Cartilage Breakdown Research Articles

In vitro and in vivo characterisation of senescence markers in osteoarthritis

Purpose: Osteoarthritis (OA) is the most prevalent osteoarticular disease and a major cause of disability in aging adult. OA is characterized by cartilage breakdown, synovial inflammation, osteophyte formation, and subchondral bone remodelling. While OA is associated with a huge societal and economic burden, no efficient disease-modifying drug still exists today. In addition to obesity, metabolic disorders, and trauma, one of the major risks of OA is ageing. Ageing is a complex physiological process that relates to a gradual decline in certain functions, coordination, loss of homeostasis, and physiological integrity.

Changes in small non-coding RNA expression in synovial fluid during disease progression in an equine model of experimental osteoarthritis

Purpose: Osteoarthritis (OA) is a disease affecting all joint tissues. The ability to identify OA early, prevent the initial cartilage breakdown and stimulate repair would provide an effective strategy for both its prevention and treatment. Synovial fluid (SF) represents a potential source of disease-specific small non-coding RNAs (sncRNAs) that could be used as biomarkers and aid in the understanding of the pathogenesis of OA. SncRNAs are short, typically less than 200 base pairs (bp), RNA species, which are not translated into protein but have other structural or regulatory roles.

Effects of disease and dexamethasone on human cartilage breakdown kinetics

Effects of disease and dexamethasone on human cartilage breakdown kinetics

Functional repertoire of EV-associated miRNA profiles after lipoprotein depletion via ultracentrifugation and size exclusion chromatography from autologous blood products

Cartilage breakdown, inflammation and pain are hallmark symptoms of osteoarthritis, and autologous blood products such as citrate-anticoagulated platelet-rich plasma (CPRP) or hyperacute serum (hypACT) have been developed as a regenerative approach to rebuild cartilage, inhibit inflammation and reduce pain. However, mechanisms of action of these blood derivatives are still not fully understood, in part due to the large number of components present in these medical products. In addition, the discovery of extracellular vesicles (EVs) and their involvement in intercellular communication mediated by cargo molecules like microRNAs (miRNAs) opened up a whole new level of complexity in understanding blood products. In this study we focused on the development of an isolation protocol for EVs from CPRP and hypACT that can also deplete lipoproteins, which are often co-isolated in EV research due to shared physical properties. Several isolation methods were compared in terms of particle yield from CPRP and hypACT. To gain insights into the functional repertoire conveyed via EV-associated miRNAs, we performed functional enrichment analysis and identified NFκB signaling strongly targeted by CPRP EV miRNAs, whereas hypACT EV miRNAs affect IL6- and TGFβ/SMAD signaling.

Biomarkers of Joint Damage in Osteoarthritis: Current Status and Future Directions.

Osteoarthritis (OA) is a disease of the whole joint organ, characterized by the loss of cartilage, and structural changes in bone including the formation of osteophytes, causing disability and loss of function. It is also associated with systemic mediators and low-grade inflammation. Currently, there is negligible/no availability of specific biomarkers that can be used to facilitate the diagnosis and treatment of OA. The most unmet clinical need is, however, related to the monitoring of disease progression over a short period that can be used in clinical trials. In this review, the value of biomarkers identified over the past decade has been highlighted. These biomarkers are associated with the synthesis and breakdown of cartilage, including collagenous and noncollagenous biomarkers, inflammatory and anti-inflammatory biomarkers, expressed in the biological fluid such as serum, synovial fluid, and urine. Broad validation of novel and clinically applicable biomarkers and their involvement in the pathways are particularly needed for early-stage diagnosis, monitoring disease progression, and severity and examining new drugs to mitigate the effects of this highly prevalent and debilitating condition.

Human Osteochondral Explants: Reliable Biomimetic Models to Investigate Disease Mechanisms and Develop Personalized Treatments for Osteoarthritis.

IntroductionLikely due to ignored heterogeneity in disease pathophysiology, osteoarthritis (OA) has become the most common disabling joint disease, without effective disease-modifying treatment causing a large social and economic burden. In this study we set out to explore responses of aged human osteochondral explants upon different OA-related perturbing triggers (inflammation, hypertrophy and mechanical stress) for future tailored biomimetic human models.MethodsHuman osteochondral explants were treated with IL-1β (10 ng/ml) or triiodothyronine (T3; 10 nM) or received 65% strains of mechanical stress (65% MS). Changes in chondrocyte signalling were determined by expression levels of nine genes involved in catabolism, anabolism and hypertrophy. Breakdown of cartilage was measured by sulphated glycosaminoglycans (sGAGs) release, scoring histological changes (Mankin score) and mechanical properties of cartilage.ResultsAll three perturbations (IL-1β, T3 and 65% MS) resulted in upregulation of the catabolic genes MMP13 and EPAS1. IL-1β abolished COL2A1 and ACAN gene expression and increased cartilage degeneration, reflected by increased Mankin scores and sGAGs released. Treatment with T3 resulted in a high and significant upregulation of the hypertrophic markers COL1A1, COL10A1 and ALPL. However, 65% MS increased sGAG release and detrimentally altered mechanical properties of cartilage.ConclusionWe present consistent and specific output on three different triggers of OA. Perturbation with the pro-inflammatory IL-1β mainly induced catabolic chondrocyte signalling and cartilage breakdown, while T3 initiated expression of hypertrophic and mineralization markers. Mechanical stress at a strain of 65% induced catabolic chondrocyte signalling and changed cartilage matrix integrity. The major strength of our ex vivo models was that they considered aged, preserved, human cartilage of a heterogeneous OA patient population. As a result, the explants may reflect a reliable biomimetic model prone to OA onset allowing for development of different treatment modalities.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00287-y.

Effect of Rubus idaeus Extracts in Murine Chondrocytes and Explants.

Osteoarthritis is characterized by cartilage loss resulting from the activation of chondrocytes associated with a synovial inflammation. Activated chondrocytes promote an increased secretion of matrix proteases and proinflammatory cytokines leading to cartilage breakdown. Since natural products possess anti-inflammatory properties, we investigated the direct effect of Rubus idaeus extracts (RIE) in chondrocyte metabolism and cartilage loss. The effect of RIE in chondrocyte metabolism was analyzed in murine primary chondrocytes and cartilage explants. We also assessed the contribution of RIE in an inflammation environment by culturing mice primary chondrocytes with the supernatant of Raw 264.7 macrophage-like cells primed with RIE. In primary chondrocytes, RIE diminished chondrocyte hypertrophy (Col10), while increasing the expression of catabolic genes (Mmp-3, Mmp-13) and reducing anabolic genes (Col2a1, Acan). In cartilage explants, Rubus idaeus prevented the loss of proteoglycan (14.84 ± 3.07% loss of proteoglycans with IL1 alone vs. 3.03 ± 1.86% with IL1 and 100 µg/mL of RIE), as well as the NITEGE neoepitope expression. RIE alone reduced the expression of Il1 and Il6 in macrophages, without changes in Tnf and Cox2 expression. The secretome of macrophages pre-treated with RIE and transferred to chondrocytes decreases the gene and protein expression of Mmp-3 and Cox2. In conclusion, these data suggest that RIE may protect from chondrocyte catabolism and cartilage loss in inflammatory conditions. Further evaluations are need before considering RIE as a candidate for the treatment for osteoarthritis.

Patients Walking Faster After Anterior Cruciate Ligament Reconstruction Have More Gait Asymmetry

BackgroundGait asymmetries after anterior cruciate ligament reconstruction (ACLR) may lead to radiographic knee osteoarthritis. Slower walking speeds have been associated with biomarkers suggesting cartilage breakdown. The relationship between walking speed and gait symmetry after ACLR is unknown.Hypothesis/PurposeTo determine the relationship between self-selected walking speeds and gait symmetry in athletes after primary, unilateral ACLR.Study DesignSecondary analysis of a clinical trial.MethodsAthletes 24±8 weeks after primary ACLR walked at self-selected speeds as kinematics, kinetics, and electromyography data were collected. An EMG-driven musculoskeletal model was used to calculate peak medial compartment contact force (pMCCF). Variables of interest were peak knee flexion moment (pKFM) and angle (pKFA), knee flexion and extension (KEE) excursions, peak knee adduction moment (pKAM), and pMCCF. Univariate correlations were run for walking speed and each variable in the ACLR knee, contralateral knee, and interlimb difference (ILD).ResultsWeak to moderate positive correlations were observed for walking speed and all variables of interest in the contralateral knee (Pearson’s r=.301-.505, p≤0.01). In the ACLR knee, weak positive correlations were observed for only pKFM (r=.280, p=0.02) and pKFA (r=.263, p=0.03). Weak negative correlations were found for ILDs in pKFM (r=-0.248, p=0.04), KEE (r=-.260, p=0.03), pKAM (r=-.323, p<0.01), and pMCCF (r=-.286, p=0.02).ConclusionThose who walk faster after ACLR have more asymmetries, which are associated with the development of early OA. This data suggests that interventions that solely increase walking speed may accentuate gait symmetry in athletes early after ACLR. Gait-specific, unilateral, neuromuscular interventions for the ACLR knee may be needed to target gait asymmetries after ACLR.Level of EvidenceIII

The impact of a key nutraceutical complex on chondrocyte cells and matrix Gla protein expression

Osteoarthritis (OA) is the most common type of arthritis among adults, which is associated with cartilage breakdown. Chondrocytes are the only type of cell in articular cartilage that secrete extracellular matrix (ECM). Therefore, to prevent and manage the occurrence of arthritic cartilage, it is important to consider approaches to increase the survival of chondrocyte cells. The production of reactive oxygen species (ROS), the release of pro-inflammatory cytokines (e.g. interleukin-1β (IL-1β)), and cartilage calcification play an imperative role in OA pathophysiology. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4 (Nox4) is an enzyme that regulates the production of ROS in chondrocyte cells. ROS and cytokines lead to ECM degradation and chondrocyte apoptosis. Moreover, the matrix γ-carboxyglutamic acid (Gla) protein (MGP) acts as a decalcification agent in chondrocytes, which can inhibit the pathogenic mineralisation of cartilage. The correct balance of nutrients may potentially have a protective effect against OA. In the present study, the effect of essential nutrients on Nox4 activity in chondrocyte cells, chondrocyte viability, and MGP expression was investigated. Chondrocyte cells were pre-treated with the nutrients, and the cells were subsequently assessed for Nox4 activity using the chemiluminescence technique. It was found that the production of ROS significantly decreased after preincubation in the presence of nutrients in comparison to the control samples. Furthermore, it was found that the presence of nutraceuticals improved the viability of chondrocyte cells and the expression of MGP, which acts as a mineralisation inhibitor in the chondrocyte growth plate. The results of this study suggest that the correct balance of key nutrients at the molecular level plays an essential role in supporting chondrocyte cells and promoting cartilage decalcification.

Differences between infected and noninfected synovial fluid.

AimsThe diagnosis of joint infections is an inexact science using combinations of blood inflammatory markers and microscopy, culture, and sensitivity of synovial fluid (SF). There is potential for small molecule metabolites in infected SF to act as infection markers that could improve accuracy and speed of detection. The objective of this study was to use nuclear magnetic resonance (NMR) spectroscopy to identify small molecule differences between infected and noninfected human SF.MethodsIn all, 16 SF samples (eight infected native and prosthetic joints plus eight noninfected joints requiring arthroplasty for end-stage osteoarthritis) were collected from patients. NMR spectroscopy was used to analyze the metabolites present in each sample. Principal component analysis and univariate statistical analysis were undertaken to investigate metabolic differences between the two groups.ResultsA total of 16 metabolites were found in significantly different concentrations between the groups. Three were in higher relative concentrations (lipids, cholesterol, and N-acetylated molecules) and 13 in lower relative concentrations in the infected group (citrate, glycine, glycosaminoglycans, creatinine, histidine, lysine, formate, glucose, proline, valine, dimethylsulfone, mannose, and glutamine).ConclusionMetabolites found in significantly greater concentrations in the infected cohort are markers of inflammation and infection. They play a role in lipid metabolism and the inflammatory response. Those found in significantly reduced concentrations were involved in carbohydrate metabolism, nucleoside metabolism, the glutamate metabolic pathway, increased oxidative stress in the diseased state, and reduced articular cartilage breakdown. This is the first study to demonstrate differences in the metabolic profile of infected and noninfected human SF, using a noninfected matched cohort, and may represent putative biomarkers that form the basis of new diagnostic tests for infected SF.Cite this article: Bone Joint Res 2021;10(1):85–95.

The role of microRNA-3085 in chondrocyte function

MicroRNAs have been shown to play a role in cartilage development, homeostasis and breakdown during osteoarthritis. We previously identified miR-3085 in humans as a chondrocyte-selective microRNA, however it could not be detected by Northern blot. The aim of the current study was to prove that miR-3085 is a microRNA and to investigate the function of miR-3085 in signaling pathways relevant to cartilage homeostasis and osteoarthritis. Here, we confirm that miR-3085 is a microRNA and not another class of small RNA using (1) a pre-miR hairpin maturation assay, (2) expression levels in a Dicer null cell line, and (3) Ago2 pulldown. MicroRNA-3085-3p is expressed more highly in micromass than monolayer cultured chondrocytes. Transfection of miR-3085-3p into chondrocytes decreases expression of COL2A1 and ACAN, both of which are validated as direct targets of miR-3085-3p. Interleukin-1 induces the expression of miR-3085-3p, at least in part via NFκB. In a feed-forward mechanism, miR-3085-3p then potentiates NFκB signaling. However, at early time points after transfection, its action appears to be inhibitory. MyD88 has been shown to be a direct target of miR-3085-3p and may be responsible for the early inhibition of NFκB signaling. However, at later time points, MyD88 knockdown remains inhibitory and so other functions of miR-3085-3p are clearly dominant. TGFβ1 also induces the expression of miR-3085-3p, but in this instance, it exerts a feedback inhibition on signaling with SMAD3 and SMAD4 shown to be direct targets. This in vitro analysis shows that miR-3085-3p functions in chondrocytes to induce IL-1-signaling, reduce TGFβ1 signaling, and inhibit expression of matrix genes. These data suggest that miR-3085-3p has a role in chondrocyte function and could contribute to the process of osteoarthritis.

Sex-Specific Associations between Cartilage Structure and Metabolism at Rest and Acutely Following Walking and Drop-Landing.

Cartilage health is thought to be dependent on the relationship between mechanics, structure, and metabolism, rather than these individual components in isolation. Due to sex differences in cartilage health, there is need to determine if the relationships between these cartilage components separately for males and females. Therefore, we sought to determine the sex-specific associations between cartilage structure and metabolism at rest and their acute response following walking and drop-landing in healthy individuals. A cartilage ultrasound assessment and an ante-cubital blood draw were performed before and after walking and drop-landing conditions in 20 males and 20 females. Cartilage structure was assessed via medial and lateral femoral cartilage cross-sectional area. Cartilage metabolism was quantified with serum cartilage oligomeric matrix protein (COMP) concentration. Percent change scores from pre- to postloading were used to calculate acute alterations in cross-sectional area and COMP. Correlational analyses were used to assess the association between cartilage structure and metabolism measures separately for males and females. In females, greater resting COMP concentration was associated with less cartilage cross-sectional area in the medial(ρ = -0.50, P = 0.03) and lateral (ρ = -0.69, P = 0.001) femur. Resting cartilage measures were not associated among males. Following walking and drop-landing, percent change scores in cartilage structure and metabolism were not associated. This study highlights that, in females, thinner anterior femoral cartilage is associated with greater resting serum COMP concentrations, a biomarker often linked to cartilage breakdown. Future studies into the relationships between various cartilage components should consider sex-specific analyses as these relationships are sex dependent.

The Anti-ADAMTS-5 Nanobody® M6495 Protects Cartilage Degradation Ex Vivo.

Osteoarthritis (OA) is associated with cartilage breakdown, brought about by ADAMTS-5 mediated aggrecan degradation followed by MMP-derived aggrecan and type II collagen degradation. We investigated a novel anti-ADAMTS-5 inhibiting Nanobody® (M6495) on cartilage turnover ex vivo. Bovine cartilage (BEX, n = 4), human osteoarthritic - (HEX, n = 8) and healthy—cartilage (hHEX, n = 1) explants and bovine synovium and cartilage were cultured up to 21 days in medium alone (w/o), with pro-inflammatory cytokines (oncostatin M (10 ng/mL) + TNFα (20 ng/mL) (O + T), IL-1α (10 ng/mL) or oncostatin M (50 ng/mL) + IL-1β (10 ng/mL)) with or without M6495 (1000−0.46 nM). Cartilage turnover was assessed in conditioned medium by GAG (glycosaminoglycan) and biomarkers of ADAMTS-5 driven aggrecan degradation (huARGS and exAGNxI) and type II collagen degradation (C2M) and formation (PRO-C2). HuARGS, exAGNxI and GAG peaked within the first culture week in pro-inflammatory stimulated explants. C2M peaked from day 14 by O + T and day 21 in co-culture experiments. M6495 dose dependently decreased huARGS, exAGNxI and GAG after pro-inflammatory stimulation. In HEX C2M was dose-dependently reduced by M6495. M6495 showed no effect on PRO-C2. M6495 showed cartilage protective effects by dose-dependently inhibiting ADAMTS-5 mediated cartilage degradation and inhibiting overall cartilage deterioration in ex vivo cartilage cultures.

Degenerative osteoarthritis a reversible chronic disease.

Osteoarthritis (OA) is the most common chronic musculoskeletal disorder. It can affect any joint and is the most frequent single cause of disability in older adults.OA is a progressive degenerative disease involving the entire joint structure in a vicious circle that includes the capsule-bursa tissue inflammation, synovial fluid modifications, cartilage breakdown and erosions, osteochondral inflammatory damage leading to bone erosion and distortion.Research has identified the initial inflammatory-immunologic process that starts this vicious cycle leading to so-called early OA. Research has also identified the role played in the disease advancement by synoviocytes type A and B, chondrocytes, extracellular matrix, local immune-inflammatory mediators and proteases.This article investigates the joint-resident MSCs that play an essential local homeostatic role and regulate cell turn over and tissue repair. Resident MSCs establish and maintain a local regenerative microenvironment.The understanding of OA physiopathology clarifies the core mechanisms by which minimally invasive interventions might be able to halt and reverse the course of early stage OA. Interventions employing PRP, MSCs and exosomes are considered in this article.

A Preliminary Study of Combined Detection of COMP, TIMP-1, and MMP-3 in Synovial Fluid: Potential Indicators of Osteoarthritis Progression.

Osteoarthritis (OA) commonly affects weight-bearing joints and is characterized by articular cartilage breakdown combined with osteophyte formation at the joint margins and chronic nonspecific inflammation of synovium. Understanding the profile of inflammation in a patient population is an essential starting point to predict or prevent OA progression. The aim of this study was to identify the profile of selected biomolecules in synovial fluid (SF) and investigate the correlation according to gender, age, and severity of the disease within patients from among the general knee OA population. In our study SF samples were aspirated from the knees of 65 OA patients (46 patients with early knee OA and 19 patients with end-stage knee OA according to the Kellgren-Lawrence grading scale). The concentration of interleukins (IL-6, IL-8), matrix metalloproteinases (MMP-1, MMP-3, MMP-13), MMPs inhibitors (TIMP-1, TIMP-2), cartilage oligomeric matrix protein (COMP), and adiponectin was analyzed using a multiplex ELISA-based approach. Our results indicate significant linear correlation of MMP-13 and COMP concentration with age (P < 0.05), but not with OA severity. In fact, 3 of the examined biomolecules, MMP-3 (P < 0.01), TIMP-1 (P < 0.01), and COMP (P < 0.05) significantly correlate with the grade of knee OA and might be associated with OA severity.

MicroRNA-34a Promotes Apoptosis of Rheumatoid Arthritis Fbroblast-Like Synoviocyte via AMPK/Akt/mTOR Signaling Pathway

Background and Objectives: Rheumatoid arthritis (RA) is an autoimmune arthropathy characterised by chronic synovitis, joint cartilage breakdown and bone erosions. The life quality of RA patients has been substantially effected by the disease and it is of great significance to search for more efficacious and novel therapeutic agents. Methods: In this study, mRNA levels of miR-34a in HFLS and RA-FLS were examined by RT-PCR. CCK8 assay was applied to detect the viability of RA-FLS transfected with miR-34a mimic or inhibitor. Furthermore, TUNEL assay and Hoechest-33342 assay was applied to detect the apoptosis of RA-FLS transfected with miR-34a mimic or inhibitor. The expressions of proteins related to AMPK/Akt/mTOR and autophagy were also detected by western blot. Results: The RT-PCR result showed that miR-34a mRNA levels was markedly downregulated in RA-FLS compared to HFLS. CCK8 assay results demonstrated that miR-34a overexpression significantly suppressed RA-FLS proliferation and miR-34a interference had the opposite effect. TUNEL assay and Hoechest-33342 assay demonstrated that miR-34a overexpression significantly promoted RA-FLS apoptosis and miR-34a interference had the opposite effect. The western blot results revealed that miR-34a can affect autophagy via AMPK/Akt/mTOR signaling pathway. Conclusion: This study suggested that miR-34a can regulate proliferation and apoptosis in RA-FLS by affecting autophagy through AMPK/Akt/mTOR signaling pathway.

Fewer Steps Per Day Associates With Greater Cartilage Breakdown Biomarkers Post Anterior Cruciate Ligament Reconstruction

PURPOSE: Individuals with anterior cruciate ligament reconstruction (ACLR) engage in fewer steps per day (steps/day) compared to uninjured controls. While regular physical activity can improve outcomes of idiopathic knee osteoarthritis such as disability, it is unknown if physical activity influences post-traumatic knee osteoarthritis outcomes following ACLR. Cartilage oligomeric matrix protein (COMP) is a biomarker outcome associated with cartilage breakdown, and it is responsive to mechanical loading during walking. Therefore, the purpose was to determine the association between steps/day and change in COMP (∆COMP) following walking in individuals with an ACLR. METHODS: : Steps/day was assessed over 7 days using ActiGraph accelerometers worn on the right hip in 31 participants (age=22±4years, body mass index=23.9±2.9kg/m2, 52±37 months post-ACLR, 55% females) with primary unilateral ACLR ≥ 6 months at the time of testing. Subjects walked at a preferred speed for 3000 steps (~30 minutes) on a treadmill to introduce cartilage loading. Blood samples were collected immediately pre- and post-walking, and serum COMP concentrations were analyzed with ELISA kits. ∆COMP was calculated with post-walking concentrations expressed as a percentage of pre-walking levels. Greater ∆COMP was interpreted as greater cartilage breakdown during the walking protocol. A univariate linear regression was conducted to determine the association of steps/day with ∆COMP. RESULTS: Fewer steps/day (mean±SD: 9,626±2,452) associated with greater ∆COMP (+11.5±16.4%; R2=0.152, β=-0.003, p=0.030). CONCLUSIONS: Individuals after ACLR who habitually engage in fewer steps/day demonstrated greater ∆COMP during a walking protocol. We postulate fewer steps/day in individuals with a history of ACLR may result in deleterious changes in cartilage homeostasis due to inadequate mechanical stimulation of joint tissues. Future studies should determine if increasing steps/day improves knee cartilage outcomes following ACLR.

Differences in articular hip cartilage gene expression between femoroacetabular impingement (FAI) and end-stage hip osteoarthritis

Objectives:The morphological deformities in Femoroacetabular Impingement (FAI) have been associated with hip osteoarthritis (OA), however the molecular mechanisms for OA initiation and progression are poorly understood. The purpose of this study was to use whole genome RNA sequencing to characterize differences in gene expression articular cartilage samples isolated from patients undergoing surgery for FAI and idiopathic OA. We hypothesized that there would be significant differences in genes expression in pathways related to inflammation as well as cartilage and bone turnover.Methods:20 patients undergoing either hip arthroscopy for FAI (5 male, 5 female) or total hip arthroplasty (5 male, 5 female) for end-stage osteoarthritis were included in the study. FAI patients required a Cam deformity with an Alpha Angle greater than 55 while patients with dysplasia (LCEA<25) or prior hip surgery were excluded. Exclusion criteria for the THA cohort included dysplasia, and post-traumatic OA or inflammatory OA. Cartilage samples were obtained over the Cam deformity prior to femoroplasty in the FAI group or over anterosuperior femoral head-neck junction in the OA group following extraction of the femoral head. Following RNA isolation, Next Generation RNA sequencing was performed to evaluate gene expression. Differential expression data was incorporated into the Ingenuity Pathway Analysis (IPA) platform to identify differences in canonical signaling pathways associated with osteoarthritis.Results:There were 3531 genes that were significantly differentially expressed between the FAI and OA cohorts. Of these, there were 27 genes that were upregulated by a greater than 2 log-fold change in the OA cohort and 524 genes that were upregulated by a greater than 2 log-fold change in the FAI cohort. There was significant differential expression in genes related to cartilage metabolism (Table 1) and canonical osteoarthritis pathways involving BMP, TGFβ, and Wnt signaling. (Table 2). Additionally, FAI samples had significant upregulation of EGF-ERBB mediated signaling which compared to osteoarthritic tissue.Conclusion:The results of the present study support our hypothesis that there are significant differences in gene expression between FAI and OA samples in multiple pathways that are implicated in osteoarthritis. Osteoarthritis samples had increased expression of cartilage breakdown and inflammation while femoroacetabular impingement samples had greater expression of chondroprotective genes. Further study of cartilage samples from FAI patients may provide insight into the molecular mechanisms of osteoarthritis progression.Table 1.Differential gene expression in genes related to cartilage metabolism. Osteoarthritic samples had elevated COL10, 24, 8, and 9 genes while FAI had elevated COMP, COL4, and COL6 genes.Cartilage MetabolismUpregulated OA Padj Upregulated FAI Padj COL10A10.0001638COMP0.034951COL24A10.0117991COL4A35.96E-33COL8A10.0274064COL4A49.46E-14COL9A10.0004479COL4A51.49E-14COL9A20.0090092COL6A69.56E-05ADAMTS40.0003928COL6A62.23E-08Table 2.Differential expression of genes previously implicated in osteoarthritis. Osteoarthritis samples had elevated markets of end stage cartilage breakdown (ADAMTS4, MMP13, TNF) while FAI samples had increased expression of chondroprotective genes (FGF18, WNT 16, BMPR18)Canonical Osteoarthritis PathwayUpregulated OA Upregulated FAI GREM13.32E-12SMAD40.002188MMP13.24E-05C/EBP2.32E-04COL10A11.64E-04WNT160.001925FRZB3.32E-08PGC12.11E-07MMP132.77E-04FGF189.67E-09MATN30.00205VEGFD1.03E-12 MMP30.007351SOX100.000216ADAMTS43.93E-04NOS11.87E-34Osteopontin0.006119DKK20.007801MMP90.004763GDF61.08E-07S1PR30.003633BMPR1B1.31E-22TNF0.001382 RUNX21.19E-04 SPHK18.83E-05 TGFB13.44E-04 CTR0.012398 RANK3.77E-06

Longitudinal Analysis of Serum Biochemical Changes following Anterior Cruciate Ligament Injury and Reconstruction: A Matched Comparison-Control Analysis

Objectives:Individuals with an anterior cruciate ligament (ACL) injury are at high risk of developing posttraumatic osteoarthritis (PTOA). A comprehensive study is needed to determine the time course of joint tissue metabolic changes occurring following ACL injury and reconstruction (ACLR). The purpose of this longitudinal nested comparison-control study was to simultaneously evaluate serum biomarkers of inflammation and cartilage matrix damage in ACL injured patients prior to ACLR and 6 and 12 months post-ACLR, as well as in matched uninjured controls.Methods:Serum was collected from 34 ACL injured individuals (53% female, 20.7±2.4 years old, 24.2±4.1 body mass index [BMI]) within 14 days of primary ACL injury (baseline), as well as at 6 and 12 months following bone-patellar-tendon-bone autograft ACLR. Serum was also collected from 34 uninjured matched controls (53% Female, 20.5±2.4 years old, 24.1±3.5 BMI) at a single timepoint. Blood was collected from the antecubital fossa, centrifuged and stored at -80°C prior to batch analysis. Commercial enzyme-linked immunosorbent assays were used to evaluate concentrations of: 1) a pro-inflammatory cytokine [Monocyte Chemoattractant Protein; MCP-1]; 2) a matrix degrading enzyme [matrix metalloproteinase-3; MMP-3]; 3) a cartilage breakdown biomarker [cartilage oligomeric matrix protein; COMP]; and type-II collagen turnover [type-II collagen cleavage: synthesis; C2C:CPII]. Separate Bonferroni-corrected independent t-tests were used to determine differences between the ACL injured group at each timepoint and uninjured controls for each biomarker (P ≤ 0.015). Similarly, separate Bonferroni-corrected dependent t-tests were used to determine differences in biomarker concentrations over time for the ACLR group.Results:Serum concentrations of MCP-1 and COMP were greater in the ACL injured individuals at all timepoints compared to the controls (P ≤ 0.015, Table 1), yet no differences were found over time in the ACL injured group. MMP-3 concentrations increased between baseline and 6 months post-ACLR (P ≤ 0.015, see Table), yet no differences were found between 6 and 12 months post-ACLR, between baseline and 12 months, or between ACLR and controls at any of the time points. C2C:CPII was not different between ACL injured individuals and controls at baseline or 6 months post-ACLR. C2C:CPII was significantly increased between 6 and 12 months-post ACLR, and was found to be greater than baseline and greater than controls at 12 months post-ACLR (P ≤ 0.015, see Table).Conclusion:Our study is critical in demonstrating the time course of multiple joint tissue metabolic changes following ACL injury and ACLR. Elevated serum MCP-1 and COMP concentrations, linked to early deleterious metabolic processes associated with PTOA development, are evident soon after ACL injury and persist at 12 months post-ACLR. Serum MMP-3 concentrations were elevated 6 months post-ACLR compared to the baseline measurements, suggesting factors occurring after ACLR initiate upregulation of matrix degrading enzymes. Furthermore, elevated C2C:CPII occurs within the first 12 months post ACLR but not until after the 6-month post-ACLR timepoint. Further studies are needed to determine how long these joint tissue metabolic changes persist after ACL injury and ACLR, as well as how joint tissue metabolism is affected by the type and timing of different surgical and nonsurgical treatments.

Strength and Aerobic Exercise for the Treatment of Osteoarthritis Symptoms

Background: Arthritis is a prevalent joint disease characterized by joint inflammation. Osteoarthritis is the most common form of arthritis which causes progressive cartilage breakdown at the ends of bones and may affect surrounding ligaments, menisci and muscles. Osteoarthritis puts individuals at an increased risk of developing comorbid conditions. The use of exercise is growing as a low-risk treatment for symptoms of osteoarthritis. Purpose: The purpose of this narrative review is to examine how strength and aerobic exercise interventions can be used for the management of osteoarthritis symptoms. Methodology: A literature search was conducted utilizing PubMed, Medline, Google Scholar, and UBC Library. Selected literature included quasi-experimental studies, randomized-controlled trials, systematic reviews, narrative reviews, and exercise guidelines. Results: The literature indicates that strength exercise is beneficial to symptom management and physical function among individuals with osteoarthritis. Research specific to quadriceps strengthening showed significant improvements in physical performance, walking self-efficacy, and pain. While aerobic exercise plays a vital role in overall well-being, it also is shown to be as effective as strength exercise for symptom management and physical function. Conclusion: Evidence suggests that strength and aerobic exercise can enhance the quality of life among individuals with osteoarthritis. Greater dissemination of evidence is needed to increase awareness of strength and aerobic exercise as a valuable treatment option for osteoarthritis. Further research is required to determine optimal exercise parameters prescribed for individuals with osteoarthritis. Health & Fitness Journal of Canada 2019;XXX(X):X-XX. https://doi.org/10.14288/hfjc.XXX.XXX Keywords: Physical Activity, Quadricep Strengthening, Exercise Prescription, Randomized-Controlled Trial, Systematic Review, Medications