performed on September 9, 2019. All publications were assessed and allocated to one or several BIPED-categories, based on the utility of biomarkers. Of the initial 1307 publications found, 27 were eligible for inclusion. The majority (81%, n = 32/42) was cross-sectional in design, including relatively small numbers of patients (median 44, interquartile range 35-78). Fourteen percent (n = 6/42) investigated dynamic changes around a bleeding or treatment. Only two studies investigated the prognostic value of biomarkers. Most promising biomarkers were serum Coll2-1, COL-18N, COMP, C1,2C, C2M, CS846, MIF, plasma sVCAM-1 and urinary CTX-II. Comparing performances and pooling data was not possible due to heterogeneity. Currently, biomarker research in HA is still in an explorative stage and not yet sufficient for translation into daily practice. Clearly, larger homogeneous longitudinal studies in well-defined populations should be performed for further development.

The molecular profile of synovial fluid changes upon joint distraction and is associated with clinical response in knee osteoarthritis.

OBJECTIVE: Surgical knee joint distraction (KJD) leads to clinical improvement in knee osteoarthritis (OA) and also apparent cartilage regeneration by magnetic resonance imaging. We investigated if alteration of the joint's mechanical environment during the 6 week period of KJD was associated with a molecular response in synovial fluid, and if any change was associated with clinical response. METHOD: 20 individuals undergoing KJD for symptomatic radiographic knee OA had SF sampled at baseline, midpoint and endpoint of distraction (6 weeks). SF supernatants were measured by immunoassay for 10 predefined mechanosensitive molecules identified in our previous pre-clinical studies. The composite Knee injury and OA Outcome Score-4 (KOOS4) was collected at baseline, 3, 6 and 12 months. RESULTS: 13/20 (65%) were male with mean age 54°±°5yrs. All had Kellgren-Lawrence grade ≥2 knee OA. 6/10 analytes showed statistically significant change in SF over the 6 weeks distraction (activin A; TGFß-1; MCP-1; IL-6; FGF-2; LTBP2), P < 0.05. Of these, all but activin A increased. Those achieving the minimum clinically important difference of 10 points for KOOS4 over 6 months showed greater increases in FGF-2 and TGFß-1 than non-responders. An increase in IL-8 during the 6 weeks of KJD was associated with significantly greater improvement in KOOS4 over 12 months. CONCLUSION: Detectable, significant molecular changes are observed in SF following KJD, that are remarkably consistent between individuals. Preliminary findings appear to suggest that increases in some molecules are associated with clinically meaningful responses. Joint distraction may provide a potential opportunity in the future to define regenerative biomarker(s) and identify pathways that drive intrinsic cartilage repair.

A short-term evaluation of a thermoplastic polyurethane implant for osteochondral defect repair in an equine model.

Cartilage repair remains a major challenge and treatment of (osteo)chondral defects generally results in poor quality fibrous repair tissue. Our approach aims to address some of the major biomechanical issues encountered in scaffold-based cartilage repair, such as insufficient stiffness of the scaffolds, step formation at the interface with the native tissue and inadequate integration with the original tissue. Two osteochondral defects were created on the medial femoral trochlear ridge in each stifle of six Shetland ponies. The defects were filled with a bi-layered implant consisting of a polyetherketoneketone (PEKK) bone anchor and a polyurethane elastomer. The defects in the contralateral joint served as unfilled controls. After 12 weeks, the ponies were euthanased and tissues were evaluated macroscopically and using micro-computed tomography, histology and immunohistochemistry. Post-operative recovery was good in all ponies and minimal lameness was observed. After 12 weeks, the proximally located plug was partially covered (mean±standard deviation [SD] percentage surface area covered 72.5±19.7%) and the distal plug was nearly completely covered (mean±SD percentage surface area covered 98.5±6.1%) with stiff and smooth repair tissue. Histology and immunohistochemistry confirmed that the repair tissue was well connected to the native cartilage but contained negligible amounts of collagen type II and glycosaminoglycans (GAGs). The repair tissue was stiff and fibrous in nature and presented a nearly flush surface with the surrounding native cartilage distally. This approach therefore resolves a number of issues related to scaffold-based cartilage repair and compares favourably with results of several other studies in large animal models. However, long-term follow-up is needed to evaluate the true potential of this type of implant.

Canine IL4-10 fusion protein provides disease modifying activity in a canine model of OA; an exploratory study.

OBJECTIVE: An ideal disease modifying osteoarthritis drug (DMOAD) has chondroprotective, anti-inflammatory, and analgesic effects. This study describes the production and characterization of a canine IL4-10 fusion protein (IL4-10 FP) and evaluates its in vivo DMOAD activity in a canine model of osteoarthritis (OA). DESIGN: The canine Groove model was used as an in vivo model of degenerative knee OA. Six weeks after OA induction dogs were intra-articularly injected weekly, for ten weeks, with either IL4-10 FP or phosphate buffered saline (PBS). In addition to the use of human IL4-10 FP, canine IL4-10 FP was developed and characterized in vitro, and tested in vivo. Force plate analysis (FPA) was performed to analyze joint loading as a proxy measure for pain. After ten weeks dogs were euthanized and cartilage and synovial tissue samples were analyzed by histochemistry (OARSI scores) and biochemistry (cartilage proteoglycan turnover). RESULTS: Repetitive intra-articular injections with human IL4-10 FP led to antibody formation, that blocked its functional activity. Therefore, a canine IL4-10 FP was developed, which completely inhibited LPS-induced TNFα production by canine blood cells, and increased proteoglycan synthesis of canine cartilage in vitro (p = 0.043). In vivo, canine IL4-10 FP restored the, by OA impaired, joint loading (p = 0.002) and increased cartilage proteoglycan content (p = 0.029). CONCLUSIONS: This first study on the potential DMOAD activity upon prolonged repeated treatment with IL4-10 FP demonstrates that a species-specific variant has anti-inflammatory and chondroprotective effects in vitro and chondroprotective and analgesic effects in vivo. These data warrant further research on the DMOAD potential of the IL4-10 FP.

Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet.

OBJECTIVE: C-reactive protein (CRP) levels can be elevated in osteoarthritis (OA) patients. In addition to indicating systemic inflammation, it is suggested that CRP itself can play a role in OA development. Obesity and metabolic syndrome are important risk factors for OA and also induce elevated CRP levels. Here we evaluated in a human CRP (hCRP)-transgenic mouse model whether CRP itself contributes to the development of 'metabolic' OA. DESIGN: Metabolic OA was induced by feeding 12-week-old hCRP-transgenic males (hCRP-tg, n = 30) and wild-type littermates (n = 15) a 45 kcal% high-fat diet (HFD) for 38 weeks. Cartilage degradation, osteophytes and synovitis were graded on Safranin O-stained histological knee joint sections. Inflammatory status was assessed by plasma lipid profiling, flow cytometric analyses of blood immune cell populations and immunohistochemical staining of synovial macrophage subsets. RESULTS: Male hCRP-tg mice showed aggravated OA severity and increased osteophytosis compared with their wild-type littermates. Both classical and non-classical monocytes showed increased expression of CCR2 and CD86 in hCRP-tg males. HFD-induced effects were evident for nearly all lipids measured and indicated a similar low-grade systemic inflammation for both genotypes. Synovitis scores and synovial macrophage subsets were similar in the two groups. CONCLUSIONS: Human CRP expression in a background of HFD-induced metabolic dysfunction resulted in the aggravation of OA through increased cartilage degeneration and osteophytosis. Increased recruitment of classical and non-classical monocytes might be a mechanism of action through which CRP is involved in aggravating this process. These findings suggest interventions selectively directed against CRP activity could ameliorate metabolic OA development.

Initial tissue repair predicts long-term clinical success of knee joint distraction as treatment for knee osteoarthritis.

OBJECTIVE: Knee joint distraction (KJD), a joint-preserving surgery for severe osteoarthritis (OA), provides clinical and structural improvement and postpones the need for total knee arthroplasty (TKA). This study evaluates 9-year treatment outcome and identifies characteristics predicting long-term treatment success. DESIGN: Patients with severe tibiofemoral OA (n = 20; age<60 years) indicated for TKA were treated with KJD. Questionnaires, radiographs, and magnetic resonance imaging (MRI) were used for evaluation. Survival after treatment was analyzed, where 'failure' was defined by TKA over time. RESULTS: 9-year survival was 48%, and 72% for men (compared to 14% for women; P = 0.035) and 73% for those with a first-year minimum joint space width (JSW) increase of >0.5 mm (compared to 0% for <0.05 mm; P = 0.002). Survivors still reported clinical improvement compared to baseline (ΔWOMAC +29.9 points (95%CI 16.9-42.9; P = 0.001), ΔVAS -46.8 mm (-31.6-61.9; P < 0.001)). Surprisingly, patients getting TKA years after KJD still reported clinical improvement although less pronounced (ΔWOMAC +20.5 points (-1.8-42.8; P = 0.067), ΔVAS -25.4 mm (-3.2-47.7; P = 0.030)). Survivors showed long-lasting minimum JSW increase (baseline 0.3 mm (IQR 1.9), follow-up 1.3 mm (2.5); P = 0.017) while 'failures' did not (baseline 0.4 mm (1.8), follow-up 0.2 mm (1.5); P = 0.161). First-year minimum JSW on radiographs and cartilage thickness increase on MRI predict 9-year survival (HR 0.05 and 0.12, respectively; both P < 0.026). Male gender was associated with survival (HR 0.24; P = 0.050). CONCLUSIONS: KJD shows long-lasting clinical and structural improvement. In addition to a greater survival rate for males (>two out of three), the initial cartilage repair activity appears to be important for long-term clinical success.

IL4-10 fusion protein has chondroprotective, anti-inflammatory and potentially analgesic effects in the treatment of osteoarthritis.

OBJECTIVE: Effective disease-modifying drugs for osteoarthritis (DMOAD) should preferably have chondroprotective, anti-inflammatory, and analgesic activity combined in a single molecule. We developed a fusion protein of IL4 and IL10 (IL4-10 FP), in which the biological activity of both cytokines is preserved. The present study evaluates the chondroprotective, anti-inflammatory, and analgesic activity of IL4-10 FP in in vitro and in vivo models of osteoarthritis. METHODS: Human osteoarthritic cartilage tissue and synovial tissue were cultured with IL4-10 FP. Cartilage proteoglycan turnover and release of pro-inflammatory, catabolic, and pain mediators by cartilage and synovial tissue were measured. The analgesic effect of intra-articularly injected IL4-10 FP was evaluated in a canine model of osteoarthritis by force-plate analysis. RESULTS: IL4-10 FP increased synthesis (P = 0.018) and decreased release (P = 0.018) of proteoglycans by osteoarthritic cartilage. Release of pro-inflammatory IL6 and IL8 by cartilage and synovial tissue was reduced in the presence of IL4-10 FP (all P < 0.05). The release of MMP3 by osteoarthritic cartilage and synovial tissue was decreased (P = 0.018 and 0.028) whereas TIMP1 production was not significantly changed. Furthermore, IL4-10 FP protected cartilage against destructive properties of synovial tissue mediators shown by the increased cartilage proteoglycan synthesis (P = 0.0235) and reduced proteoglycan release (P = 0.0163). Finally, intra-articular injection of IL4-10 FP improved the deficient joint loading in dogs with experimentally induced osteoarthritis. CONCLUSION: The results of current preliminary study suggest that IL4-10 FP has DMOAD potentials since it shows chondroprotective and anti-inflammatory effects in vitro, as well as potentially analgesic effect in a canine in vivo model of osteoarthritis.

Local and systemic inflammatory lipid profiling in a rat model of osteoarthritis with metabolic dysregulation.

OBJECTIVE: Bioactive oxidised lipids (oxylipins) are important signalling mediators, capable of modulating the inflammatory state of the joint and anticipated to be of importance in joint homeostasis and status of osteoarthritis. The aim of this study was to quantify oxylipin levels in plasma and synovial fluid from rats with experimentally induced osteoarthritis to investigate the potential role of oxylipins as a marker in the disease process of early osteoarthritis. DESIGN: Forty rats were randomly allocated to a standard or high-fat diet group. After 12 weeks, local cartilage damage was induced in one knee joint in 14 rats of each diet group. The remaining 6 rats per group served as controls. At week 24, samples were collected. Oxylipin levels were quantified by liquid chromatography-mass spectrometry. RESULTS: Overall, 31 lipid-derived inflammatory mediators were detected in fasted plasma and synovial fluid. Principal component analysis identified four distinct clusters associated with histopathological changes. Diet induced differences were evident for 13 individual plasma oxylipins, as well as 5,6-EET in synovial fluid. Surgical-model induced differences were evident for three oxylipins in synovial fluid (15-HETE, 8,9-DHET and 17R-ResolvinD1) with a different response in lipid concentrations for synovial fluid and plasma. CONCLUSIONS: We demonstrate the quantification of oxidised lipids in rat plasma and synovial fluid in a model of early experimental osteoarthritis. Oxylipins in the synovial fluid that were altered as consequence of the surgically induced osteoarthritis were not represented in the plasma. Our findings suggest differential roles of the oxylipins in the local versus peripheral compartment.

Variable cartilage degradation in mice with diet-induced metabolic dysfunction: food for thought.

OBJECTIVE: Human cohort studies have demonstrated a role for systemic metabolic dysfunction in osteoarthritis (OA) pathogenesis in obese patients. To explore the mechanisms underlying this metabolic phenotype of OA, we examined cartilage degradation in the knees of mice from different genetic backgrounds in which a metabolic phenotype was established by various dietary approaches. DESIGN: Wild-type C57BL/6J mice and genetically modified mice (hCRP, LDLr-/-. Leiden and ApoE*3Leiden.CETP mice) based on C57BL/6J background were used to investigate the contribution of inflammation and altered lipoprotein handling on diet-induced cartilage degradation. High-caloric diets of different macronutrient composition (i.e., high-carbohydrate or high-fat) were given in regimens of varying duration to induce a metabolic phenotype with aggravated cartilage degradation relative to controls. RESULTS: Metabolic phenotypes were confirmed in all studies as mice developed obesity, hypercholesteremia, glucose intolerance and/or insulin resistance. Aggravated cartilage degradation was only observed in two out of the twelve experimental setups, specifically in long-term studies in male hCRP and female ApoE*3Leiden.CETP mice. C57BL/6J and LDLr-/-. Leiden mice did not develop HFD-induced OA under the conditions studied. Osteophyte formation and synovitis scores showed variable results between studies, but also between strains and gender. CONCLUSIONS: Long-term feeding of high-caloric diets consistently induced a metabolic phenotype in various C57BL/6J (-based) mouse strains. In contrast, the induction of articular cartilage degradation proved variable, which suggests that an additional trigger might be necessary to accelerate diet-induced OA progression. Gender and genetic modifications that result in a humanized pro-inflammatory state (human CRP) or lipoprotein metabolism (human-E3L.CETP) were identified as important contributing factors.

Technical feasibility of personalized articulating knee joint distraction for treatment of tibiofemoral osteoarthritis.

BACKGROUND: Knee osteoarthritis is a highly prevalent degenerative joint disorder characterized by joint tissue damage and pain. Knee joint distraction has been introduced as a joint preserving surgical procedure to postpone knee arthroplasty. An often used standard externally fixation device for distraction poses a burden to patients due to the absence of joint flexion during the 6weeks treatment. Therefore, a personalized articulating distraction device was developed. The aim of this study was to test technical feasibility of this device. METHODS: Based on an often applied rigid device, using equal bone pin positions and connectors, a hinge mechanism was developed consisting of a cam-following system for reproducing the complex joint-specific knee kinematics. In support, a device was developed for capturing the joint-specific sagittal plane articulation. The obtained kinematic data were translated into joint-specific cam shapes that were installed bilaterally in the hinge mechanism of the distraction device, as such providing personalized knee motion. Distraction of 5mm was performed within a range of motion of 30deg. joint flexion. Pre-clinical evaluation of the working principle was performed on human cadaveric legs and system stiffness characteristics were biomechanically evaluated. FINDINGS: The desired range of motion was obtained and distraction was maintained under physiologically representative loading. Moreover, the joint-specific approach demonstrated tolerance of deviations from anatomical and alignment origin during initial placement of the developed distraction device. INTERPRETATION: Articulation during knee distraction is considered technically feasible and has potential to decrease burden and improve acceptance of distraction therapy. Testing of clinical feasibility is warranted.