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"Persistent organic pollutants (POPs)" have a plethora of deleterious effects on humans and the environment due to their bioaccumulative, persistent, and mimicking properties. Individually, each of these chemicals has been tested and its effects measured, however they are rather found as parts of complex mixtures of which we do not fully grasp the extent of their potential consequences. Here we studied the effects of realistic, environmentally relevant mixtures of 29 POPs on cartilage and bone development using zebrafish as a model species. We observed developmental issues in cartilage, in the form of diverse malformations such as micrognathia, reduced size of the Meckel's and other structures. Also, mineralized bone formation was disrupted, hence impacting the overall development of the larvae at later life stages. Assessment of the transcriptome revealed disruption of nuclear receptor pathways, such as androgen, vitamin D, and retinoic acid, that may explain the mechanisms of action of the compounds within the tested mixtures. In addition, clustering of the compounds using their chemical signatures revealed structural similarities with the model chemicals vitamin D and retinoic acid that can explain the effects and/or enhancing the phenotypes we witnessed. Further mechanistic studies will be required to fully understand this kind of molecular interactions and their repercussions in organisms. Our results contribute to the already existing catalogue of deleterious effects caused by exposure to POPs and help to understand the potential consequences in at risk populations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Guerrero-Limón et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To assess intraindividual biological variability of serum cartilage specific biomarker Coll2-1 and define the best standardized conditions for blood sampling., Design: Blood samples were taken from 116 subjects with knee osteoarthritis (OA) at a single time point (PRODIGE study) and from 15 healthy subjects under various conditions, including fasting condition, sampling time and season, blood treatment, and type of blood collection tube (COVAR study). Type II collagen-specific biomarker Coll2-1 was directly measured in serum using an immunoassay., Results: There was no significant difference on Coll2-1 values between samples collected at any of the 5 sampling times or at any of the sampling days measured. None of the sampling parameters tested had a significant impact on Coll2-1 value (clotting time, clotting temperature and temperature of blood centrifugation, type of tube). On the contrary, differences were found in between subjects and between subjects with knee OA and healthy subjects., Conclusion: Coll2-1 measurement is not affected by sampling specific conditions, circadian rhythm or seasons but was found elevated in subject with knee OA indicating that Coll2-1 serum variation is not linked to the study environment, but to cartilage degradation in OA. Coll2-1 assay is sufficiently robust for use in OA clinical trials.

Objective: The aim of this study was to evaluate the effects of a lyophilized inactivated culture (LIC) from Bifidobacterium longum CBi0703 in a spontaneous model of osteoarthritis (OA) in Dunkin Hartley guinea pigs. Histology of cartilage and synovial membrane was the primary outcome. Biomarkers were also considered to evaluate the treatment efficacy., Design: LIC (1 µg/kg) with or without vitamin C (1 mg/kg) were tested in Dunkin Hartley guinea pigs spontaneously developing OA and compared with control (sterile water; CTL). Treatment was initiated orally in 16-week-old animals over a period of 12 weeks. Histological lesions of articular cartilage and synovial membrane were scored according to the OARSI (Osteoarthritis Research Society International) recommendations. Four biomarkers (Coll2-1, PIINAP, Fib3-2, and osteocalcin) were measured in animal sera., Results: The global OARSI score increased with time in all group but no significant difference between groups was observed. When score items were analyzed individually, a significant lower score of cartilage structure was observed in the LIC + vitamin C group compared with CTL ( P < 0.0001). Synovial membrane showed a mild inflammatory reaction that was not affected by the treatment. LIC significantly decreased serum levels of Coll2-1 ( P = 0.0004 vs. CTL), a marker of type II collagen degradation and LIC + vitamin C significantly increased PIINAP ( P = 0.0003), a marker of type II collagen synthesis. The ratio Coll2-1/PIINAP was significantly decreased in both LIC groups ( P < 0.001)., Conclusion: Lyophilized inactivated culture of B. longum CBi0703 administrated orally over a period of 12 weeks decreased cartilage structure lesions and decreased type II collagen degradation suggesting a potential prophylactic effect on OA development.

Objective: Syndecan-4 plays a critical role in cartilage degradation during osteoarthritis (OA). The aim of this study was to investigate the expression and localization of syndecan-4 in different OA joint tissues., Design: Syndecan-4 mRNA levels were quantified by reverse transcription-polymerase chain reaction in human OA primary cells. Syndecan-4 was localized by immunohistochemistry in knee, hip, or shoulder OA bone/cartilage biopsies. Syndecan-4 was quantified by immunoassay in chondrocytes culture supernatant and cell fraction., Results: Using immunochemistry, syndecan-4 was observed in chondrocytes clusters in the superficial zone of OA knee, but not in OA hip or shoulder cartilage. No significant difference was detected in syndecan-4 expression level in sclerotic compared with nonsclerotic osteoblasts or in inflamed synoviocytes compared to normal/reactive ones. Differentiated hypertrophic chondrocytes from knee, but not from hip cartilage, expressed more syndecan-4 than nonhypertrophic cells. Using an immunoassay for the extracellular domain of syndecan-4, we found 68% of the syndecan-4 in the culture supernatant of OA chondrocytes culture, suggesting that a large majority of the syndecan-4 is shed and released in the extracellular medium. The shedding rate was not affected by hypertrophic differentiation state of the chondrocytes or their joint origin., Conclusions: Even if chondrocytes clusters are seen in OA knee, hip and shoulder cartilage and hypertrophic differentiation appears in knee and hip OA articular chondrocytes, syndecan-4 synthesis only increased in knee. These findings suggest the presence of biochemical difference between articular cartilage according to their location and that syndecan-4 could be a biochemical marker specific for knee OA.

Objective: To assess the cross-sectional association between serum levels of Coll2-1 and Coll2-1NO2, two cartilage degradation biomarkers; the burden of magnetic resonance imaging (MRI) features and clinical outcomes; and to evaluate the predictive value of these biomarkers on progression., Design: A total of 121 subjects with knee osteoarthritis (OA) were followed during 1 year with pain, function, and MRI assessment (PRODIGE study). Type II collagen-specific biomarker Coll2-1 and its nitrated form Coll2-1NO2 were directly measured in serum using immunoassays at baseline and after 3-, 6-, and 12-month follow-up., Results: Serum Coll2-1 and Coll2-1NO2 were correlated with several baseline knee features quantified with Whole-Organ Magnetic Resonance Imaging Score (WORMS). Coll2-1 was significantly correlated with periarticular cysts/bursitis (ρ = 0.29, P < 0.01), subarticular bone attrition (ρ = 0.25, P = 0.01), subarticular cysts (ρ = 0.24, P = 0.02), and articular cartilage integrity (ρ = 0.23, P = 0.03) WORMS subscores for the whole joint as well as with the medial femorotibial joint sum score (ρ = 0.26, P = 0.01) and medial femorotibial joint cartilage (ρ = 0.23, P = 0.02). Coll2-1NO2 correlated with WORMS total score (ρ = 0.23, P = 0.02), WORMS scores in the patellofemoral (ρ = 0.23, P = 0.02) and medial femorotibial compartments (ρ = 0.21, P = 0.03), with osteophytes scores (ρ = 0.27, P < 0.01), subarticular cysts (ρ = 0.24, P = 0.019), and intraarticular loose bodies (ρ = 0.27, P = 0.007). Baseline Coll2-1NO2 was higher in subjects with a pain worsening (426.4 pg/mL [278.04-566.95]) as compared to non-progressors (306.84 pg/mL [200.37-427.84]) over 1 year (AUC = 0.655, P = 0.015)., Conclusion: Serum cartilage biomarkers Coll2-1 and Coll2-1NO2 are associated with several knee OA features quantified with WORMS. Our study also shows that the baseline value of Coll2-1NO2 is positively associated with pain worsening.

Context: Men with congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS) have both low circulating testosterone and estradiol levels. Whether bone structure is affected remains unknown., Objective: To characterize bone geometry, volumetric density and microarchitecture in CHH/KS., Methods: This cross-sectional study, conducted at a single French tertiary academic medical center, included 51 genotyped CHH/KS patients and 40 healthy volunteers. Among CHH/KS men, 98% had received testosterone and/or combined gonadotropins. High-resolution peripheral quantitative computed tomography (HR-pQCT), dual-energy x-ray absorptiometry (DXA), and measurement of serum bone markers were used to determine volumetric bone mineral density (vBMD) and cortical and trabecular microarchitecture., Results: CHH and controls did not differ for age, body mass index, and levels of vitamin D and PTH. Despite long-term hormonal treatment (10.8 ± 6.8 years), DXA showed lower areal bone mineral density (aBMD) in CHH/KS at lumbar spine, total hip, femoral neck, and distal radius. Consistent with persistently higher serum bone markers, HR-pQCT revealed lower cortical and trabecular vBMD as well as cortical thickness at the tibia and the radius. CHH/KS men had altered trabecular microarchitecture with a predominant decrease of trabecular thickness. Moreover, CHH/KS men exhibited lower cortical bone area, whereas total and trabecular areas were higher only at the tibia. Earlier treatment onset (before age 19 years) conferred a significant advantage for trabecular bone volume/tissue volume and trabecular vBMD at the tibia., Conclusion: Both vBMD and bone microarchitecture remain impaired in CHH/KS men despite long-term hormonal treatment. Treatment initiation during adolescence is associated with enhanced trabecular outcomes, highlighting the importance of early diagnosis., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Viscosupplementation (VS) is a symptomatic treatment for knee and other joint osteoarthritis (OA). Despite a long history of use, conflicting opinions remain on the best clinical indications and the most appropriate patients to be treated with intra-articular hyaluronic acid (IA-HA), the optimal dosing regimen and the modalities of retreatment. A multidisciplinary committee of European experts on OA (EUROVISCO) was constituted to formulate recommendations, aimed at helping physicians in the decision-making and the optimal achievement of VS. Before each session members were tasked to collate an exhaustive literature review. Level of evidence and strength of recommendation were based on the level of agreement for each item according to the Delphi method. In 2015, a consensus position was proposed for 24 statements. Among those that obtained a consensual agreement, the working group stressed that VS is effective in mild/moderate knee OA but is not an alternative to surgery in advanced OA, and that dosing regimen must be supported by controlled trials. In 2018, two decision algorithms for the retreatment with IA-HA in knee OA were published. Among the key recommendations, the experts recommended to re-treat every year patients with high risk of OA progression, even if not symptomatic. In 2020, EUROVISCO published two sets of recommendations for the design of clinical trials on the disease-modifying effect of VS and for optimizing the results of VS. The working group underlined that an accurate analysis of radiological features and symptoms and a careful clinical examination may improve the chances of success of VS, as well as good technique of injection and the use of imaging guidance. Based on the exhaustive analysis of the literature and their own clinical experience, the EUROVISCO experts offer a wide range of recommendations intended to help practitioners, particularly in certain cases where the specific characteristics of the patients make the therapeutic decision difficult., Competing Interests: Conflict of interest statement: Yves Henrotin: Received honorarium from Menarini, Flexion therapeutics, IBSA, BioIberica, Expansciences, Royal canin, MagPharm, Pfizer, Fidia and LABRHA and Tilman SA, for consultant services. Founder and shareholder of KIOmed pharma. Founder and shareholder of Artialis SA. Raghu Raman: Received honorarium from Sanofi and LABRHA for consultant services. Pascal Richette: Received fees from BioIbérica, Fidia, IBSA, Expanscience, Genévrier, Sanofi, Rottapharm, Servier, Flexion Therapics and Ménarini. Hervé Bard: Received speaker and expert fees from Sanofi, Pfizer, Labrha, Expanscience, TRB Chemedica Jörg Jerosch: Received honorarium from Sanofi for speaker services Thierry Conrozier: Received honorarium from Sanofi, MEDAC, Fidia and Labrha for expert and consultant services Xavier Chevalier: Received fees as a Genevrier Board member, Sanofi-Aventis expert, member of the IBSA foundation, speaker in IBSA meetings, Moebius and Flexion therapics consultant Alberto Migliore: Received consulting fees from Abbvie, BMS, MSD, Fidia, Sanofi, IBSA, Pfizer and Labrha, for national and international studies and courses. Jordy Monfort: Received consulting fees from Sanofi and Bioiberica Dominique Baron: Received speaker fees from LCA and Expansciences, (© The Author(s), 2021.)

The objective of this study was to evaluate the effects of oral fish cartilage hydrolysate (FCH) on symptoms and joint tissue structure in rat developing osteoarthritis induced surgically. Osteoarthritis was induced in the right knee of mature male Lewis rats ( n  = 12/group) by surgical transection of the anterior cruciate ligament (ACLT) combined with partial medial meniscectomy (pMMx). Two weeks after surgery, rats were treated orally with either control (sterile H 2 O) or FCH for four weeks. Pain and function were assessed by dynamic weight-bearing test (incapacitance test), electronic Von Frey (EVF; hindpaw allodynia threshold), and pressure algometer (knee allodynia threshold). Time and groups differences at each time point were evaluated using a mixed model. The histological features were evaluated eight weeks after surgery using OARSI score. Mann-Whitney test nonparametric test was applied to compare OARSI score. ACTL/pMMx surgery significantly reduced weight-bearing and increased allodynia and sensitivity thresholds of the operated paw/knee. Globally, FCH improved these parameters faster, but no significant difference between control and FCH groups was observed. Eight weeks after surgery, rats developed moderate OA lesions. Compared with control, FCH did not significantly modify OA lesion severity assessed using the OARSI score. In this mechanically induced OA model, 4 weeks of supplementation with FCH had no significant effect on cartilage lesion, but tends to accelerate pain relief and joint function recovery. This positive trend may have opened the way for further investigation of FCH as potential treatment of joint discomfort associated with OA., (© 2021 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Objective: Previous work has established that the deacetylase sirtuin-1 (SIRT1) is cleaved by cathepsin B in chondrocytes subjected to proinflammatory stress, yielding a stable but inactive N-terminal (NT) polypeptide (75SIRT1) and a C-terminal (CT) fragment. The present work examined if chondrocyte-derived NT-SIRT1 is detected in serum and may serve as an investigative and exploratory biomarker of osteoarthritis (OA)., Methods: We developed a novel ELISA assay to measure the ratio of NT to CT of SIRT1 in the serum of human individuals and mice subjected to post-traumatic OA (PTOA) or age-dependent OA (ADOA). We additionally monitored NT/CT SIRT1 in mice subject to ADOA/PTOA followed by senolytic clearance. Human chondrosenescent and non-senescent chondrocytes were exposed to cytokines and analysed for apoptosis and NT/CT SIRT1 ratio in conditioned medium., Results: Wild-type mice with PTOA or ADOA of moderate severity exhibited increased serum NT/CT SIRT1 ratio. In contrast, this ratio remained low in cartilage-specific Sirt1 knockout mice despite similar or increased PTOA and ADOA severity. Local clearance of senescent chondrocytes from old mice with post-traumatic injury resulted in a lower NT/CT ratio and reduced OA severity. While primary chondrocytes exhibited NT/CT ratio increased in conditioned media after prolonged cytokine stimulation, this increase was not evident in cytokine-stimulated chondrosenescent cells. Finally, serum NT/CT ratio was elevated in humans with early-stage OA., Conclusions: Increased levels of serum NT/CT SIRT1 ratio correlated with moderate OA in both mice and humans, stemming at least in part from non-senescent chondrocyte apoptosis, possibly a result of prolonged inflammatory insult., Competing Interests: Competing interests: JHE disclosed that she is an equity holder and receives patent royalties from UNITY Biotechnology; serves as a scientific advisory board member at Camden Nexus Fund, Acell and Histogenics. JHE is a consultant at Vericel and a founder and equity holder of Aegeria Soft Tissue. AM disclosed that he has consulted for Unity Biotechnology, Kolon TissueGene and Gordian Biotechnology. Note COI forms cannot be merged, but are available with corresponding author and can be sent via email to the editorial staff upon request., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Objective: REG-O3 is a 24-aminoacid chimeric peptide combining a sequence derived from growth hormone (GH) and an analog of somatostatin (SST), molecules displaying cartilage repair and anti-inflammatory properties, respectively. This study aimed to investigate the disease-modifying osteoarthritis drug (DMOAD) potential of REG-O3 by analyzing its effect on pain, joint function and structure, upon injection into osteoarthritic rat knee joint., Design: Osteoarthritis was induced in the right knee of mature male Lewis rats (n = 12/group) by surgical transection of the anterior cruciate ligament (ACLT) combined with partial medial meniscectomy (pMMx). Treatments were administered intra-articularly from fourteen days after surgery through three consecutive injections one week apart. The effect of REG-O3, solubilized in a liposomal solution and injected at either 5, 25 or 50 μg/50 μL, was compared to liposomal (LIP), dexamethasone and hyaluronic acid (HA) solutions. The study endpoints were the pain/function measured once a week throughout the entire study, and the joint structure evaluated eight weeks after surgery using OARSI score., Results: ACLT/pMMx surgery induced a significant modification of weight bearing in all groups. When compared to liposomal solution, REG-O3 was able to significantly improve weight bearing as efficiently as dexamethasone and HA. REG-O3 (25 μg) was also able to significantly decrease OARSI histological global score as well as degeneration of both cartilage and matrix while the other treatments did not., Conclusion: This study provides evidence of a remarkable protecting effect of REG-O3 on pain/knee joint function and cartilage/matrix degradation in ACLT/pMMx model of rat osteoarthritis. REG-O3 thus displays an interesting profile as a DMOAD., Competing Interests: SP and TN have declared that no competing interest exist. SE and YH received consultancy fees from REGULAXIS RM, RP and CV are employees and stockholders at REGULAXIS. CC is stockholder and CEO of REGULAXIS.

The extracellular matrix can trigger cellular responses through its composition and structure. Major extracellular matrix components are the proteoglycans, which are composed of a core protein associated with glycosaminoglycans, among which the small leucine-rich proteoglycans (SLRPs) are the largest family. This review highlights how the codon usage pattern can be used to modulate cellular response and discusses the biological impact of post-translational events on SLRPs, including the substitution of glycosaminoglycan moieties, glycosylation, and degradation. These modifications are listed, and their impacts on the biological activities and structural properties of SLRPs are described. We narrowed the topic to skeletal tissues undergoing dynamic remodeling., Competing Interests: The authors declare no conflict of interest.

Background: Proteomic studies of the secretome of skeletal muscle cells can help us understand the processes that govern the synthesis, systemic interactions and organization of skeletal muscle and identify proteins that are involved in muscular adaptations to exercise, ageing and degeneration. In this systematic review, we aimed to summarize recent mass-spectrometry based proteomics discoveries on the secretome of skeletal muscle cells in response to disease, exercise or metabolic stress., Methods: A literature search was performed in the Medline/Ovid and Scopus electronic bibliographic databases. Only papers reporting the analysis of the secretome by mass spectrometry were included., Results: A total of 19 papers met the inclusion criteria for this systematic review. These papers included comparative analysis of differentially expressed proteins between healthy and unhealthy muscle cells and comparison of the secretome of skeletal muscle cells during myogenesis and after insulin stimulation or exercising. The proteins were separated into several categories and their differential secretion was compared. In total, 654 proteins were listed as being present in the secretome of muscle cells. Among them, 30 proteins were differentially regulated by physical exercise, 130 during myogenesis, 114 by dystrophin deficiency, 26 by muscle atrophy, 27 by insulin stimulation and finally 176 proteins secreted by insulin-resistant muscle cells., Conclusions: This systematic review of the secretome of skeletal muscle cell in health and disease provides a comprehensive overview of the most regulated proteins in pathological or physiological conditions. These proteins might be therapeutic targets or biochemical markers of muscle diseases., Competing Interests: Yves Henrotin has received consulting fees from Artialis SA, Tilman, Laboratoires Expanscience, Nestle., (© 2020 The Authors.)

Objectives: Hyaluronic acid viscosupplementation is a commonly used intra-articular treatment for osteoarthritis (OA). Some recent preclinical and clinical trials have demonstrated a potential for its disease-modifying effects. The goal of this expert opinion, consensus-driven exercise is to provide guidelines for the design and conduct of clinical trials assessing the disease-modifying effect of viscosupplementation in the knee., Methods: The EUROVISCO group constitutes 10 members who had expertise in clinical research methodology in the field of OA and viscosupplementation. They initially drafted issues through an iterative process and had to vote on their degree of agreement on these recommendations. The scores were pooled to generate a median agreement score for each recommendation., Results: The document includes 31 recommendations regarding study population, imaging, clinical and biological assessment of disease-modifying effects of viscosupplementation. Agreements were reached on some recommendations. In particular, the experts reached unanimous agreement on double-blind study design, imaging primary outcomes, time interval between 2 radiographs, x-ray procedure standardization, and the combined use of imaging and biological markers. The group did not recommend the use of ultrasonography, computed tomography (CT) scan and CT arthrography as a tool for OA diagnosis or to assess progression over time., Conclusion: In summary, the working group identified 31 recommendations that represent the current best practices regarding clinical trials that target the assessment of viscosupplementation disease-modifying effects in patients with knee OA. These recommendations integrate new imaging technologies and soluble biomarkers.

Objectives: The 3 aims of the work were to identify population subgroups that can benefit the most from viscosupplementation (VS), to provide recommendations on injection techniques, and to discuss VS appropriateness in clinical situations that are commonplace in daily practice., Methods: The task force members voted on their degree of agreement on 27 statements, 36 recommendations, and 22 clinical scenarios using a 9-point scale. The strength of agreement/appropriateness/recommendation (SOA/SOR) was classified as strong if the median agreement score was ≥8. The level of consensus (LOC) was also obtained., Results: Among the assumed predictors for VS failure, obesity, radiographic severity, large synovial fluid effusion, severe patellofemoral involvement, major malalignment, and gross joint instability received a large majority of agreements. The lateral mid-patellar approach was recommended for knee injection. Imaging guidance was unanimously recommended for hip and ankle. Agreement was achieved to strictly respect the dosing regimen proven by controlled trials. There was agreement for treating with VS patients with mild to moderate knee and hip OA, with normal weight or moderate overweight, insufficiently improved by first-line therapies, or who do not wish get oral treatment or who have contraindications to pain killers. The group considered the patient's wishes as a key element in therapeutic decision making., Conclusion: Based on literature data and clinical experience, the EUROVISCO group proposed a set of recommendations for optimizing the results of VS, aimed to help practitioners, especially in some cases in which the patients' specificities make the therapeutic decision difficult.

Objective: We evaluated the ability of Coll2-1, a type II collagen peptide, to activate pro-inflammatory pathways in synovial cells and to induce arthritis in Lewis rats., Method: Human synoviocytes and chondrocytes from knee OA patients were cultured for 24 h with/without Coll2-1 and/or purified immunoglobulin G (AS0619) binding specifically this peptide, and/or CLI-095, a TLR-4 signaling inhibitor and/or apocynin and diphenyleneiodonium, Reactive oxygen species (ROS) production inhibitors. The Interleukin (IL)-8 and Vascular Endothelium Growth Factor (VEGF) expression, the IL-8 production, the IκB-α and p65 phosphorylation and ROS were evaluated. Coll2-1 peptide, bovine type II collagen (CIA), streptococcal cell wall (SCW) or saline solution were injected into Lewis rats. The Coll2-1 peptide was injected subcutaneously (SC; 20-200μg/100μl/animal) or intra-articularly (IA; 0.5-5μg/50μl/animal) and compared to CIA injected in SC (200μg/100μl/animal) and SCW in IA (5μg/50μl/animal). The animals were injected on day 0 and monitored for 28 days. Histological lesions assessment was performed using an arthritis score., Results: Coll2-1 peptide significantly increased IL-8 gene expression and production by synoviocytes. AS0619 and CLI-095 significantly decreased IL-8 expression. Coll2-1 induced p65 and IκBα phosphorylation and oxidative stress inhibitors decreased it. In human chondrocytes culture, Coll2-1 significantly increased MMP-3 and VEGF gene expression. In Lewis rats, CIA, SCW or Coll2-1 injection triggered arthritis. Like CIA or SCW, Coll2-1 induced synovitis, loss of cartilage proteoglycans, cartilage structure lesion and subchondral bone remodeling., Conclusions: Coll2-1 activates synoviocytes to produce IL-8 and induces arthritis in rat. These findings suggest that neutralizing Coll2-1 could be a therapeutic approach of arthritis., (Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Introduction : Osteoarthritis (OA) is the most common form of arthritis. However, there are no structure or disease-modifying OA drugs (DMOADs). Introducing personalized healthcare to patients and health-care practitioners is a high priority for the management of arthritic and musculoskeletal diseases. However, there are no biomarker tools that can be used for patient stratification, disease management, and drug development. Biomarkers are capable of diagnosing and prognosing some arthritic and musculoskeletal diseases. Cartilage-based biomarkers have the potential to be used in this context to guide the precision treatment of OA. Areas covered : The aim of this review is to focus on the pre-clinical and clinical utility of the Coll2-1 and Coll2-1NO2 biomarkers as unique cartilage-based biomarkers that can guide the development of new treatments for OA. This expert report will begin with a background to collagens and their important biomechanical roles in the musculoskeletal system, but particularly cartilage, before exploring the data and scientific evidence to support the utility of Coll2-1 and Coll2-1NO2 as unique biomarkers. Expert opinion : This review summarises the authors' expert view on the pre-clinical and clinical utility of the Coll2-1 and Coll2-1NO2 biomarkers and their potential for use as drug development tools.

Objectives: Comparison of two doses of bio-optimized Curcuma longa extract (BCL) in the management of symptomatic knee osteoarthritis (OA)., Methods: A prospective, randomized, 3-month, double-blind, multicenter, three-group, placebo-controlled trial assessing Patient Global Assessment of Disease Activity (PGADA) and serum sColl2-1, a biomarker of cartilage degradation, as co-primary endpoints. Pain on visual analog scale (VAS), Knee injury and Osteoarthritis Outcome Score (KOOS), and paracetamol/non-steroidal anti-inflammatory drug (NSAID) consumption were used as secondary endpoints., Results: One hundred fifty patients with knee OA were followed for 90 days. Low and high doses of BCL showed a greater decrease of PGADA than placebo. Analysis of sColl2-1 showed in the placebo and BCL low-dose groups, but not in the BCL high-dose group, a transient but non-significant increase of sColl2-1 between T0 and T1. Thereafter, in all groups, sColl2-1 decreased between T1 and T3 (all p < 0.01), but no difference between the groups was found. Pain reduction at day 90 in the low- and high-dose BCL groups (- 29.5 mm and - 36.5 mm) was higher than that in the placebo (- 8 mm; p = 0.018). The global KOOS significantly decreased overtime, but changes were comparable across treatment arms. The ratio of patients with adverse events (AE) related to the product was similar in the placebo and treatment groups, but the number of AE linked to the product was higher in the high-dose BCL group compared to the placebo (p = 0.012)., Conclusions: BCL appeared safe and well-tolerated with no evidence of severe adverse effects. Efficacy analysis suggested positive trends for measurements of PGADA and serum levels of an OA biomarker and showed a rapid and significant decrease of pain in knee OA (Trial registration: ISRCTN, ISRCTN12345678. Registered 21 September 2016-retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02909621?term=osteoarthritis+curcumin&rank=5-Evaluation of FLEXOFYTOL® Versus PLACEBO (COPRA) NCT02909621).

We aimed to compare serum biomarkers of inflammation, redox status and cartilage degradation between chronic low back pain (cLBP) patients with and without Modic 1 changes. We used a convenience sample of patients recruited from a single center, case-control study, conducted in a tertiary care center. From December, 2014 to May, 2016, 2,292 patients were consecutively screened, 34 met inclusion criteria and were prospectively enrolled in the present study. Cases (n = 13) were defined as patients with Modic 1 changes detected on MRI and controls (n = 21) as cLBP patients without (Modic 0). To assess serum biomarkers of inflammation, redox status and cartilage degradation, fasting serum samples were collected in a standardized manner and analyzed by immunoassays and spectrophotometry. Mean (95% CI) age was 44.1 (40.0-48.1) years and mean LBP duration was 72.5 (53.0-91.9) months. Serum biomarkers of inflammation (IL-1β, IL-6, IL-8 and TNF-α), redox status (total thiols, advanced oxidation protein products and carbonyl groups) and cartilage degradation (Coll2-1 and Coll2-1NO 2 ) did not differ between cLBP patients with and without Modic 1 changes. In summary, we did not find any differences in serum biomarkers between cLBP patients with and without Modic 1 changes. Interpretation is limited by convenience sampling and small sample size.

Objective: Fibulin-3 is a glycoprotein highly expressed in osteoarthritic cartilage and inhibits angiogenesis and chondrocyte differentiation. Recent studies have indicated that fibulin-3 has potential value as a biomarker in osteoarthritis. The aim of the present study is to examine the role of 3 fibulin-3 peptides (Fib3-1, Fib3-2, and Fib3-3) and a type II collagen degradation product in a rat osteoarthritis model with systemic metabolic alterations combined with local cartilage damage., Design: Forty, 12-week-old male, Wistar rats were randomly divided over 2 groups: a standard or a high-fat diet inducing metabolic dysregulation. After 12 weeks, articular cartilage damage was induced on the femoral condyles (groove model), in 1 knee joint in 14 rats of each diet group. At endpoint, blood was collected and serum was isolated. Enzyme-linked immunosorbent assay on all selected fibulin-3 fragments was performed from serum samples in addition to immunohistochemical analysis for Fib3-3., Results: Serum concentrations of Fib3-3 were increased by 29.9%, when cartilage damage was induced in addition to a high-fat diet. Fib3-3 was also associated with an increased histological total joint degeneration ( r = 0.435) and cartilage degeneration ( r = 0.435). Immunostainings demonstrated increased Fib3-3 in the superficial cartilage of animals with high-fat diet and/or cartilage damage., Conclusions: In the rat groove model combined with high-fat diet-induced metabolic dysregulation an increased Fib3-3 concentration was observed systemically, which is associated with local joint degeneration. This suggests that systemic Fib3-3 concentrations can indicate the status of joint degeneration and function as a biomarker in osteoarthritis.

Background: The objective of this pilot study was to identify biological, clinical or structural biomarkers of an intra-articular hyaluronic acid injection efficacy (HYMOVIS®) for the design of a larger placebo-controlled clinical trial studying the disease-modifying activity of this treatment., Methods: Forty six patients with symptomatic knee Osteoarthritis (OA) were enrolled in this open-label, prospective, multicenter, pilot study. Patients received two treatment cycles of intra-articular injections (3 mL) of HYMOVIS® (8 mg/mL of hyaluronic acid hexadecylamide) at 6 months interval. Each treatment cycle involved two intra-articular injections 1 week apart. All patients had Magnetic Resonance Imaging (MRI) of the target knee at baseline and 1 year, and blood samples to assess joint biomarkers. The primary outcome was the change in type II collagen-specific biomarkers (Coll2-1, Coll2-1NO2 and CTX-II) after HYMOVIS® treatment versus baseline. Secondary endpoints included levels changes in aggrecan chondroitin sulfate 846 epitope (CS-846), Cartilage Oligomeric Matrix Protein (COMP), procollagen type II N-terminal propeptide (PIIANP), Matrix Metalloprotease (MMP)-3, Myeloperoxidase (MPO) and Interleukin (IL)-6 serum biomarkers, the ratio Coll2-1/PIIANP, CTX-II/PIIANP, variation of MRI cartilage volume, and Knee injury and Osteoarthritis Outcome Score (KOOS) index., Results: Coll2-1 serum levels significantly increased overtime while Coll2-1NO2 levels were only increased at D360. Serum PIIANP levels also progressively and significantly enhanced with time. In contrast, other serum biomarker levels including CTX-II, CS-846, COMP, MMP-3, MPO or IL-6 did not change significantly overtime. Interestingly, the ratios Coll2-1/PIIANP and CTX-II/PIIANP decreased, indicating a decrease of cartilage catabolism. Compared to baseline value, MRI cartilage volume and thickness increased in lateral femoral and lateral trochlea compartments and not in medial compartment. These results, in addition to an improvement of T2 mapping score suggest a positive structural effect of the product. Interestingly, WORMS effusion score, an indicator of synovitis, significantly decreased. Finally, global KOOS score and subscales significantly increased overtime while pain at rest, walking pain and patients or investigators global assessment of disease activity decreased. The safety profile was favorable with a low incidence of injection-site pain., Conclusion: HYMOVIS®, a well-tolerated intra-articular treatment, significantly enhanced type II collagen turnover as suggested by the increase in Coll2-1 and PIIANP levels and cartilage volume observed by MRI in lateral knee compartment. Importantly, this study provides critical information for the design of a larger phase III clinical trial investigating Disease Modifying effect of HYMOVIS®., Trial Registration: http://www.isrctn.com/ISRCTN12227846 11/02/2015.

A recent study reported the expression of receptor activator of nuclear factor-κB (RANK) in mesenchymal stem cells (MSCs) surface that negatively regulates osteogenesis of MSCs. Empirical evidence from the previous study confirmed the role of parathyroid hormone-related protein (PTHrP) in osteoblastogenesis. However, it is necessary to understand the paracrine role of PTHrP and RANKL for osteogenesis in order to explore the hidden secrets in bone biology. Considering the above concept, paracrine cues of soluble-receptor activator of nuclear factor-κB ligand (sRANKL) and PTHrP in osteogenic differentiation of MSCs were investigated. Our results confirmed that sRANKL increased the expression of surface-RANK in MSCs at the earlier stage of osteogenesis, which was downregulated later in differentiated MSCs. In contrast, RANKL expression was low at the earlier stage of MSCs proliferation and high at the differentiation stage of MSCs, which may play a fundamental role in osteoclast formation. sRANKL downregulated osteogenesis of MSCs by decreasing progressive ankylosis (ANK) protein expression while PTHrP upregulated the osteogenic exploitive effect of sRANKL. Interestingly, when they were co-cultured with MSCs, T-lymphocytes expressed high membrane-RANKL levels that contribute to osteogenesis inhibition during MSC differentiation. Thus, our results disclose that sRANKL treatment downregulates osteogenesis of MSCs by increasing RANK expression at the earlier stage of differentiation and by inhibiting ANK. Further, we demonstrated that PTHrP accelerated the downregulating osteogenic effect of sRANKL.

Recent studies have identified the regulatory mechanism of collagen in bone ossification and resorption. Due to its excellent bio-mimicry property, collagen is used for the treatment of several bone and joint disease such as arthritis, osteoporosis, and osteopenia. In bone, the biological action of collagen is highly influenced by the interactions of other bone materials such as glycosaminoglycan and minerals. In view of the above perceptions, collagen was crosslinked with chitosan, hydroxyapatite (H), and chondroitin sulfate (Cs), to produce a natural bone-like 3D structure and to evaluate its effect on bone homeostasis using bone marrow mesenchymal stem cells, osteoblast, and bone marrow macrophages. The XRD and micro-CT data confirmed the arrangement of H crystallites in the chitosan-collagen-H-Cs (CCHCs) three-dimensional (3D)-matrix and the three-dimensional structure of the matrix. The stimulatory osteoblastogenic and exploitive osteoclastogenic activity of 3D-matrices were identified using differentiated osteoblasts and osteoclasts, respectively. Besides, osteogenic progenitor's paracrine cues for osteoclastogenesis showed that the differentiated osteoblast secreted higher levels of RANKL to support osteoclastogenesis, and the effect was downregulated by the CCHCs 3D-matrix. From that, it was hypothesized that the morphology of the CCHCs 3D-matrix resembles trabecular bone, which enhances bone growth, limits bone resorption, and could be a novel biomaterial for bone tissue engineering., Competing Interests: The authors declare no conflict of interest.

Purpose of Review: This review focuses on the molecular taxonomy of osteoarthritis from the perspective of molecular biomarkers. We discuss how wet biochemical markers may be used to understand disease pathogenesis and progression and define molecular endotypes of osteoarthritis and how these correspond to clinical phenotypes., Recent Findings: Emerging evidence suggests that osteoarthritis is a heterogeneous and multifaceted disease with multiple causes, molecular endotypes and corresponding clinical phenotypes. Biomarkers may be employed as tools for patient stratification in clinical trials, enhanced disease management in the primary care centres of the future and for directing more rational and targeted osteoarthritis drug development. Proximal molecular biomarkers (e.g synovial fluid) are more likely to distinguish between molecular endotypes because there is less interference from systemic sources of biomarker noise, including comorbidities., Summary: In this review, we have focused on the molecular biomarkers of four distinct osteoarthritis subtypes including inflammatory, subchondral bone remodelling, metabolic syndrome and senescent age-related endotypes, which have corresponding phenotypes. Progress in the field of osteoarthritis endotype and phenotype research requires a better understanding of molecular biomarkers that may be used in conjunction with imaging, pain and functional assessments for the design of more effective, stratified and individualized osteoarthritis treatments.

Collagen from a marine resource is believed to have more potential activity in bone tissue engineering and their bioactivity depends on biochemical and structural properties. Considering the above concept, pepsin soluble collagen (PSC) and acid soluble collagen (ASC) from blue shark ( Prionace glauca ) skin were extracted and its biochemical and osteogenic properties were investigated. The hydroxyproline content was higher in PSC than ASC and the purified collagens contained three distinct bands α₁, α 2, and β dimer. The purity of collagen was confirmed by the RP-HPLC profile and the thermogravimetric data showed a two-step thermal degradation pattern. ASC had a sharp decline in viscosity at 20⁻30 °C. Scanning electron microscope (SEM) images revealed the fibrillar network structure of collagens. Proliferation rates of the differentiated mouse bone marrow-mesenchymal stem (dMBMS) and differentiated osteoblastic (dMC3T3E1) cells were increased in collagen treated groups rather than the controls and the effect was dose-dependent, which was further supported by higher osteogenic protein and mRNA expression in collagen treated bone cells. Among two collagens, PSC had significantly increased dMBMS cell proliferation and this was materialized through increasing RUNX2 and collagen-I expression in bone cells. Accordingly, the collagens from blue shark skin with excellent biochemical and osteogenic properties could be a suitable biomaterial for therapeutic application.

Background Viscosupplementation (VS) is a symptomatic treatment of knee osteoarthritis. Although systematic reviews of its repeat use showed favorable benefit/risk ratio, no study has focused on the indication of retreatment. Methods A task force was created to look at issues regarding retreatment with VS in knee osteoarthritis. An attempt was made to reach consensus on several issues: (1) to define treatment "success" and "failure," (2) to determine when to retreat patients successfully treated by a previous VS, (3) to determine how to retreat patients in whom VS failed, (4) to define what to do in case of adverse reaction following previous VS, and (5) to examine the interests of soluble biomarkers to manage retreatment. After debate and review of literature the working group voted on 88 issues. Two "decision trees" were built based on the results of the votes. Results In case of failure, the authors draw attention to the need of a rigorous clinical and radiological analysis, and consider evidence-based medicine. When VS was previously successful, retreatment can be considered after recurrence or increase in pain. However, in subjects with high risk of disease progression, in young patients, and in professional sportsmen, retreatment could be considered systematically, because of the probability of hyaluronic acid to slow osteoarthritis progression. Evidence on soluble biomarkers was not considered as enough strong to support their use as decision tools for patient retreatment. Conclusion The decision algorithms are intended to facilitate consideration of the therapeutic options, in patients with knee osteoarthritis previously treated with VS.

Background: Changes of serum concentrations of glycated, oxidized, and nitrated amino acids and hydroxyproline and anticyclic citrullinated peptide antibody status combined by machine learning techniques in algorithms have recently been found to provide improved diagnosis and typing of early-stage arthritis of the knee, including osteoarthritis (OA), in patients. The association of glycated, oxidized, and nitrated amino acids released from the joint with development and progression of knee OA is unknown. We studied this in an OA animal model as well as interleukin-1β-activated human chondrocytes in vitro and translated key findings to patients with OA., Methods: Sixty male 3-week-old Dunkin-Hartley guinea pigs were studied. Separate groups of 12 animals were killed at age 4, 12, 20, 28 and 36 weeks, and histological severity of knee OA was evaluated, and cartilage rheological properties were assessed. Human chondrocytes cultured in multilayers were treated for 10 days with interleukin-1β. Human patients with early and advanced OA and healthy controls were recruited, blood samples were collected, and serum or plasma was prepared. Serum, plasma, and culture medium were analyzed for glycated, oxidized, and nitrated amino acids., Results: Severity of OA increased progressively in guinea pigs with age. Glycated, oxidized, and nitrated amino acids were increased markedly at week 36, with glucosepane and dityrosine increasing progressively from weeks 20 and 28, respectively. Glucosepane correlated positively with OA histological severity (r = 0.58, p < 0.0001) and instantaneous modulus (r = 0.52-0.56; p < 0.0001), oxidation free adducts correlated positively with OA severity (p < 0.0009-0.0062), and hydroxyproline correlated positively with cartilage thickness (p < 0.0003-0.003). Interleukin-1β increased the release of glycated and nitrated amino acids from chondrocytes in vitro. In clinical translation, plasma glucosepane was increased 38% in early-stage OA (p < 0.05) and sixfold in patients with advanced OA (p < 0.001) compared with healthy controls., Conclusions: These studies further advance the prospective role of glycated, oxidized, and nitrated amino acids as serum biomarkers in diagnostic algorithms for early-stage detection of OA and other arthritic disease. Plasma glucosepane, reported here for the first time to our knowledge, may improve early-stage diagnosis and progression of clinical OA.

Homeostasis of osteoclast formation from bone marrow macrophages (BMM) is regulated by paracrine signals of the neighbourhood bone cells particularly mesenchymal stem cells (MSC), osteoblasts and osteocytes (OC). Besides paracrine cues, collagen and glycosaminoglycan are involved in controlling bone homeostasis. Towards this approach, different molecular weight collagens were reacted with MSC, OC and BMM to understand the bone homeostasis activity of collagen. The up-regulating effect of collagens on osteogenic cell growth was confirmed by the presence of mineralized nodules in the osteoblastogenic lineage cells and increased osteogenic stimulatory gene expression. The decreased BMM-derived TRAP+ osteoclasts number and osteoclastogenic regulatory gene expression of OC could demonstrate the exploitive osteoclastogenic activity of collagens. Osteoclastogenesis from BMM was triggered by paracrine cues of OC in some extend, but it was down-regulated by collagen. Overall, the effect of collagen on osteoclastogenesis and osteoblastogenesis may depend on the molecular weight of collagens, and collagen suppresses osteoclastogenesis, at least in part by downregulating the secretion of cytokines in OC.

Objective: Osteoarthritis (OA) is characterized by cartilage degradation but also by other joint tissues modifications like subchondral bone sclerosis. In this study, we used a proteomic approach to compare secretome of osteoblast isolated from sclerotic (SC) or non sclerotic (NSC) area of OA subchondral bone., Design: Secretome was analyzed using differential quantitative and relative label free analysis on nanoUPLC G2 HDMS system. mRNA of the more differentially secreted proteins were quantified by RT-PCR in cell culture from 5 other patients. Finally, osteomodulin and fibulin-3 sequences were quantified by western blot and immunoassays in serum and culture supernatants., Results: 175 proteins were identified in NSC osteoblast secretome. Data are available via ProteomeXchange with identifier PXD008494. Compared to NSC osteoblast secretome, 12 proteins were significantly less secreted (Osteomodulin, IGFBP5, VCAM-1, IGF2, 78 kDa glucose-regulated protein, versican, calumenin, IGFBP2, thrombospondin-4, periostin, reticulocalbin 1 and osteonectin), and 13 proteins were significantly more secreted by SC osteoblasts (CHI3L1, fibulin-3, SERPINE2, IGFBP6, SH3BGRL3, SERPINE1, reticulocalbin3, alpha-2-HS-glycoprotein, TIMP-2, IGFBP3, TIMP-1, SERPINF1, CSF-1). Similar changes in osteomodulin, IGF2, SERPINE1, fibulin-3 and CHI3L1 mRNA levels were observed. ELISAs assays confirm the decrease by half of osteomodulin protein in SC osteoblasts supernatant compared to NSC and in OA patients serum compared to healthy subjects. Fibulin-3 epitopes Fib3-1, Fib3-2 and Fib3-3 were also increased in SC osteoblasts supernatant compared to NSC., Conclusions: We highlighted some proteins differentially secreted by the osteoblasts coming from OA subchondral bone sclerosis. These changes contribute to explain some features observed in OA subchondral bone, like the increase of bone remodeling or abnormalities in bone matrix mineralization. Among identified proteins, osteomodulin was found decreased and fibulin-3 increased in serum of OA patients. These findings suggest that osteomodulin and fibulin-3 fragments could be biomarkers to monitor early changes in subchondral bone metabolism in OA.

Rheumatoid arthritis is one of the most common types of inflammatory joint diseases. Women, smokers, and people with positive family history are more susceptible to this disease. Diagnostic criteria include at least one swollen joint that has not been caused by other diseases. MicroRNAs are non-coding RNAs that are evolutionarily conserved and have a length of 18-25 nucleotides. MicroRNAs control gene expression at the post-transcriptional level via promoting mRNA degradation or translational repression. Recognition of alterations in microRNA status and their respective targets, may offer an opportunity to better identify the pathways that are involved in the etiopathogenesis of autoimmune diseases. It has been suggested that microRNAs may serve as potential biomarkers for both diagnosis and prognosis of autoimmune diseases. Here, we review the available evidence on the deregulations of microRNA expression in rheumatoid arthritis. More precisely, this review focuses on the microRNA involved in T cell regulation and gives perspectives on the use of this microRNA as biomarkers of diagnosis, prognosis, or intervention efficacy. J. Cell. Biochem. 119: 478-487, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: We have previously demonstrated that a mixture of Curcuminoids extract, hydrolyzed COllagen and green Tea extract (CCOT) inhibited inflammatory and catabolic mediator's synthesis by bovine and human chondrocytes. A randomly allocated, double-blind, prospective, placebo-controlled study was performed to evaluate the efficacy of a diet containing this CCOT mixture on dogs with naturally occurring osteoarthritis (OA). Therefore, 42 owner's dogs with OA were randomly assigned to receive for 3 months an experimental diet (control) or the same diet supplemented with CCOT., Results: Ground reaction forces did not show statistical differences between groups. After 3 months of feeding, there was a significant reduction of pain at manipulation in the CCOT group, but not in the control group. The evolution for pain at manipulation depended on the diet. The three other parameters evaluated by veterinary subjective assessment (lameness, pain at palpation and joint mobility) did not show statistical differences. Concerning owner subjective assessment, pain severity score worsened in the control group but remained stable in CCOT group. The evolution for pain severity depended on the diet. No statistical difference was found for pain interference, except for the ability to rise to standing from lying down, which was significantly improved in the CCOT compared to the control group. Serum OA biomarkers did not show statistical differences., Conclusions: Objective variables measured, such as ground reaction forces and OA biomarkers, did not show statistical differences. However, indicators of pain appeared reduced in dogs receiving CCOT mixture for 3 months. The difference of evolution between groups suggests that a greater number of dogs may be necessary to reach a stronger effect on other parameters.

Extracellular vesicles (EVs) secreted by stem cells are potential factors mediating tissue regeneration. They travel from bone marrow stem cells into damaged tissues, suggesting that they can repair tissue injuries without directly replacing parenchymal cells. We have discovered that hyaluronan (HA) synthesis is associated with the shedding of HA-coated EVs. The aim of this study was to test whether bone marrow-derived hMSCs secrete HA-coated EVs. The EVs secreted by MSCs were isolated by differential centrifugation and characterized by nanoparticle tracking analysis. Their morphology and budding mechanisms were inspected by confocal microscopy and correlative light and electron microscopy. Hyaluronan synthesis of hMSCs was induced by lipopolysaccharide and inhibited by RNA interference and 4-methylumbelliferone. It was found that the MSCs have extremely long apical and lateral HA-coated filopodia, typical for cells with an active HA secretion. Additionally, they secreted HA-coated EVs carrying mRNAs for CD44 and all HAS isoforms. The results show that stem cells have a strong intrinsic potential for HA synthesis and EV secretion, and the amount of HA carried on EVs reflects the HA content of the original cells. These results show that the secretion of HA-coated EVs by hMSCs is a general process, that may contribute to many of the mechanisms of HA-mediated tissue regeneration. Additionally, an HA coat on EVs may regulate their interactions with target cells and participate in extracellular matrix remodeling., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We examined whether mental state disorders (lifetime mood, anxiety, eating, substance misuse) with comorbid personality disorder are associated with physical multimorbidity in a population-based sample of women. Mental state and personality disorders were assessed using semi-structured diagnostic interviews. Clinical measures were performed and medical conditions, medication use and lifestyle factors were documented by questionnaire. Mental state disorders were associated with higher odds of physical multimorbidity; risk was especially high for those with comorbid personality disorder. These findings suggest that mental state and physical comorbidity might be worsened by the additional comorbidity of personality disorder., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To explore effects of weight loss and maintenance on serum cartilage biomarkers denaturation neoepitope for Collagen2 (Coll2-1) and Fibulin3 fragment (Fib3-2), as well as correlations between Coll2-1 and Fib3-2 and symptomatic improvement, in a knee osteoarthritis (KOA) population., Design: 192 obese KOA patients followed a 16 week weight loss intervention and 52 weeks weight maintenance (ClinicalTrials.gov identifier: NCT00655941). Assessments were at 0, 8, 16 and 68 weeks. Serum Coll2-1 and Fib3-2 were determined with ELISA, and symptoms by the Knee Osteoarthritis Outcome Score (KOOS) questionnaire. Changes from week 0 and association between changes from baseline in body weight and Coll2-1, Fib3-2, and the 5 KOOS domains were assessed at all time points., Results: Coll2-1 changes from baseline showed a decrease at week 8 (P = 0.0002), no change at week 16 (P = 0.49), and an increase at week 68 (P = 0.036). Fib3-2 showed an increase from baseline at week 8 (P = 0.0015) and 16 (P < 0.0001), but none at week 68 (P = 0.23). No statistically significant correlations were found between changes in body weight and Coll2-1 and Fib3-2 at any time point (r < 0.05; P > 0.49). At all time-points there were significant positive correlations between changes from baseline in Coll2-1 and in KOOS Sports/Recreation (week 8, 16, 68: r = 0.17; P = 0.03; r = 0.16; P = 0.04; and r = 0.17; P = 0.04, respectively)., Conclusion: The clinical improvement after a substantial weight loss and weight maintenance in KOA patients was not associated with decrease in markers of cartilage breakdown Coll2-1 or Fib3-2, even with indications of a slightly negative effect., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability. Recent work suggests that the global burden of OA is increasing, and costs associated with treatment are expected to increase dramatically as the aging human population expands. OA is currently diagnosed using radiography, but this technique is an indirect and insensitive measure of alterations in articular cartilage and fails to measure dynamic inflammatory processes in the joint. Radiographic changes detected overtime are small and occur in only a subset (progressors) of patients with OA. Therefore, we diagnose patients with OA on the basis of a diagnostic classification that is outdated. We also use the same tools and approaches for assessing the efficacy of new pharmacological and nonpharmacological interventions. In this review, we discuss the utility of soluble biochemical markers as biomarkers of OA and discuss whether we are close to using them in clinical practice. Combining patient information, functional imaging and carefully selected panels of biomarkers can help in achieving enhanced patient stratification and lead to better designed clinical trials. Biomarkers can be used for molecular endotyping and for developing more effective and more personalized treatments that will enhance clinical care for patients with OA., (Copyright © 2018. Published by Elsevier Ltd.)

Altogether 95 children with primary bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Two children with multiple peripheral and spinal fractures and low BMD had novel disease-causing PLS3 variants. Children with milder phenotypes had no pathogenic variants. PLS3 screening is indicated in childhood-onset primary osteoporosis., Introduction: The study aimed to determine the role of pathogenic PLS3 variants in children's bone fragility and to elucidate the associated phenotypic features., Methods: Two cohorts of children with bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Cohort I comprised 31 patients with childhood-onset primary osteoporosis of unknown etiology. Cohort II comprised 64 children who had sustained multiple fractures but were otherwise healthy. Clinical and radiological data were reviewed. Peripheral blood DNA was Sanger sequenced for coding exons and flanking intronic regions of PLS3., Results: In two patients of cohort I, where other common genetic causes had been excluded, we identified two novel disease-causing PLS3 variants. Patient 1 was a male with bilateral femoral fractures at 10 years, low BMD (Z-score -4.1; 18 years), and multiple vertebral compression fractures. He had a novel nonsense variant in PLS3. Patient 2 was a girl with multiple long bone and vertebral fractures and low BMD (Z-score -6.6 at 6 years). She had a de novo missense variant in PLS3; whole exome sequencing and array-CGH identified no other genetic causes. Iliac crest bone biopsies confirmed low-turnover osteoporosis in both patients. In cohort II, no pathogenic PLS3 variants were identified in any of the subjects., Conclusions: Two novel disease-causing variants in PLS3 were identified in a boy and a girl with multiple peripheral and spinal fractures and very low BMD while no pathogenic variants were identified in children with less severe skeletal fragility. PLS3 screening is warranted in male and female patients with childhood-onset primary osteoporosis.

Objectives: The present study was designed to evaluate the effect of a lifestyle intervention aimed to reduce body weight and of oral glucosamine sulphate on the incidence of knee osteoarthritis (OA) after 6-7 years in a population of middle-aged, overweight women, without knee OA at baseline., Methods: The Prevention of knee Osteoarthritis in Overweight Females study, ISRCTN42823086, was a randomized controlled trial with a 2 × 2 factorial design. Four hundred and seven women aged 50-60 years with a BMI of ⩾27 kg/m 2 and free of knee OA were randomized., Results: Four hundred and seventy-seven knees from 245 participants were available after a mean follow-up time of 6.6 years. Nineteen per cent of all knees showed incident knee OA. Both interventions showed no significant preventive effect on incident knee OA. Despite the fact that per protocol analyses showed greater differences between both groups for the lifestyle intervention, significance was not reached. A significant effect of losing ⩾5 kg or ⩾ 5% of baseline weight in the first 12 months on the incidence of knee OA according to the primary outcome was found (odds ratio = 0.10; 95% CI: 0.02, 0.41)., Conclusion: No significant preventive effect on incident knee OA of either the lifestyle intervention or the glucosamine intervention was found. As a proof of concept, the preventive effect of moderate weight loss in 1 year on the incidence of clinical knee OA is demonstrated. This trial provides important insights for future studies on the prevention of knee OA, which are currently lacking., Trial Registration: ISRTCN registry, http://www.isrctn.com , ISRCTN42823086., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Articular cartilage is a connective tissue consisting of a specialized extracellular matrix (ECM) that dominates the bulk of its wet and dry weight. Type II collagen and aggrecan are the main ECM proteins in cartilage. However, little attention has been paid to less abundant molecular components, especially minor collagens, including type IV, VI, IX, X, XI, XII, XIII, and XIV, etc. Although accounting for only a small fraction of the mature matrix, these minor collagens not only play essential structural roles in the mechanical properties, organization, and shape of articular cartilage, but also fulfil specific biological functions. Genetic studies of these minor collagens have revealed that they are associated with multiple connective tissue diseases, especially degenerative joint disease. The progressive destruction of cartilage involves the degradation of matrix constituents including these minor collagens. The generation and release of fragmented molecules could generate novel biochemical markers with the capacity to monitor disease progression, facilitate drug development and add to the existing toolbox for in vitro studies, preclinical research and clinical trials.

The extracellular matrix (ECM) of articular cartilage is comprised of complex networks of proteins and glycoproteins, all of which are expressed by its resident cell, the chondrocyte. Cartilage is a unique tissue given its complexity and ability to resist repeated load and deformation. The mechanisms by which articular cartilage maintains its integrity throughout our lifetime is not fully understood, however there are numerous regulatory pathways known to govern ECM turnover in response to mechanical stimuli. To further our understanding of this field, we envision that proteomic analysis of the secretome will provide information on how the chondrocyte remodels the surrounding ECM in response to load, in addition to providing information on the metabolic state of the cell. In this review, we attempt to summarize the recent mass spectrometry-based proteomic discoveries in healthy and diseased cartilage and chondrocytes, to facilitate the discovery of novel biomarkers linked to degenerative pathologies, such as osteoarthritis (OA)., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Objective Osteoarthritis (OA) is one of the leading causes of disability within the adult population. Currently, its diagnosis is mainly based on clinical examination and standard radiography. To date, there is no way to detect the disease at a molecular level, before the appearance of structural changes and symptoms. So an attractive alternative for monitoring OA is the measurement of biochemical markers in blood, urine, or synovial fluid, which could reflect metabolic changes in joint tissue and therefore disease onset and progression. Animal models are relevant to investigate the early stage of OA and metabolic changes occurring in joint tissues. The goal of this narrative review is to summarize the scientific data available in the literature on soluble biomarkers in animal models of OA. Design A literature search was conducted using the PubMed/Medline and Scopus databases between February 1995 and December 2015. All original articles, systematic and narrative reviews published in French or in English were considered. Results We summarized the data of 69 studies and proposed a classification scheme for OA biomarkers in animal studies, largely inspired by the BIPEDS classification. Conclusions Studies about biomarkers and animal models indicate that some markers could be valuable to monitor OA progression and assess therapeutic response in some animal models.

Reduced SIRT1 activity and levels during osteoarthritis (OA) promote gradual loss of cartilage. Loss of cartilage matrix is accompanied by an increase in matrix metalloproteinase (MMP) 13, partially because of enhanced LEF1 transcriptional activity. In this study, we assessed the role of SIRT1 in LEF1-mediated MMP13 gene expression in human OA chondrocytes. Results showed that MMP13 protein levels and enzymatic activity decreased significantly during SIRT1 overexpression or activation by resveratrol. Conversely, MMP13 gene expression was reduced in chondrocytes transfected with SIRT1 siRNA or treated with nicotinamide (NAM), a sirtuin inhibitor. Chondrocytes challenged with IL-1β, a cytokine involved in OA pathogenesis, enhanced LEF1 protein levels and gene expression, resulting in increased MMP13 gene expression; however, overexpression of SIRT1 during IL-1β challenge impeded LEF1 levels and MMP13 gene expression. Previous reports showed that LEF1 binds to the MMP13 promoter and transactivates its expression, but we observed that SIRT1 repressed LEF1 protein and mRNA expression, ultimately reducing LEF1 transcriptional activity, as judged by luciferase assay. Finally, mouse articular cartilage from Sirt1 -/- presented increased LEF1 and MMP13 protein levels, similar to human OA cartilage. Thus, demonstrating for the first time that SIRT1 represses MMP13 in human OA chondrocytes, which appears to be mediated, at least in part, through repression of the transcription factor LEF1, a known modulator of MMP13 gene expression.-Elayyan, J., Lee, E.-J., Gabay, O., Smith, C. A., Qiq, O., Reich, E., Mobasheri, A., Henrotin, Y., Kimber, S. J., Dvir-Ginzberg, M. LEF1-mediated MMP13 gene expression is repressed by SIRT1 in human chondrocytes., (© The Author(s).)

Background: Viscosupplementation is a symptomatic treatment of the knee osteoarthritis based on the intra-articular injection of hyaluronic acid (IAHA). Although many studies have investigated its effect on symptoms, few clinical studies have focused on its effects on biologicals markers of cartilage metabolism. In this study, we assessed the effect of an intra-articular injection of a reticulated hyaluronic acid compound on the level of a specific biomarker of type II collagen degradation., Methods: Eighty one patients with symptomatic knee osteoarthritis were included in this randomized placebo controlled trial testing a reticulated hyaluronic acid (HA) with mannitol (KARTILAGE® CROSS, 16 mg/ml, one single injection of 2.2 mL; IAHA) versus saline solution. Primary outcome was the percentage of patients with a reduction of at least 10 nmol/l of serum Coll2-1 between baseline and day 90 (D90, 3 months after injection). Secondary outcomes concerned clinical evaluation and tolerance to the study product., Results: A significant effect of IAHA was revealed by the sensitivity analysis of the decrease in cartilage marker. In the intention-to-treat population, the percentage of patients showing a decrease in the levels of serum Coll2-1 between inclusion and D90 showed was higher in HA (56.8%) than in placebo group (28.6%; P = 0.01). The same significant difference was observed between groups in the per protocol population (57.1% vs 29.0%; P = 0.02) corresponding to all patients having received the intra-articular injection (IA), being evaluated for the primary outcome on D-10 and D90, and with no major defined deviation. No significant differences between groups were observed on the changes in function (Lequesne index) or pain and on the number of adverse events., Conclusions: This is the first randomized double-blind placebo controlled trial showing that IA injection of reticulated HA with mannitol in knee osteoarthritis patients can reduce the serum levels of Coll2-1, a marker specific of type II collagen degradation. This finding suggests that IAHA may have a beneficial effect on cartilage degradation and that Coll2-1 could be used for the assessment of a single intra-articular treatment in clinical trials., Trial Registration: NCT02951585 ; clinicaltrial.gov. Retrospectively registered on October 28, 2016.

Context: The short-term benefits of bisphosphonates (BPs) are evident in the treatment of children with osteogenesis imperfecta (OI), but some concerns related to long-term effects remain., Objective: To elucidate the effect of BPs on characteristics of femoral fractures in children with OI., Design and Setting: Retrospective cohort study at a university hospital., Patients and Main Outcome Measure: The study included 93 patients with OI. We recorded fracture histories and analyzed all femoral fractures for location and fracture type using radiographs obtained at fracture diagnosis. Effects of BPs were evaluated by comparing fracture characteristics in three groups: patients (1) naive to BPs, (2) receiving ongoing BP treatment, and (3) whose treatment was discontinued., Results: In total, 127 femoral fractures occurred in 24 patients. Of the fractures, 63 (50%) occurred in patients naive to BPs, 44 (35%) during BP treatment, and 20 (16%) after treatment discontinuation. Mid or distal shaft fractures were most common (41%), followed by subtrochanteric (33%) and distal (20%) fractures. Almost all fractures were transverse (65%) or oblique (28%). The pattern of femoral fractures was similar in all three BP treatment groups (P = 0.78 for location; P = 0.35 for fracture type) and was not related to cumulative BP dose. Instead, OI type correlated with fracture characteristics, and distal location and transverse configuration were more common in the more severe types III and IV compared with type I OI., Conclusion: Characteristics of femoral fractures in children with OI are affected by OI type but not by BP exposure., (Copyright © 2017 by the Endocrine Society)