Development Of OA Research Articles

Downregulation of miR-3680–3p inhibits the progression of osteoarthritis via targeting OGG1

BackgroundOsteoarthritis (OA) is a degenerative joint disease that seriously endangers the health of middle-aged and elderly people. MicroRNA (miRNA) regulation is associated with several diseases, including OA. This study aimed to explore the role and mechanism of miR-3680–3p in regulating OA progression. MethodsGSE105027 and GSE143514 were downloaded from Gene Expression Omnibus (GEO) and differentially expressed miRNAs between control and OA-affected cartilage were obtained by R software. GSE55235 gene expression profile was downloaded and analyzed the differentially expressed genes. In vitro study, chondrocyte was administrated by interleukin-1β (IL-1β) to mimic an in vitro model of OA. The apoptotic and cell cycle arrest were assessed by flowcytometry. IL-6 and TNF-α expressions were measured by the enzyme-linked immunosorbant assay (ELISA). Moreover, the OA rat model was established to explore the function of miR-3680–3p/OGG1 axis in vivo. ResultsGSE105027 identified 266 differentially expressed miRNAs and GSE143514 identified 160 differentially expressed miRNAs. MiR-3680–3p was significantly upregulated in OA samples in comparison to normal cartilage samples. IL-1β significantly reduced the cell viability than control chondrocytes, this effect was reversed by miR-3680–3p antagomir. Treatment with miR-3680–3p antagomir could partially reversed the IL-1β-induced promotion of apoptosis of chondrocytes. IL-1β increased the expression of MMP1 and MMP13, while the expression of matrix related protein, such as aggrecan, was significantly downregulated in IL-1β-treated chondrocytic cells. Inhibition of miR-3680–3p expression by an antagomir could reverse this phenotype. OGG1 was predicted and verified as a direct target of miR-3680–3p. Moreover, our in vivo study found that after knockdown of miR-3680–3p alleviated the development of OA in rat models. ConclusionInhibition of miR-3680–3p reversed the IL-1β induced chondrocytes injury and delayed the progression of OA via targeting OGG1.

Tangeretin suppresses osteoarthritis progression via the Nrf2/NF-κB and MAPK/NF-κB signaling pathways

BackgroundOsteoarthritis (OA) is a globally prevalent degenerative disease characterized by extracellular matrix (ECM) degradation and inflammation. Tangeretin is a natural flavonoid that has anti-inflammatory properties. Studies have not explored whether tangeretin modulates OA development. PurposeThe aim of this study was to explore the potential effects and mechanism underlying the anti-OA properties of tangeretin. Study designEffects of tangeretin on OA were detected in chondrocytes and OA mouse model. MethodsProtective effects of tangeretin on murine articular chondrocytes treated with interleukin-1β (IL-1β) were evaluated using qPCR, western blot analysis, ELISA, ROS detection and immunofluorescent staining in vitro. Healing effect of tangeretin on cartilage degradation in mice was assessed through X-ray imaging, histopathological analysis, immunohistochemical staining and immunofluorescent staining in vivo. ResultsTangeretin suppressed IL-1β-mediated inflammatory mediator secretion and degradation of ECM in chondrocytes. The results showed that tangeretin abrogated destabilized medial meniscus (DMM)-induced cartilage degradation in mice. Mechanistic studies showed that tangeretin suppressed OA development by downregulating activation of NF-κB by activating Nrf2/HO-1 axis and suppressing MAPK signaling pathway. ConclusionTangeretin abrogates OA progression by inhibiting inflammation as well as ECM degradation in chondrocytes and animal models. Effects of tangeretin are mediated through Nrf2/NF-κB and the MAPK/NF-κB pathways. Thus, tangeretin is a potential therapeutic agent for osteoarthritis treatment.

T2 MAPPING OF THE ARTICULAR CARTILAGE AS A BIOMARKER FOR OA IN A POPULATION BASED COHORT: THE ROTTERDAM STUDY

While quantitative T2 mapping has been well established as a non-invasive tool for assessing (early) OA progression, there have been a limited number of studies investigating this in large population-based cohorts, other than the OAI. The objectives of the current study were to evaluate 1) the relationship between T2 relaxation times and patient characteristics age and BMI, and 2) the relationship between T2 relaxation times and MRI-based OA status, in a population-based study. We included 1327 knees from 665 females (mean age 59.8 years;SD:3.7 and mean BMI 26.9 kg/m2; SD:4.7) from a subcohort of the population based Rotterdam Study. All knees underwent 1.5 Tesla MRI at two different time-points (mean time between scans 5.1 years; SD: 0.4) comprising sagittal dual-echo FSE proton density–weighted, spoiled gradient echo with fat suppression, and fast imaging employing steady-state acquisition (FIESTA) sequences. The second time-point included an additional sagittal T2-weighted FSE sequence with fat suppression (4 echo times (15, 30, 45, 60 ms), repetition time 4100ms, field of view 160 x 160mm; slice thickness 3.2mm; matrix 256 x 256) for the purpose of T2 mapping. T2 relaxation times were calculated in six femoral and tibial regions of interest of full-thickness tibiofemoral cartilage: LF, LT, pLF, MF, MT, and pMF. Differences between groups were calculated using Student's t-tests for continuous data. Associations between T2 relaxation times and MRI Osteoarthritis Knee Score (MOAKS)-based tibiofemoral OA were analyzed using logistic regression with age and BMI adjustments. We defined early OA as OA developed between time-points, and late OA as OA established at the first time-point, prior to T2 mapping sequencing. Statistical analyses were performed using R (version 3.6.3). One hundred thirty-six knees had MRI defined OA at baseline, and 235 knees had OA at follow-up, meaning 99 knees developed OA the follow-up. T2 relaxation times were positively correlated with BMI, which was most pronounced in the lateral compartment (R 2 range: 0.38-0.44, all p-values <0.001). Very weak associations were found between T2 relaxation times and age for both compartments (R 2 range: 0.01-0.08). Knees with OA at follow-up had higher T2 values compared to knees without OA in the LF weight-bearing cartilage (35.7 vs. 35.3 ms, p=0.04), LT weight-bearing cartilage (35.8 vs. 34.8 ms, p<0.001), pLF cartilage (37 vs. 35.6 ms, p<0.001), MT weight-bearing cartilage (35.1 vs. 34.7, p=0.02), and pMF cartilage (37.9 vs. 36.9 ms, p<0.001). At the first time-point the LT (OR:1.11; 95%CI:1.04-1.18), pLF (OR:1.32; 95%CI:1.21-1.45), MF (OR:1.12; 95%CI:1.03-1.22), MT (OR:1.12; 95%CI:1.02-1.22), and pMF (OR:1.18; 95%CI:1.08-1.29) cartilage were significantly associated with OA after adjustments. At follow-up, LT (OR:1.08; 95%CI: 1.02-1.14), pLF (OR:1.27; 95%CI: 1.18-1.37) and pMF (OR:1.17; 95%CI:1.09-1.26) were associated with OA. In knees that developed OA during follow-up, T2 values of the pLF cartilage (OR:1.16; 95%CI:1.04-1.29) were associated with OA development. In this population-based cohort, early OA was associated with T2 values of the pLF, whereas advanced OA was associated with LT, pLF, MF, MT, and pMF cartilage segments. T2 values had very weak correlations with age, whereas weak to moderate correlations were observed between T2 relaxation values and BMI. none none. The authors are grateful to the participants and staff of the Rotterdam Study CORRESPONDENCE ADDRESS: e.oei@erasmusmc.nl

Long-Term Outcomes Following Manipulation Under Anaesthetic for Patients with Primary and Secondary Frozen Shoulder.

Frozen Shoulder (FS) is a common, debilitating condition for which manipulation under anaesthetic (MUA) is a non-invasive and effective treatment option. Current literature evaluates short to medium-term outcomes, but there is a paucity of long-term (>10 years) studies. Knowledge of long-term outcomes is also needed to evaluate whether FS or its treatment pre-disposes to other shoulder pathology in the long-term. A retrospective analysis of 398 shoulders undergoing MUA for FS between Jan 1999 and Jan 2010; 240 complete datasets were obtained. Outcomes were Oxford Shoulder Score (OSS), recurrence and development of other shoulder pathology (arthritis or rotator cuff tear). At long-term follow-up (mean 13.2 years), 71.3% had no symptoms (OSS 48), 16.6% had minor symptoms (OSS 42-47) and 12.1% had significant symptoms (OSS < 42). There were 4/240 (1.7%) self-reported recurrences > 5 years after initial MUA and 2/240 (0.8%) repeat MUAs. In the long-term 6.7% developed rotator cuff pathology and 3.8% shoulder OA. This study suggests that long-term outcome after MUA for FS is favourable. Late recurrence of FS is uncommon and the development of OA or rotator cuff pathology is no greater than that of the general population.

The Emerging Role of Non-Coding RNAs in Osteoarthritis.

Osteoarthritis (OS) is the most frequent degenerative condition in the joints, disabling many adults. Several abnormalities in the articular cartilage, subchondral bone, synovial tissue, and meniscus have been detected in the course of OA. Destruction of articular cartilage, the formation of osteophytes, subchondral sclerosis, and hyperplasia of synovial tissue are hallmarks of OA. More recently, several investigations have underscored the regulatory roles of non-coding RNAs (ncRNAs) in OA development. Different classes of non-coding RNAs, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), have been reported to affect the development of OA. The expression level of these transcripts has also been used as diagnostic tools in OA. In the present article, we aimed at reporting the role of these transcripts in this process. We need to give a specific angle on the pathology to provide meaningful thoughts on it.

Low bone mass resulting from impaired estrogen signaling in bone increases severity of load-induced osteoarthritis in female mice.

Reduced subchondral bone mass and increased remodeling are associated with early stage OA. However, the direct effect of low subchondral bone mass on the risk and severity of OA development is unclear. We sought to determine the role of low bone mass resulting from a bone-specific loss of estrogen signaling in load-induced OA development using female osteoblast-specific estrogen receptor-alpha knockout (pOC-ERαKO) mice. Osteoarthritis was induced by cyclic mechanical loading applied to the left tibia of 26-week-old female pOC-ERαKO and littermate control mice at peak loads of 6.5N, 7N, or 9N for 2weeks. Cartilage damage and thickness, osteophyte development, and joint capsule fibrosis were assessed from histological sections. Subchondral bone morphology was analyzed by microCT. The correlation between OA severity and intrinsic bone parameters was determined. The loss of ERα in bone resulted in an osteopenic subchondral bone phenotype, but did not directly affect cartilage health. Following two weeks of cyclic tibial loading to induce OA pathology, pOC-ERαKO mice developed more severe cartilage damage, larger osteophytes, and greater joint capsule fibrosis compared to littermate controls. Intrinsic bone parameters negatively correlated with measures of OA severity in loaded limbs. Subchondral bone osteopenia resulting from bone-specific loss of estrogen signaling was associated with increased severity of load-induced OA pathology, suggesting that reduced subchondral bone mass directly exacerbates load-induced OA development. Bone-specific changes associated with estrogen loss may contribute to the increased incidence of OA in post-menopausal women.

Asporin regulated by miR-26b-5p mediates chondrocyte senescence and exacerbates osteoarthritis progression via TGF-β1/Smad2 pathway.

This study aimed to investigate the role and mechanism of asporin in modulating chondrocyte senescence in OA pathology. Asporin and senescence-related hallmark expression were examined in human and experimental OA mouse cartilage samples. Twelve-week-old male C57 mice were administered with recombinant protein (rm-asporin)- or asporin-siRNA-expressing lentiviruses via intra-articular injection once a week after destabilization of the medial meniscus (DMM) surgery to induce OA. Cartilage damage was measured using the Osteoarthritis Research Society International score. Senescence-associated β-galactosidase (SA-β-Gal) staining, γH2AX, p21 and p16INK4a were analysed by immunofluorescence staining and western blot to assess the specific role of asporin in chondrocyte senescence. The TGF-β1-Smad2 signalling pathway and miR-26b-5p were further evaluated to explore the mechanism of asporin in OA. Asporin was upregulated in articular chondrocytes of OA patients and DMM mice and accompanied by accumulation of senescent cells. Asporin overexpression exaggerated OA progression, whereas silencing asporin restored chondrocyte homeostasis and deferred chondrocyte senescence, leading to markedly attenuated DMM-induced OA. Cellular and molecular analyses showed that asporin can be inhibited by miR-26b-5p, which was significantly downregulated in OA cartilage, leading to exacerbation of experimental OA partially through inhibition of TGF-β1-Smad2 signalling in chondrocytes. Our findings indicate that asporin plays an essential role in chondrocyte senescence and OA pathogenesis. Upregulated by miR-26b-5p, asporin inhibits the TGF-β1-Smad2 pathway to accelerate chondrocyte senescence and exacerbate cartilage degeneration. Targeting the miR-26b-5p-asporin-Smad2 axis may serve as a practical therapeutic strategy to delay chondrocyte senescence and OA development.

Epidemiological study of post-traumatic ankle osteoarthritis after ankle sprain in 195,393 individuals over middle age using the National Health Insurance Database: A retrospective design

ObjectivesThis study aimed to determine the risk of ankle OA onset after an incidence of sprain, relative to the risk of onset in healthy population, and to investigate the effect of gender, age, BMI, and exercise on the development of ankle OA after sprain. DesignRetrospective cohort study. MethodsUsing a sample cohort dataset from 2002 to 2013 provided by the Korean National Health Insurance Sharing Service, we calculated the mean survival time and cumulative incidence rate in sprained and healthy populations using Kaplan-Meier analysis. A Cox proportional hazards model was used to analyze the adjusted hazard ratio (HR) of sprain for the development of OA with 95% confidence intervals (CIs). Adjusted HRs of gender, age, BMI, and exercise (yes/no) were analyzed in the sprained group. ResultsAmong the selected population of 195,393 individuals, 40,876 (20.9%) were diagnosed with an ankle sprain, and 1543 (3.85%) of those individuals developed ankle OA. Of the 154,517 healthy individuals (79.1%), 4062 (2.66%) cases had progressed to OA. The sprained group had 46% (HR, 1.46; 95% CI, 1.38–1.55) greater rate of progression to ankle OA than did healthy individuals. In the sprain group, individuals who were female, obese, and overweight had 40% (HR, 1.40; 95% CI, 1.26–1.55), 43% (HR, 1.43; 95% CI, 1.12–1.82), and 22% (HR, 1.22; 95% CI, 1.10–1.35) higher incidence to develop ankle OA, respectively, compared to those who were male, underweight and normal. ConclusionsThis study found that ankle sprain was a significant risk factor for a diagnosis of early OA. Female gender and high BMI increased the incidence of ankle OA after sprain.

LOXL2 attenuates osteoarthritis through inactivating Integrin/FAK signaling

Temporomandibular joint OA (TMJOA) is a common degenerative joint disease, leads to structural damage and ultimately loss of function. Matrix degradation is one of the first pathogenesis during the progression of OA, it was effective to inhibit matrix degradation to block the development of OA. In this study, an in vivo model (compressive mechanical force) and an in vitro model (IL-1β) were used to induce OA-like changes in TMJ cartilage and chondrocytes. We revealed lysyl oxidase like-2 (LOXL2) play a critical role in TMJOA. LOXL2 expression decreased in mechanical stress/IL-β induced TMJOA-like lesions in both in vivo models and in vitro models. Furthermore, recombinant LOXL2 (rhLOXL2) treatment ameliorated the degenerative changes induced by mechanical stress in vivo, including the thinning cartilage, down-expression of collagen II and proteoglycan, and over-expression of TNF-a, while LOXL2 antibody (anti-LOXL2) treatment exacerbated these changes. Mechanistically, the protection of LOXL2 in chondrocytes was induced partly through activation of the Integrin/FAK pathway. The inhibition of the Integrin/FAK pathway could neutralized the effects caused by rhLOXL2. Collectively, our study suggests that the LOXL2 plays a protective role in mechanical stress induced TMJOA-like changes, and the Integrin/FAK pathway may be a key downstream pathway in this process.

DNA methylation and noncoding RNA in OA: Recent findings and methodological advances

IntroductionOsteoarthritis (OA) is a chronic musculoskeletal disease characterized by progressive loss of joint function. Historically, it has been characterized as a disease caused by mechanical trauma, so-called ‘wear and tear’. Over the past two decades, it has come to be understood as a complex systemic disorder involving gene-environmental interactions. Epigenetic changes have been increasingly implicated. Recent improvements in microarray and next-generation sequencing (NGS) technologies have allowed for ever more complex evaluations of epigenetic aberrations associated with the development and progression of OA. MethodsA systematic review was conducted in the Pubmed database. We curated studies that presented the results of DNA methylation and noncoding RNA research in human OA and OA animal models since 1985. ResultsHerein, we discuss recent findings and methodological advancements in OA epigenetics, including a discussion of DNA methylation, including microarray and NGS studies, and noncoding RNAs. Beyond cartilage, we also highlight studies in subchondral bone and peripheral blood mononuclear cells, which highlight widespread and potentially clinically important alterations in epigenetic patterns seen in OA patients. Finally, we discuss epigenetic editing approaches in the context of OA. ConclusionsAlthough a substantial body of literature has already been published in OA, much is still unknown. Future OA epigenetics studies will no doubt continue to broaden our understanding of underlying pathophysiology and perhaps offer novel diagnostics and/or treatments for human OA.

Possible role of MRI-detected osteophytes as a predictive biomarker for development of osteoarthritis of the knee: A study using data from the Osteoarthritis Initiative

ObjectiveTo elucidate the possible role of MRI-detected osteophytes as a predictive imaging biomarker for knee osteoarthritis (KOA). DesignSubjects (n ​= ​303) were selected according to the following inclusion criteria from the Osteoarthritis Initiative (OAI) data set: (1) ​< ​55 years old; (2) Western Ontario and McMaster Universities Arthritis Index pain score of 0; (3) Kellgren-Lawrence (KL) system grade 0 or 1; and (4) Complete MRI data set of the right knee. A pre-OA group (POA) consisted of subjects who developed KL grade 2 or more within 96 months, and a non-OA group (NOA) that remained KL 0 or 1 during that period. Baseline MRIs were assessed for osteophyte formation. Twenty-five locations were examined according to the MOAKS osteophyte score. Osteophytes at each location were assessed in terms of their predictive value for OA development. ResultsThirty-two subjects were POA and 271 were NOA. Age, BMI, and sex did not differ between the two groups. In the POA group, the number of subjects with osteophytes tended to be higher at all 25 sites. Forward stepwise regression analysis revealed five locations - medial patella, lateral intra-condylar notch of the femur, lateral femoral condyle, tibial spine, and lateral posterior condyle - were important for the prediction of KOA development. Having more than two osteophytes at these five locations predicted KOA development with a sensitivity of 0.75 and specificity of 0.79. ConclusionsMRI-detected osteophytes could serve as a predictive biomarker of KOA development within 96 months after detection.

Effect of Tobacco on Knee Joint Recovery of College Students After Sports

Objectives: By analyzing the protective effect and mechanism of tobacco on knee joint cartilage in rats, this paper studies the effect of tobacco on knee joint recovery of college students after sports. Methods: Firstly, the main subunits of nAChRs were systematically studied by using the rat knee arthritis model α 7 and α 4 and β To clarify the correlation between nAChRs and the occurrence and development of OA. Then, the OA rat model prepared by iodoacetic acid was used as the experimental object to observe the protective effect of nicotine on knee osteoarthritis cartilage in rats. Results: The histological changes of rats in MIA group were obvious after operation. The results of light microscope score and Mankin's score at 15 and 30 days were significantly higher than those in con group. Of right knee cartilage in rats in MIA group α 7, α 4 and β The expression of 2 did not change significantly on the 15th day, but increased significantly on the 30th day compared with the blank control group. Conclusion: Nicotine has a protective effect on knee bone and joint cartilage and promotes the accelerated recovery of knee bone and joint after exercise.. Key words: nicotine, knee joint, cartilage, recovery after exercise.

Neither Critical Shoulder Angle Nor Acromion Index Were Related with Specific Pathology 20 Years Later!

The critical shoulder angle (CSA) and the acromion index (AI) are measurements of acromial shape reported as predictors of degenerative rotator cuff tears (RCT) and glenohumeral osteoarthritis (GH OA). Whether they are the cause or effect of shoulder pathologies is uncertain since pre-morbid radiographs most often are lacking. The main aim of this study was to investigate if CSA or AI were related to the development of RCT or GH OA after 20 years. A secondary aim was to investigate if the CSA and AI had changed over time. In the hospital archive, 273 preoperative plain shoulder radiographs were found of patients scheduled for elective surgery other than cuff repair and arthroplasty. Forty-five images fulfilled the strict criteria published by Suter and Henninger (2015) and were used to measure CSA and AI with two independent assessors. No patient had any sign of OA in the index radiographs or any information in the medical records indicating RCT. After a median of 20 (16–22) years, 30 of these patients were radiologically re-examined with bilateral true frontal views and ultrasound of the rotator cuff. There were 19 men (20 study shoulders) and 11 females (12 study shoulders). Mean age at follow-up was 56 (32–78) years. There was no correlation between CSA (r = 0.02) (n.s) or AI (r = − 0.13) (n.s) in the primary radiographs and OA at follow-up. Nor was any correlation found between index CSA (r = 0.12) (n.s) or AI (r = − 0.13) (n.s) and RCT at follow-up. Mean difference in CSA was − 1.7 (− 10–3) degrees and mean AI difference was − 0.04 (− 0.13–0.09) between the first and the second radiographs, 20 years later. Bilaterally, mean CSA was 32 and AI 0.61 at follow-up. In this study, no correlation between the CSA, AI and development of OA or RCT could be found. The mean CSA and AI decreased over a 20-year period but the difference was very small. No difference was found between the study shoulders and the contralaterals. These findings question previously reported etiological associations between scapular anatomy and the development of OA or RCT and thereby the use of these calculations as the basis of treatment. III.

Circ-SPG11 knockdown hampers IL-1\u03b2-induced osteoarthritis progression via targeting miR-337-3p/ADAMTS5

BackgroundOsteoarthritis (OA) is responsible for the impotent disability in old people. Circular RNA (circRNA) has been reported to be related to the development of diseases. The lack of research on the role of circRNA spastic paraplegia 11 (circ-SPG11) results in conducting this study.MethodsThe expression of circ-SPG11, microRNA-337-3p (miR-337-3p), and aggrecanases like a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) mRNA was detected by quantitative real-time polymerase chain reaction (qRT-PCR). Western blot was used to measure the protein expression of extracellular matrix (ECM) degradation-related markers and ADAMTS5. Ribonuclease R (RNase R) was applied to test the stability of circ-SPG11 in CHON-001 cells. The viability, apoptosis, TNF-α and IL-6 production were determined by cell counting kit-8 (CCK-8) assay, flow cytometry assay, and enzyme-linked immunosorbent assay (ELISA), respectively. Meanwhile, the interaction between miR-337-3p and circ-SPG11 or ADAMTS5 was respectively predicted by Circinteractome or Starbase2.0, which was further verified by dual-luciferase reporter system and RNA binding protein immunoprecipitation (RIP) assay.ResultsCirc-SPG11 and ADAMTS5 were upregulated and miR-337-3p was downregulated in OA tissues and OA model cells. Circ-SPG11 knockdown allayed interleukin 1β (IL-1β)-induced restraint in viability and promotion in apoptosis, TNF-α, and IL-6 generation and ECM degradation in CHON-001 cells. Anti-miR-337-3p or ADAMTS5 overexpression correspondingly reversed si-circ-SPG11 or miR-337-3p overexpression-mediated facilitation in viability, and inhibition in apoptosis, TNF-α and IL-6 generation and ECM degradation in OA model cells. Moreover, anti-miR-337-3p ameliorated si-circ-SPG11-mediated inhibition in ADAMTS5 mRNA and protein expression in OA model cells.ConclusionCirc-SPG11 facilitated OA development via regulating miR-337-3p/ADAMTS5 axis. This finding might contribute to the improvement of OA therapy.

Long non-coding RNA KCNQ1OT1 promotes cell viability and migration as well as inhibiting degradation of CHON-001 cells by regulating miR-126-5p/TRPS1 axis

BackgroundOsteoarthritis (OA) is defined as a degenerative disease. Pivotal roles of long non-coding RNA (lncRNAs) in OA are widely elucidated. Herein, we intend to explore the function and molecular mechanism of lncRNA KCNQ1OT1 in CHON-001 cells.MethodsRelative expression of KCNQ1OT1, miR-126-5p and TRPS1 was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was examined by MTT assay. The migratory ability of chondrocytes was assessed by transwell assay. Western blot was used to determine relative protein expression of collagen II, MMP13 and TRPS1. Dual-luciferase reporter (DLR) assay was applied to test the target of lncRNA KCNQ1OT1 or miR-126-5p.ResultsRelative expression of KCNQ1OT1 and TRPS1 was reduced, whereas miR-126-5p was augmented in cartilage tissues of post-traumatic OA patients compared to those of subjects without post-traumatic OA. Increased KCNQ1OT1 or decreased miR-126-5p enhanced cell viability and migration, and repressed extracellular matrix (ECM) degradation in CHON-001 cells. MiR-126-5p was the downstream target of KCNQ1OT1, and it could directly target TRPS1. There was an inverse correlation between KCNQ1OT1 and miR-126-5p or between miR-126-5p and TRPS1. Meantime, there was a positive correlation between KCNQ1OT1 and TRPS1. The promoting impacts of KCNQ1OT1 on cell viability and migration as well as the suppressive impact of KCNQ1OT1 on ECM degradation were partially abolished by miR-126-5p overexpression or TRPS1 knockdown in CHON-001 cells.ConclusionsOverexpression of KCNQ1OT1 attenuates the development of OA by sponging miR-126-5p to target TRPS1. Our findings may provide a possible therapeutic strategy for human OA in clinic.

OSTEOARTHRITIS – А MODERN CONCEPT OF ETIOLOGY AND PATHOGENESIS

Osteoarthritis (ОА) is a disease of synovial joints, damaging all the structures of the articular apparatus with a chronic progressive course, resulting in an articular dysfunction. The modern concepts present OA as a “disease of the entire organism” – an active disease process, determined by a group of factors –systemic (genetic, neuro-humoral, hormonal) and local ( biomechanical. These factors are “general” for the development of OA, but of different extent of significance in the different articular locations. In the descriptive review are presented the modern concepts of the role and the interaction between the different factors, concerning the aetiology and pathogenesis of the disease. Also a lot of data, referring to the incidence and prevalence of OA all over the world and in our region are pointed out.

The gut microbiome as non-invasive biomarkers for identifying overweight people at risk for osteoarthritis

ObjectiveTo evaluate the potential for identifying overweight people at risk for osteoarthritis from a gut microbiome biomarker. BackgroundOsteoarthritis (OA) is the most common form of arthritis, affecting millions of people worldwide. Being overweight increases the load placed on the joints such as the knee, which increases stress and could hasten the breakdown of cartilage. Identifying overweight people at risk for osteoarthritis remains a challenge. However, emerging evidence indicates that microbial dysbiosis in the human gut might play an important role in many inflammatory diseases. Considering the role of inflammation in OA development, analysis of the gut microbiome might be a potential non-invasive tool for overweight individuals to evaluate their risk for OA. ResultsIn this prospective study, we collected 182 stool samples from overweight OA patients (n = 86) and overweight normal people (n = 96) (25 kg/m2<BMI<30 kg/m2). 16S ribosomal RNA gene sequencing for V3 and V4 regions on the Illumina MiSeq platform was used to identify bacteria at different levels and it showed that both the diversity and richness of the gut microbiome decreased in overweight OA patients. Correspondingly, 9 phyla and 87 genera had significantly differences between overweight OA patients and overweight normal people. Finally, we identified 7 optimal microbial biomarkers in genus levels as a panel, including Gemmiger, Klebsiella, Akkermansia, Bacteroides, Prevotella, Alistipes and Parabacteroides, to build the random forest model, and achieved a 83.36% area under the curve (AUC) of receiver operating characteristic (ROC). ConclusionWe present the first 16S rRNA gene sequencing profiling study of stool microbiomes in overweight people to discover and validate microbial biomarkers indicating risk for OA. Our study successfully established a 7 biomarkers prediction panel, moving towards affordable non-invasive early diagnostic biomarkers for OA in stool samples from overweight individuals.

Neither critical shoulder angle nor acromion index were related with specific pathology 20 years later!

PurposeThe critical shoulder angle (CSA) and the acromion index (AI) are measurements of acromial shape reported as predictors of degenerative rotator cuff tears (RCT) and glenohumeral osteoarthritis (GH OA). Whether they are the cause or effect of shoulder pathologies is uncertain since pre-morbid radiographs most often are lacking. The main aim of this study was to investigate if CSA or AI were related to the development of RCT or GH OA after 20 years. A secondary aim was to investigate if the CSA and AI had changed over time.MethodsIn the hospital archive, 273 preoperative plain shoulder radiographs were found of patients scheduled for elective surgery other than cuff repair and arthroplasty. Forty-five images fulfilled the strict criteria published by Suter and Henninger (2015) and were used to measure CSA and AI with two independent assessors. No patient had any sign of OA in the index radiographs or any information in the medical records indicating RCT. After a median of 20 (16–22) years, 30 of these patients were radiologically re-examined with bilateral true frontal views and ultrasound of the rotator cuff. There were 19 men (20 study shoulders) and 11 females (12 study shoulders).ResultsMean age at follow-up was 56 (32–78) years. There was no correlation between CSA (r = 0.02) (n.s) or AI (r = − 0.13) (n.s) in the primary radiographs and OA at follow-up. Nor was any correlation found between index CSA (r = 0.12) (n.s) or AI (r = − 0.13) (n.s) and RCT at follow-up. Mean difference in CSA was − 1.7 (− 10–3) degrees and mean AI difference was − 0.04 (− 0.13–0.09) between the first and the second radiographs, 20 years later. Bilaterally, mean CSA was 32 and AI 0.61 at follow-up.ConclusionIn this study, no correlation between the CSA, AI and development of OA or RCT could be found. The mean CSA and AI decreased over a 20-year period but the difference was very small. No difference was found between the study shoulders and the contralaterals. These findings question previously reported etiological associations between scapular anatomy and the development of OA or RCT and thereby the use of these calculations as the basis of treatment.Level of evidenceIII.

Cellular carbon stress is a mediator of obesity-associated osteoarthritis development

'Carbon stress' is a newly found mechanism that links obesity and dysregulated metabolism. It is defined as the cellular accumulation of metabolites during obesity post-translationally modifying metabolic proteins and decreasing their enzymatic activity. The objective of this study was to investigate if 'carbon stress' also occurs in cartilage and contributes to obesity associated OA development. We histologically evaluated for OA pathology in wild-type (WT) and hyperphagic mice (Pomc-neuron specific enhancer one deficient, PomcΔ1) that were subjected to standard chow (Chow, n=6 for both genotypes) or high-fat feeding (HFD, n=7 for both genotypes). Joints were stained and quantified for 'carbon stress' markers, including succinyl-lysine (SCK), malonyl-lysine (MAK), and acetyl-lysine (ACK). Lastly, we used a mouse model with deletion of Sirt5 (n=7), which is an enzyme that removes SCK and MAK, to test if changing the abundance of 'carbon stress' would affect OA pathogenesis. Both HFD and Pomc deficiency associated obesity induced cartilage degeneration as well as greater abundance of SCK and MAK in the cartilage. PomcΔ1-HFD mice did not have exacerbated OA pathology as compared to PomcΔ1-Chow mice. ACK was mildly increased in the obese groups comparing to WT-Chow. Sirt5-/- mice developed early-OA like phenotype at 40 weeks of age as characterized by cartilage fibrillation and more hypertrophic chondrocytes. Cartilage from Sirt5-/- mice also had increased SCK and MAK, while ACK remained unchanged comparing to WT mice. Our data suggests that carbon stress also occurs in cartilage tissue during obesity and can potentially contribute to obesity-associated OA.

CircATRNL1 protects against osteoarthritis by targeting miR-153-3p and KLF5

BackgroundOsteoarthritis (OA) is characterized by chondrocyte injury. Circular RNAs (circRNAs) are involved in the pathogenesis of various diseases, including OA. The purpose of this study was to determine the potential role of circATRNL1 in OA pathology in vitro. MethodsHuman chondrocytes were isolated and treated with interleukin-1 beta (IL-1β) to mimic OA in vitro. High-throughput RNA sequencing was performed to identify differentially expressed circRNAs, miRNAs and mRNAs between IL and 1β-treated chondrocytes and normal chondrocytes. The expression of circATRNL1, miR-153-3p and KLF5 was measured using quantitative real-time polymerase chain reaction (qRT-PCR). For functional analyses, cell apoptosis was assessed using a flow cytometry assay. Extracellular matrix (ECM) degradation was monitored by measuring the levels of ECM-associated proteins by Western blot. The potential target miRNAs of circATRNL1 were screened by bioinformatics analysis and verified by dual-luciferase reporter assay. ResultsThe expression of circATRNL1 was decreased in IL-1β-treated chondrocytes. CircATRNL1 overexpression ameliorated cell apoptosis and ECM degradation, which were promoted by IL-1β treatment. Mechanistic analysis revealed that circATRNL1 directly targeted miR-153-3p and that miR-153-3p could reverse the inhibitory effects of circATRNL1 overexpression on inflammatory responses, cell apoptosis and ECM degradation. KLF5 is a target of miR-153-3p. ConclusionTaken together, the results in this study suggested that circATRNL1 might ameliorate the development and progression of OA through regulating miR-153-3p/KLF5 axis. Our study increased the understanding of circRNAs as therapeutic targets in the treatment of OA.