ArticleLiterature Review

Defining the Osteoarthritis Patient: Back to the Future

Authors:
  • Orthopaedic Research Institute of Queensland
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Abstract

The history of osteoarthritis (OA) is important because it can help broaden our perspective on past and present controversies. The naming of OA, beginning with Heberden's nodes, is itself a fascinating story. According to Albert Hoffa, R. Llewellyn Jones and Archibald Edward Garrod, the name OA was introduced in the mid-19th century by surgeon Richard von Volkmann who distinguished it from rheumatoid arthritis and gout. Others preferred the terms 'chronical rheumatism', 'senile arthritis', 'hypertrophic arthritis' or 'arthritis deformans'. A similar narrative applies to the concept of OA affecting the whole joint vs. the 'wear-and-tear' hypothesis, inflammation and the role of the central nervous system (CNS). In the late 19th and early 20th centuries, the Garrods (father and son) and Hermann Senator argued that OA was a whole joint disease, and that inflammation played a major role in its progression. Garrod Jnr and John Spender also linked OA to a neurogenic lesion 'outside the joint'. The remaining 20th century was no less dynamic, with major advances in basic science, diagnostics, treatments, surgical interventions and technologies. Today, OA is characterized as a multi-disease with inflammation, immune and CNS dysfunction playing central roles in whole joint damage, injury progression, pain and disability. In the current 'omics' era (genomics, proteomics and metabolomics), we owe a great debt to past physicians and surgeons who dared to think 'outside-the-box' to explain and treat OA. Over 130 years later, despite these developments, we still don't fully understand the unravelling complexities of OA, and we still don't have a cure.

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... Osteoarthritis (OA) is one of the most common joint disorders currently affecting about 528 million people globally [1]. It typically affects knees, hips, hands, spine, and feet, with a profound impact on several health outcomes [2]. Actually, arthritis has a tremendous influence on individuals; the physical impairment resulting from pain and loss of functional capability reduces the quality of life and increases the incidence of further morbidity. ...
... The increasing prevalence of obesity and a sedentary lifestyle nowadays, which are prominent risk factors for OA, resulted in a substantial increase in the number of people living with hip or knee OA [2]. Similarly to OA prevalence, obesity is dramatically increasing along with its accompanying consequences which places it at the top of public healthcare priorities. ...
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Osteoarthritis (OA) is a prevalent progressive disease that frequently coexists with obesity. For several decades, OA was thought to be the result of ageing and mechanical stress on cartilage. Researchers’ perspective has been greatly transformed when cumulative findings emphasized the role of adipose tissue in the diseases. Nowadays, the metabolic effect of obesity on cartilage tissue has become an integral part of obesity research; hoping to discover a disease-modifying drug for OA. Recently, several adipokines have been reported to be associated with OA. Particularly, metrnl (meteorin-like) and retinol-binding protein 4 (RBP4) have been recognized as emerging adipokines that can mediate OA pathogenesis. Accordingly, in this review, we will summarize the latest findings concerned with the metabolic contribution of obesity in OA pathogenesis, with particular emphasis on dyslipidemia, insulin resistance and adipokines. Additionally, we will discuss the most recent adipokines that have been reported to play a role in this context. Careful consideration of these molecular mechanisms interrelated with obesity and OA will undoubtedly unveil new avenues for OA treatment.
... 10,11 OA has historically been conceptualized as a degenerative joint disease associated with cartilage loss owing to mechanical wear and tear. 12 The history of OA is checkered with confusion with other forms of arthritis, and its very name is a misnomer because it implies an inflammatory process. 13 Although often described as wear and tear on the joint, [14][15][16][17] this description of OA as a passive erosion of the joint is inaccurate. ...
... Instead, evidence suggests that OA is an active, dynamic alteration of joint tissue caused by an imbalance between injury and repair. 12,18 The observation that pain severity is poorly associated with structural changes seen on imaging 18 has shifted the focus away from the articular cartilage alone; OA is now considered a complex whole person condition associated with comorbidities 7 and influenced by epigenetic factors, 19 psychosocial factors, 20 and the central nervous system. 21 There is strong evidence that OA symptoms and disease risk are affected by modifiable biopsychosocial factors that can be within an individual's control. ...
Article
Misconceptions about osteoarthritis can disempower individuals by perpetuating beliefs that wear and tear is beyond their control and creating dependency on experts to fix the problem. Clinical discourses play a crucial role in creating awareness that patients can be empowered to take control and successfully self-manage osteoarthritis. Communication is a key competency for clinicians working with osteoarthritis, but there are no documented frameworks to guide osteoarthritis education or communication to optimize understanding and facilitate empowerment. This review examines existing empowerment models to understand the characteristics of empowerment in health and inform an empowerment-based communication framework for osteoarthritis.
... Patientreported outcome measures are used across trials to evaluate health status, and disease course or monitor patient progress after the intervention. 8,18 The widely used WOMAC has been suggested as one of the highest-performing outcome measures for knee and hip OA in terms of reliability, validity, responsiveness, and feasibility. 34 By evaluating included researches, we found that there was a lack of clarity and uniformity in how an outcome measure was used, making it more difficult to accurately interpret results between studies. ...
... Were the outcome measures clearly defined, valid, reliable, and implemented consistently across all study participants? (7) Was the length of follow-up adequate?(8) Were the statistical methods well-described?(9) ...
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Background Genicular artery embolization (GAE) is an innovative technique that has been investigated as a supplementary treatment method for chronic pain secondary to knee osteoarthritis (OA). Purpose To evaluate the current evidence on the effectiveness and safety of GAE for OA-related knee pain. Study Design Systematic review; Level of evidence, 4. Methods A systematic literature search was conducted in the PubMed, Web of Science, EMBASE, and Scopus databases to identify studies related to knee OA treated with GAE. Treatment agents were categorized as Embozene, imipenem/cilastatin, resorbable microspheres, and polyvinyl alcohol. The main outcomes were the mean difference (MD) in pre- and postembolization pain based on the visual analog scale (VAS) or the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores as well as changes in the need for pain medication. Random- and fixed-effects models were applied for data analysis. Results Of 379 initially inspected publications, 11 (N = 225 patients; 268 knees) were included in the final review. The quality of the studies was fair in 8 and poor in 3—categorized according to the National Institutes of Health quality assessment tool. Overall, 119, 72, 13, and 21 patients were treated with imipenem/cilastatin, Embozene, resorbable microspheres, and polyvinyl alcohol, respectively. Symptomatic improvement was reported in all studies. The pooled effect size, characterized by MD, showed a significant improvement in the VAS and WOMAC pain scores, with better functional status after GAE. Pre- versus postembolization MDs in VAS scores ranged from 32 within the first week to 58 after a 2-year follow-up (equivalent to 54% and 80% improvement, respectively). There was a similar trend in the overall WOMAC scores, with MDs ranging from 28.4 to 36.8 (about 58% and 85% improvement, respectively). GAE resulted in a decreased need for pain medication for knee OA, with a 27%, 65%, and 73% decline in the number of patients who used opioids, nonsteroidal anti-inflammatory drugs, and intra-articular hyaluronic acid injection, respectively ( P < .00001 for all). No significant difference between embolic agents was seen with regard to post-GAE pain reduction. No severe or life-threatening complications were reported. Conclusion OA treated by GAE using different embolic particles can be considered generally safe, with good efficacy and no reported serious complications.
... Pada osteoartritis stadium akhir, terdapat kristal kalsium fosfat dan kalsium pirofosfat dihidrat. Peran mereka tidak jelas, tetapi dianggap berkontribusi terhadap peradangan synovial (Dobson et al, 2018). ...
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Sistematika buku ini dengan judul “Epidemiologi Penyakit Tidak Menular”, mengacu pada konsep dan pembahasan hal yang terkait. Buku ini terdiri atas 17 bab yang dijelaskan secara rinci dalam pembahasan antara lain mengenai Konsep Dasar Epidemiologi Penyakit Tidak Menular; Epidemiologi Kanker Serviks; Epidemiologi Kanker Payudara; Epidemiologi Hipertensi; Epidemiologi Diabetes Mellitus; Epidemiologi Stroke; Epidemiologi Penyakit Jantung Koroner (PJK); Epidemiologi Gagal Ginjal Kronik; Epidemiologi Gastritis; Epidemiologi Katarak; Epidemiologi Osteoarthritis; Epidemiologi Penyakit Paru Obstruktif Kronis; Epidemiologi Gangguan Jiwa; Epidemiologi Obesitas; Epidemiologi Alkoholisme; Epidemiologi Penyakit Akibat Kerja; dan Epidemiologi Kecelakaan Lalu Lintas. Buku ini memberikan nuansa yang berbeda dengan buku lainnya, karena membahas berbagai epidemiologi penyakit tidak menular sesuai dengan update keilmuan. Akhirnya kami mengucapkan terima kasih yang tak terhingga kepada semua pihak yang telah mendukung dalam proses penyusunan dan penerbitan buku ini, secara khusus kepada Penerbit Media Sains Indonesia sebagai inisiator buku ini. Semoga buku ini dapat bermanfaat bagi pembaca sekalian
... Osteoarthritis has a complex pathogenesis involving inflammation, immunity, and central nervous system dysfunction and leads to joint damage, damage progression, pain, and disability 29 . Studies have shown that during the progression of the osteoarthritic process, biological and physical crosstalk occurs between bone cartilage units, leading to irreversible damage in the osteochondral units 30 . ...
Article
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Osteoarthritis (OA) is a chronic degenerative disease characterized by articular cartilage destruction and subchondral bone reconstruction in the early stages. Bergenin (Ber) is a cytoprotective polyphenol found in many medicinal plants. It has been proven to have anti-inflammatory, antioxidant, and other biological activities, which may reveal its potential role in the treatment of OA. This study aimed to determine the potential efficacy of Ber in treating OA and explore the possible underlying mechanism through network pharmacology and validation experiments. The potential co-targets and processes of Ber and OA were predicted by using network pharmacology, including a Venn diagram for intersection targets, a protein‒protein interaction (PPI) network to obtain key potential targets, and GO and KEGG pathway enrichment to reveal the probable mechanism of action of Ber on OA. Subsequently, validation experiments were carried out to investigate the effects and mechanisms of Ber in treating OA in vitro and vivo. Ber suppressed IL-1β-induced chondrocyte apoptosis and extracellular matrix catabolism by inhibiting the STAT3, NF-κB and Jun signalling pathway in vitro. Furthermore, Ber suppressed the expression of osteoclast marker genes and RANKL-induced osteoclastogenesis. Ber alleviated the progression of OA in DMM-induced OA mice model. These results demonstrated the protective efficacy and potential mechanisms of Ber against OA, which suggested that Ber could be adopted as a potential therapeutic agent for treating OA.
... Individuals with advanced OA may experience pain from nociceptive, inflammatory mechanisms, excessive (neuropathic) excitability, and/or deficient endogenous inhibitory control in pain processes (Fu et al., 2018). Classically characterized by local cartilage degeneration, bone remodeling, synovium inflammation, and soft-tissue alterations (Dobson et al., 2018), OA establishes a complex pain process described as nociplastic (Fitzcharles et al., 2021;Buldys et al., 2023), involving chronic pain with increased sensitivity due to altered function in pain-related sensory pathways (Chimenti et al., 2018). ...
Article
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Background Micro-RNAs could provide great insights about the neuropathological mechanisms associated with osteoarthritis (OA) pain processing. Using the validated Montreal Induction of Rat Arthritis Testing (MI-RAT) model, this study aimed to characterize neuroepigenetic markers susceptible to correlate with innovative pain functional phenotype and targeted neuropeptide alterations. Methods Functional biomechanical, somatosensory sensitization (peripheral–via tactile paw withdrawal threshold; central–via response to mechanical temporal summation), and diffuse noxious inhibitory control (via conditioned pain modulation) alterations were assessed sequentially in OA (n = 12) and Naïve (n = 12) rats. Joint structural, targeted spinal neuropeptides and differential expression of spinal cord micro-RNAs analyses were conducted at the sacrifice (day (D) 56). Results The MI-RAT model caused important structural damages (reaching 35.77% of cartilage surface) compared to the Naïve group (P < 0.001). This was concomitantly associated with nociceptive sensitization: ipsilateral weight shift to the contralateral hind limb (asymmetry index) from −55.61% ± 8.50% (D7) to −26.29% ± 8.50% (D35) (P < 0.0001); mechanical pain hypersensitivity was present as soon as D7 and persisting until D56 (P < 0.008); central sensitization was evident at D21 (P = 0.038); pain endogenous inhibitory control was distinguished with higher conditioned pain modulation rate (P < 0.05) at D7, D21, and D35 as a reflect of filtrated pain perception. Somatosensory profile alterations of OA rats were translated in a persistent elevation of pro-nociceptive neuropeptides substance P and bradykinin, along with an increased expression of spinal miR-181b (P = 0.029) at D56. Conclusion The MI-RAT OA model is associated, not only with structural lesions and static weight-bearing alterations, but also with a somatosensory profile that encompasses pain centralized sensitization, associated to active endogenous inhibitory/facilitatory controls, and corresponding neuropeptidomic and neuroepigenetic alterations. This preliminary neuroepigenetic research confirms the crucial role of pain endogenous inhibitory control in the development of OA chronic pain (not only hypersensitivity) and validates the MI-RAT model for its study.
... Fig 1. Key Points to Understand Osteoarthritis [7] Symptoms of Osteoarthritis OA can present with a variety of symptoms, and these can vary depending on the affected joint. [8][9][10][11][12] Common symptoms of osteoarthritis include: ...
Article
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Osteoarthritis (OA) is a prevalent degenerative joint disease that affects millions of people worldwide, causing pain, stiffness, and reduced mobility. Conventional treatments often focus on managing symptoms, but holistic healing approaches, particularly through Homoeopathy, offer a unique perspective by addressing the underlying causes and promoting overall well-being. This manuscript explores the principles of holistic healing in the context of Homoeopathic strategies for relieving osteoarthritis. Firstly, it's crucial to acknowledge the lack of conclusive scientific evidence regarding homoeopathy's efficacy in treating specific medical conditions, including osteoarthritis. However, several theoretical principles and anecdotal reports suggest it could offer benefits. In osteoarthritis, homoeopaths aim to address the underlying imbalances and triggers contributing to the disease process, rather than simply masking symptoms. Commonly used homoeopathic remedies for osteoarthritis include Rhus toxicodendron, Bryonia, and Calcarea carbonica. These remedies, chosen based on individualization and symptom presentation, are believed to address joint pain, inflammation, stiffness, and overall well-being.
... Fig 1. Key Points to Understand Osteoarthritis [7] Symptoms of Osteoarthritis OA can present with a variety of symptoms, and these can vary depending on the affected joint. [8][9][10][11][12] Common symptoms of osteoarthritis include: ...
Article
Osteoarthritis (OA) is a prevalent degenerative joint disease that affects millions of people worldwide, causing pain, stiffness, and reduced mobility. Conventional treatments often focus on managing symptoms, but holistic healing approaches, particularly through Homoeopathy, offer a unique perspective by addressing the underlying causes and promoting overall well-being. This manuscript explores the principles of holistic healing in the context of Homoeopathic strategies for relieving osteoarthritis. Firstly, it's crucial to acknowledge the lack of conclusive scientific evidence regarding homoeopathy's efficacy in treating specific medical conditions, including osteoarthritis. However, several theoretical principles and anecdotal reports suggest it could offer benefits. In osteoarthritis, homoeopaths aim to address the underlying imbalances and triggers contributing to the disease process, rather than simply masking symptoms. Commonly used homoeopathic remedies for osteoarthritis include Rhus toxicodendron, Bryonia, and Calcarea carbonica. These remedies, chosen based on individualization and symptom presentation, are believed to address joint pain, inflammation, stiffness, and overall well-being.
... Osteoarthritis (OA) is recognized as a highly prevalent and progressively debilitating articular disorder, exerting a substantial impact on individual health and quality of life. 55,56 Recent evidence has redefined OA as a metabolic disorder, transcending the traditional view of it being merely a degenerative "wear and tear" arthritis. 57,58 While a myriad of pharmacological interventions are necessary to alleviate pain and enhance life quality in OA patients, none have demonstrated efficacy in arresting or reversing the disease's progression. ...
Article
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Metrnl, recently identified as an adipokine, is a secreted protein notably expressed in white adipose tissue, barrier tissues, and activated macrophages. This adipokine plays a pivotal role in counteracting obesity-induced insulin resistance. It enhances adipose tissue functionality by promoting adipocyte differentiation, activating metabolic pathways, and exerting anti-inflammatory effects. Extensive research has identified Metrnl as a key player in modulating inflammatory responses and as an integral regulator of muscle regeneration. These findings position Metrnl as a promising biomarker and potential therapeutic target in treating inflammation-associated pathologies. Despite this, the specific anti-inflammatory mechanisms of Metrnl in immune-mediated osteolysis and arthritis remain elusive, warranting further investigation. In this review, we will briefly elaborate on the role of Metrnl in anti-inflammation function in inflammation-related osteolysis, arthritis, and pathological bone resorption, which could facilitate Metrnl’s clinical application as a novel therapeutic strategy to prevent bone loss. While the pathogenesis of elbow stiffness remains elusive, current literature suggests that Metrnl likely exerts a pivotal role in its development.
... However, the main pathogenesis pathway that worsens the OA condition is the calcification of the cartilage defect. Thus, cartilage repair may prevent the progression of osteoarthritis [3,4]. ...
Article
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Background Mesenchymal stem cells (MSCs) hold promise for osteoarthritis (OA) treatment, potentially enhanced by combining them with platelet-rich plasma (PRP) and hyaluronic acid (HA). This study aimed to assess the synergy of MSCs, PRP, and varying HA doses, and determine optimal MSC sources to treat early-stage OA in the perspective of Lysholm score, VAS Score, KSS score, and WOMAC score. Method Original articles from 2013 to 2023 were screened from four databases, focusing on clinical trials and randomized controlled trials. The Risk of Bias in Non-randomized Studies—of Interventions (ROB-2) tool evaluated bias, and a PICOS criteria table guided result construction. Revman 5.4 analyzed outcomes such as Lysholm score, VAS score, KSS, WOMAC score, cartilage volume, and defect size using MRI. This systematic review adhered to PRISMA guidelines. Result Nine studies met the final inclusion criteria. Meta-analysis revealed a significant improvement in Lysholm score (MD: 17.89; 95% CI: 16.01, 19.77; I2 = 0%, P = 0.56), a notable reduction in VAS score (MD: -2.62; 95% CI: -2.83, -2.41; I2 = 99%, P < 0.00001), elevated KSS (MD: 29.59; 95% CI: 27.66, 31.52; I2 = 95%, P < 0.0001), and reduced WOMAC score (MD: -12.38; 95% CI: -13.75, -11.01; I2 = 99%, P < 0.0001). Conclusions Arthroscopic guided high-dose subchondral application of primary cultured synovial MSCs in popliteal PRP media with HA effectively regenerates cartilage defects and improves clinical outcomes in early-stage osteoarthritis. Clarification of MSC sources and quantities enhances the understanding of this promising treatment modality.
... Knee osteoarthritis (KOA) is a common disease ranked 11th among 291 diseases in terms of causing disability across 187 countries worldwide (1). Despite 130 years of global research, the causes and pathogenesis of KOA are still not fully understood (2). KOA is a chronic disease characterized by gradual loss of cartilage, and knee cartilage declines at a faster rate with age (3). ...
Article
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Background Knee cartilage is the most crucial structure in the knee, and the reduction of cartilage thickness is a significant factor in the occurrence and development of osteoarthritis. Measuring cartilage thickness allows for a more accurate assessment of cartilage wear, but this process is relatively time-consuming. Our objectives encompass using various DL methods to segment knee cartilage from MRIs taken with different equipment and parameters, building a DL-based model for measuring and grading knee cartilage, and establishing a standardized database of knee cartilage thickness. Methods In this retrospective study, we selected a mixed knee MRI dataset consisting of 700 cases from four datasets with varying cartilage thickness. We employed four convolutional neural networks—UNet, UNet++, ResUNet, and TransUNet—to train and segment the mixed dataset, leveraging an extensive array of labeled data for effective supervised learning. Subsequently, we measured and graded the thickness of knee cartilage in 12 regions. Finally, a standard knee cartilage thickness dataset was established using 291 cases with ages ranging from 20 to 45 years and a Kellgren–Lawrence grading of 0. Results The validation results of network segmentation showed that TransUNet performed the best in the mixed dataset, with an overall dice similarity coefficient of 0.813 and an Intersection over Union of 0.692. The model’s mean absolute percentage error for automatic measurement and grading after segmentation was 0.831. The experiment also yielded standard knee cartilage thickness, with an average thickness of 1.98 mm for the femoral cartilage and 2.14 mm for the tibial cartilage. Conclusion By selecting the best knee cartilage segmentation network, we built a model with a stronger generalization ability to automatically segment, measure, and grade cartilage thickness. This model can assist surgeons in more accurately and efficiently diagnosing changes in patients’ cartilage thickness.
... The overall prevalence of primary osteoarthritis in people over 40 years old in China is as high as 46.3% and 62.2% in people over 60 years old [2], of which KOA accounts for more than 90% of osteoarthritis. The pathological manifestations of KOA are mainly cartilage fibrosis, softening, ulcer formation and deletion, subchondral osteosclerosis, osteophyte formation and synovitis [3], which seriously affect people's quality of life. The prevalence of KOA is increasing year by year, and the medical cost is huge [4], bringing a heavy burden to families and society [5]. ...
Article
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Objective To conduct a systematic review and meta-analysis to investigate the clinical efficacy of acupuncture combined with active exercise training in improving pain and function of knee osteoarthritis (KOA) individuals. Data sources PubMed, EMBASE, The Cochrane Library, Web of Science, China National Knowledge Infrastructure, Wan Fang Data, Technology Periodical Database and China Biology Medicine were searched from their inceptions to April 5, 2023. Review methods We analyzed trials of acupuncture combined with active exercise training for KOA. The included studies were of high quality (Jadad ≥ 4) and RCTs. Study selection, data extraction, risk of bias and quality assessment were independently performed by two reviewers. We performed systematic analyses based on different outcome measures, including total efficiency rate, visual analogue scale (VAS), the Western Ontario and Mcmaster Universities Osteoarthritis Index (WOMAC), the Lysholm Knee Scale (LKS) and range of motion (ROM). We used Review Manager 5.3 and Stata/MP 14.0 to analyze the data. And it was verified by trial sequence analysis (TSA). If I 2 > 50% and p < 0.05, we performed sensitivity analysis and subgroup analysis to find the source of heterogeneity. Publication bias was studied by funnel plot and Egger’s test was used to verify it. Results Full 11 high-quality studies (Jadad ≥ 4) including 774 KOA individuals were included in this review for meta-analysis. The results showed that acupuncture combined with active exercise training (combined group) was superior to the acupuncture group in improving the total effective rate [RR = 1.13, 95%CI (1.05, 1.22), I 2 = 0%, P = 0.70], reducing the pain level (VAS) [MD = − 0.74, 95%CI (− 1.04, − 0.43), I 2 = 68%, P < 0.05], improving knee joint function (WOMAC) [MD = − 6.97, 95%CI (− 10.74, − 3.19), I 2 = 76%, P < 0.05] and improving joint range of motion (ROM) [MD = 6.25, 95%CI (2.37, 10.04), I 2 = 0%, P = 0.71]. Similarly, the combined group showed significant improvements in the total effective rate [RR = 1.31, 95% CI (1.18, 1.47), I 2 = 48%, P = 0.10], pain (VAS) [MD = 1.42, 95% CI (− 1.85, − 1.00), I 2 = 65%, P = 0.02] and knee function (WOMAC) [MD = 7.05, 95% CI (− 11.43, − 2.66), I 2 = 86%, P < 0.05] compared with the non-acupuncture group. Conclusion The combined effect of all studies showed significant benefits of acupuncture combined with active exercise training in improving the total effective rate, reducing pain, promoting recovery of knee function and expanding range of motion. However, some evaluation indicators are highly subjective and need to be further confirmed by more objective and evidence-based high-quality RCTs in future. Systematic Review Registration: [PROSPERO], identifier [No. CRD42023425823].
... A multicenter group of studies developed diagnostic criteria for OA of the knees 3 . Currently, OA is recognized as a chronic inflammatory disease involving malalignment with progressive joint loads, instability, cartilage erosion, matrix degeneration, reduced joint space damage, ligament damage, and thickening of the subchondral bone; It is also characterized as a multiple diseases with immune and central nervous system dysfunction, which contributes to complete joint damage, progression of lesions, pain, and disability 4 . Treatment of injuries caused by OA of the knees is challenging, and treatment decisions for individual injuries are problematic 5 . ...
Article
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Background: The optimal treatment for patients with osteoarthritis (OA) of the knees and meniscal injuries has been extensively analyzed. Most research studies of patients treated by arthroscopic surgery have shown satisfactory results in the short and medium term. Objective: To evaluate if arthroscopic knee surgery provides additional benefit over a 3-year period in middle-aged patients with meniscal and knee-locking symptoms and to demonstrate that arthroscopic surgery of osteoarthritic knees improves patient function and satisfaction. Methods: A retrospective analysis was performed on 50 consecutive patients (51 knees) with a diagnosis of OA, treated with arthroscopic surgery. Radiological lesions were classified using the Kellgren-Lawrence scale, and the extent of OA was classified using the International Cartilage Repair Society (IRCS) classification. The results were evaluated using a postoperative knee scale that contains three parameters. The follow-up period was three years. Results: The patients had 64.7% good results, 21.56% regular results, and 13.72% bad results. The best results were obtained in patients with mild and moderate OA and symptoms of mechanical joint injury. The effect of predictive factors was uncertain due to the small sample size in subgroup analyses. Conclusion: Treatment with arthroscopic surgery can improve function and activity levels in patients with mild and moderate OA, allowing the best results to be obtained in those with symptoms of pain and blockage due to loose bodies or meniscal tears. In clinical relevance, arthroscopic surgery in knee OA produces significant improvement in selected patients that allows to improve pain, mobility and function. Level of Evidence: level IV; retrospective longitudinal cohort study.
... Cette précision dans la représentation des déformations et leur utilisation comme marqueurs d'un âge avancé tiennent probablement plus de l'observation des artistes eux-mêmes, éventuellement sur des modèles, qu'aux connaissances médicales contemporaines ; l'ensemble des pathologies atteignant les articulations était le plus souvent rassemblé sous le terme générique de goutte. Guillaume de Baillou (1538-1616) est le premier à introduire le terme de rhumatisme, sans encore faire la distinction entre inflammatoire et dégénératif [3]. ...
... All authors approved the final version to be published. ning of the synovial membrane are common in OA. 2 All of the changes above will cause joint pain. 3 The appearance of pain in the sensi will reduce the daily functional activities of the body. ...
Article
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Background: The sodium may aggravate synovial inflammation and cartilage thinning. This incidence can cause joint pain and reduce functional activity. Not many people know the effect of sodium on the incidence of osteoarthritis. Objective: This study aims to determine the relationship between sodium in the body and knee joint pain which results in functional activity. Methods: The quantitative descriptive study used accidental sampling. The study was conducted at three outpatient polyclinic orthopedics of hospitals and was approved by the Health Ethics Committee. All data were collected during the interview. The Semi-Quantitative Food Frequency Questionnaire and the Nutrisurvey Indonesia 2007 application were used as a tool to collect daily sodium intake (mg). Knee joint pain score was measured using the Visual Analog Scale (VAS), while functional body activity was measured using the Western Ontario McMaster Osteoarthritis Index (WOMAC). The Pearson and Spearman test (P<0.05) were used as a correlation test. Results: 80 subjects were recruited according to the inclusion criteria. Characteristics of the subjects were pre-elderly (32, 40%), women (74, 92.5%), body mass index ≥30 kg/m2 (54, 67.5%) and occupation (43, 53.75%). Average sodium intake = 2090.78±1084.33 mg, VAS score = 6.28±1.95 and WOMAC score = 32.65±14.88. The correlation sodium, VAS, and WOMAC were not significant (P=0.196, P=0.372). Conclusions: Increased sodium intake is not associated with knee joint pain and functional body activity.
... It occurs mainly in women. The main risk factors are age, obesity, lack of physical activity, chronic stress, and a poor diet (Dobson et al., 2018;Malfait, 2016). It is characterized by inflammation in the joints. ...
... The incidence of this disease increases with age. The onset of OA is mostly associated with factors such as gender, age, obesity, genetics, mechanical forces, and congenital abnormalities of the joint (Dobson et al. 2018). Under the combined effect of several factors, including mechanical and biological factors, degeneration of cartilage tissue occurs, the cartilage surface is roughened, and cartilage undergoes local to comprehensive destruction, eventually leading to the exposure of subchondral bone (Willy et al. 2008). ...
Article
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Context Rongjin Niantong Fang (RJNTF) is a Traditional Chinese Medicine formulation with a good therapeutic effect on osteoarthritis (OA). However, the underlying mechanisms remain unclear. Objective This study investigates whether RJNTF could delay OA cartilage degeneration by regulating the SDF-1/CXCR4-p38MAPK signalling pathway. Materials and methods The Sprague-Dawley (SD) rats were used to establish the OA model by a modified Hulth’s method. SD rats were divided into three groups (n = 10): blank group, model group (0.9% saline, 10 mL/kg/day), and treatment group (RJNTF, 4.5 g/kg/day). After 12 weeks of treatment, each group was analysed by H&E, Safranine-O solid green, ELISA, Immunohistochemistry, and Western blot. An in vitro model was induced with 100 ng/mL SDF-1 by ELISA, the blank group, model group, RJNTF group, and inhibitor group with intervention for 12 h, each group was analysed by Immunofluorescence staining and Western blot. Results SDF-1 content in the synovium was reduced in RJNTF treatment group compared to non-treatment model group (788.10 vs. 867.32 pg/mL) and down-regulation of CXCR4, MMP-3, MMP-9, MMP-13 protein expression, along with p38 protein phosphorylated were observed in RJNTF treatment group. In vitro results showed that RJNTF (IC50 = 8.925 mg/mL) intervention could down-regulate SDF-1 induced CXCR4 and p38 protein phosphorylated and reduce the synthesis of MMP-3, MMP-9, and MMP-13 proteins of chondrocytes from SD rat cartilage tissues. Discussion and conclusion RJNTF alleviates OA cartilage damage by SDF-1/CXCR4-p38MAPK signalling pathway inhibition. Our ongoing research focuses on Whether RJNTF treats OA through alternative pathways.
... OA is a progressively degenerative disease of the articular cartilage which provides protection and a cushion for smooth gliding between joint surfaces [3]. OA, rheumatoid arthritis (RA), and psoriatic arthritis were distinguished by Richard von Volkmann in the mid-1850s as the three major forms of arthritis, with osteoarthritis reintroduced and popularized by John Kent Spender in 1886 [4,5]. In 1895, Henry Waldo described patients with OA experiencing a loss of power, slight sensory deficits, weakness, fatigue, and associated pain [6]. ...
Article
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Osteoarthritis (OA) is the most common form of arthritis, affecting approximately 32.5 million adults in the United States. OA is characterized as a degenerative joint disease or "wear and tear" arthritis. Symptoms experienced by patients include, but are not limited to, swelling, stiffness, pain or aching, and decreased range of motion. The majority of individuals impacted by OA are over the age of 65. OA has long been thought of as an inevitable part of aging. Patients are typically diagnosed after the onset of symptoms once irreversible damage has occurred, such as the breakdown of bone and cartilage. Along with clinical presentations, medical professionals often relied on radiographic images to confirm the diagnosis of OA. Limited research has looked into how to catch OA early and stage patients in a pre-OA state, possibly preventing irreparable damage that is observable radiographically. This article presents the history, diagnosis, and classes of OA. In addition, we present multiple diagnostic tools currently used and others under investigation, including OA-specific biomarkers and electroarthrography (EAG). These tools show promise as aids in early OA diagnosis and intervention, ultimately slowing down or altogether stopping the progression of OA. In conjunction or individually, these techniques, if further developed, stand out as promising mechanisms that may decrease the current OA burden on the healthcare system.
... CNS has been known to play a role in OA pain and implications for rehabilitation (Murphy et al., 2012). With the development of neurophysiology, it has been known that the imbalance of body's CNS and peripheral circuits is involved in OA progression (Dobson et al., 2018). Moreover, the CNS theory in OA pathophysiology is gradually refined, the new components of which includes hypothalamic-pituitary axis, nucleus tractus solitarius, hypothalamic suprachiasmatic nucleus and other associated higher centers. ...
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Osteoarthritis (OA) is a multifactorial joint disease characterized by degeneration of articular cartilage, which leads to joints pain, disability and reduced quality of life in patients with OA. Interpreting the potential mechanisms underlying OA pathogenesis is crucial to the development of new disease modifying treatments. Although multiple factors contribute to the initiation and progression of OA, gut microbiota has gradually been regarded as an important pathogenic factor in the development of OA. Gut microbiota can be regarded as a multifunctional “organ”, closely related to a series of immune, metabolic and neurological functions. This review summarized research evidences supporting the correlation between gut microbiota and OA, and interpreted the potential mechanisms underlying the correlation from four aspects: immune system, metabolism, gut-brain axis and gut microbiota modulation. Future research should focus on whether there are specific gut microbiota composition or even specific pathogens and the corresponding signaling pathways that contribute to the initiation and progression of OA, and validate the potential of targeting gut microbiota for the treatment of patients with OA.
... Knee osteoarthritis (KOA) is the most prevalent subtype of osteoarthritis [4] that shows symptoms with pain, swell, stiffness, and loss of mobility mainly in the aging and obese populations [5]. The pathogenesis of KOA is complicated, not only associated with the "wear and tear, " which is called mechanical stress [6]. Microenvironmental and genetic factors interact during deterioration that ultimately leads to degeneration of articular cartilage, intraarticular inflammation with synovitis, and changes in subchondral bone [7,8]. ...
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Osteoarthritis, as a degenerative disease, is a common problem and results in high socioeconomic costs and rates of disability. The most commonly affected joint is the knee and characterized by progressive destruction of articular cartilage, loss of extracellular matrix, and progressive inflammation. Mesenchymal stromal cell (MSC)-based therapy has been explored as a new regenerative treatment for knee osteoarthritis in recent years. However, the detailed functions of MSC-based therapy and related mechanism, especially of cartilage regeneration, have not been explained. Hence, this review summarized how to choose, authenticate, and culture different origins of MSCs and derived exosomes. Moreover, clinical application and the latest mechanistical findings of MSC-based therapy in cartilage regeneration were also demonstrated.
... OA is now considered a complex whole joint disease, and there is a common environment in the joint cavity. 4 Most previous studies concentrated on cartilage and chondrocytes' functions in the pathogenesis and treatment of OA. 5 With the further development of medicine, studies have proved that synovitis has a high prevalence in all stages of OA. Many researchers have shown that synovial inflammation is associated with pain, dysfunction, and may even be an independent driving factor for the onset and structural progression of OA in radiology. ...
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Osteoarthritis (OA) is a severe disease and has brought a massive burden to people's daily life. This study was performed to explore the hub genes associated with OA and predict potential biomarkers for OA. The cartilage (GSE114007) and synovial (GSE55235 and GSE55457) datasets downloaded from the Gene Expression Omnibus (GEO) database were used to screen the differentially expressed genes in OA compared with normal tissues. Then, based on weighted gene co-expression network analysis, the intersection genes between cartilage and synovium data were screened. The protein-protein interaction network and receiver operating characteristic (ROC) curve analysis were utilized to identify the OA-related hub genes. The gene ontology (GO), kyoto encyclopedia of genes and genomes (KEGG), and gene set variation analysis (GSVA) databases were used to explore the potential molecular mechanism of genes. Single-sample gene set enrichment analysis was performed to analyze the immune infiltration levels in OA synovium and cartilage tissues, respectively. A total of 131 intersection genes were screened. These genes were mainly enriched in the osteoclast differentiation and PI3K-Akt signaling pathways. Then, eight OA-related hub genes were further identified, including JUN, MYC, VEGFA, ATF3, NR4A1, BTG2, DUSP1, and JUNB. ROC curve analysis showed the area under the curve of these eight genes was > 0.6 in another OA dataset, suggesting their feasible capacity for predicting OA. Finally, we found that NR4A1 and BTG2 might be involved in multiple inflammatory responses of OA tissues. Our study identified some OA-related hub genes and revealed novel insights into the biological mechanism of OA, which provided a theoretical foundation for further experimental study.
... At present, the complexity of OA, which has no cure, is still not fully understood. In recent years, integrated genomics, proteomics, metabolics, and bioelectronics were used to explore OA chondrocytes [95]. Losing weight and practicing sporting activities can improve joint pain and function in OA patients. ...
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Background: Osteoarthritis (OA) is a clinical joint degenerative disease, the pathogenic factors of which include age, obesity, and mechanical injury. Its main pathological features include cartilage loss, narrowing of joint space, and osteophyte formation. At present, there are a variety of treatment methods for OA. Natural products, which are gradually being applied in the treatment of OA, are advantageous as they present with low toxicity and low costs and act on multiple targets. Methods: The terms "natural products," "osteoarthritis," and "chondrocytes" were searched in PubMed to screen the related literature in the recent 10 years. Results: We comprehensively introduced 62 published papers on 48 natural products involving 6, 3, 5, 12, 4, and 5 kinds of terpenoids, polysaccharides, polyphenols, flavonoids, alkaloids, and saponins, respectively (and others). Conclusion: The mechanisms of their anti-OA action mainly involve reducing the production of inflammatory factors, reducing oxidative stress, regulating the metabolism of chondrocytes, promoting the proliferation of chondrocytes, or inhibiting chondrocyte apoptosis. This article summarizes the anti-OA activity of natural products in the last 10 years and provides candidate monomers for further study for use in OA treatment.
... The main pathological changes in OA are articular cartilage loss and collagen fiber degeneration [38], which can lead to bone hyperplasia and osteophyte formation when the original mechanical balance of the knee joint is disrupted [39]. Therefore, these pathological changes can reflect the clinical characteristics of this degenerative joint disease [40,41]. Mmps participate in the degradation of many matrix components, and the activities of Mmps are regulated by hormones and cytokines in vivo [20,42]. ...
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Achyranthes japonica Nakai root (AJNR) is used to treat osteoarthritis (OA) and rheumatoid arthritis (RA) owing to its anti-inflammatory and antioxidant effects. This study investigated the inhibitory effects of AJNR on arthritis. AJNR was extracted using supercritical carbon dioxide (CO2), and its main compounds, pimaric and kaurenoic acid, were identified. ANJR’s inhibitory effects against arthritis were evaluated using primary cultures of articular chondrocytes and two in vivo arthritis models: destabilization of the medial meniscus (DMM) as an OA model, and collagenase-induced arthritis (CIA) as an RA model. AJNR did not affect pro-inflammatory cytokine (IL-1β, TNF-α, IL-6)-mediated cytotoxicity, but attenuated pro-inflammatory cytokine-mediated increases in catabolic factors, and recovered pro-inflammatory cytokine-mediated decreases in related anabolic factors related to in vitro. The effect of AJNR is particularly specific to IL-6-mediated catabolic or anabolic alteration. In a DMM model, AJNR decreased cartilage erosion, subchondral plate thickness, osteophyte size, and osteophyte maturity. In a CIA model, AJNR effectively inhibited cartilage degeneration and synovium inflammation in either the ankle or knee and reduced pannus formation in both the knee and ankle. Immunohistochemistry analysis revealed that AJNR mainly acted via the inhibitory effects of IL-6-mediated matrix metalloproteinase-3 and -13 in both arthritis models. Therefore, AJNR is a potential therapeutic agent for relieving arthritis symptoms.
... 5 Thus, characterising the molecular mechanisms of chondrocytes involved in OA development and pathogenesis is crucial for improving prognosis and developing effective therapies. [6][7][8] Recently, a growing number of studies have identified various functional non-coding RNAs, including circular RNAs (circRNAs), many of which are present in the human transcriptome. 9 The expression of these circRNAs exhibits tissue specificity, while their heterocyclic structure makes them highly stable. ...
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Objectives Circular RNAs (circRNAs) have emerged as significant biological regulators. Herein, we aimed to elucidate the role of an unidentified circRNA (circPDE4B) that is reportedly downregulated in osteoarthritis (OA) tissues. Methods The effects of circPDE4B were explored in human and mouse chondrocytes in vitro. Specifically, RNA pull-down (RPD)-mass spectrometry analysis (MS), immunoprecipitation, glutathione-S-transferase (GST) pull-down, RNA immunoprecipitation and RPD assays were performed to verify the interactions between circPDE4B and the RIC8 guanine nucleotide exchange factor A (RIC8A)/midline 1 (MID1) complex. A mouse model of OA was also employed to confirm the role of circPDE4B in OA pathogenesis in vivo. Results circPDE4B regulates chondrocyte cell viability and extracellular matrix metabolism. Mechanistically, FUS RNA binding protein (FUS) was found to promote the splicing of circPDE4B, while downregulation of circPDE4B in OA is partially caused by upstream inhibition of FUS. Moreover, circPDE4B facilitates the association between RIC8A and MID1 by acting as a scaffold to promote RIC8A degradation through proteasomal degradation. Furthermore, ubiquitination of RIC8A at K415 abrogates RIC8A degradation. The circPDE4B–RIC8A axis was observed to play an important role in regulating downstream p38 mitogen-activated protein kinase (MAPK) signalling. Furthermore, delivery of a circPDE4B adeno-associated virus (AAV) abrogates the breakdown of cartilage matrix by medial meniscus destabilisation in mice, whereas a RIC8A AAV induces the opposite effect. Conclusion This work highlights the function of the circPDE4B–RIC8A axis in OA joints, as well as its regulation of MAPK-p38, suggesting this axis as a potential therapeutic target for OA.
... The current non-surgical treatments and surgical treatments for knee OA are all symptom-modifying treatments, and no disease-modifying treatment exists at present [7]. Thus, both indication and timing for each treatment are very important for ensuring improvement in the mobility of knee OA patients. ...
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Objective Knee osteoarthritis (OA) is one of the most common causes for reduction in gait speed. Research into the mechanism of underlying knee OA pain and other symptoms such as the reduction in the gait speed is essential to development of disease-modifying treatments for knee OA. We examined the magnetic resonance imaging (MRI)-detected structural alterations in knee joints those were associated with gait speed in knee OA patients. Design In this cross-sectional study, structural alterations in knee joints of 74 knee OA patients (51 females; mean 72.2 years old) were evaluated by MRI, and subjects’ gait speed was measured. Results The mean self-selected gait speed of the subjects was 0.73±0.21 m/s. A simple linear regression analysis revealed that MME was only correlated with the gait speed of the subjects with knee OA, while cartilage lesion, bone marrow lesion, subchondral bone cyst, subchondral cyst, osteophytes and meniscal pathology were not. A multiple regression analysis revealed that only MME was associated with gait speed (R²=0.484, p<0.001). The area under the receiver operating characteristic curve for determining <0.8 m/s of gait speed as evaluated by MME were 0.72 (95% confidence interval: 0.60-0.84). The relative risks at a cut-off <0.8 m/s for gait speed as evaluated by MME at 6.2 mm were 2.19 (1.28-3.46, p=0.01). Conclusions MME was associated with and the determinant for gait speed among MRI-detected structural alterations in patients with knee OA, suggesting the importance for elucidating the etiology of MME for developing a disease-modifying treatment for knee OA.
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Editorial on the Research Topic Metabolic disorders as risk factors for osteoarthritis and targeted therapies for this pathology
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Aims Machine learning (ML), a branch of artificial intelligence that uses algorithms to learn from data and make predictions, offers a pathway towards more personalized and tailored surgical treatments. This approach is particularly relevant to prevalent joint diseases such as osteoarthritis (OA). In contrast to end-stage disease, where joint arthroplasty provides excellent results, early stages of OA currently lack effective therapies to halt or reverse progression. Accurate prediction of OA progression is crucial if timely interventions are to be developed, to enhance patient care and optimize the design of clinical trials. Methods A systematic review was conducted in accordance with PRISMA guidelines. We searched MEDLINE and Embase on 5 May 2024 for studies utilizing ML to predict OA progression. Titles and abstracts were independently screened, followed by full-text reviews for studies that met the eligibility criteria. Key information was extracted and synthesized for analysis, including types of data (such as clinical, radiological, or biochemical), definitions of OA progression, ML algorithms, validation methods, and outcome measures. Results Out of 1,160 studies initially identified, 39 were included. Most studies (85%) were published between 2020 and 2024, with 82% using publicly available datasets, primarily the Osteoarthritis Initiative. ML methods were predominantly supervised, with significant variability in the definitions of OA progression: most studies focused on structural changes (59%), while fewer addressed pain progression or both. Deep learning was used in 44% of studies, while automated ML was used in 5%. There was a lack of standardization in evaluation metrics and limited external validation. Interpretability was explored in 54% of studies, primarily using SHapley Additive exPlanations. Conclusion Our systematic review demonstrates the feasibility of ML models in predicting OA progression, but also uncovers critical limitations that currently restrict their clinical applicability. Future priorities should include diversifying data sources, standardizing outcome measures, enforcing rigorous validation, and integrating more sophisticated algorithms. This paradigm shift from predictive modelling to actionable clinical tools has the potential to transform patient care and disease management in orthopaedic practice. Cite this article: Bone Joint J 2024;106-B(11):1216–1222.
Article
Objective To investigate the effect of higher cumulative defined daily dose per year (cDDD/y) compared with lower cDDD/y of statin use in the incidence of any joint osteoarthritis (OA). Design In this population-based retrospective cohort study, patients who were aged ≥40 years were newly initiated on statin therapy between 2002 and 2011, and had a statin prescription for ≥90 days in the first year of treatment were identified from the 2000 Longitudinal Generation Tracking Database. All patients were separated into groups with higher cDDD/y (>120 cDDD/y) and lower cDDD/y (≤120 cDDD/y; as an active comparator) values. Propensity score matching was performed to balance potential confounders. All recruited patients were followed up for 8 years. Marginal Cox proportional hazard models were used to estimate time-to-event outcomes of OA. Results Compared with lower cDDD/y use, higher cDDD/y use did not reduce the risk of any joint OA (adjusted hazard ratio, 1.07; 95% confidence interval, 0.99-1.14). Dose-related analysis did not reveal any dose-dependent association. A series of sensitivity analyses showed similar results. Joint-specific analyses revealed that statin did not reduce the incidence of knee, hand, hip, and weight-bearing (knee or hip) OA. Conclusions Higher cDDD/y statin use did not reduce the risk of OA in this Taiwanese nationwide cohort study. The complexity of OA pathogenesis might contribute to the ineffectiveness of statin. Repurposing statin with its anti-inflammation properties might be ineffective for OA development, and balancing the catabolism and anabolism of cartilage might be a major strategy for OA prevention.
Article
The role of this study was to evaluate the impact of gut microbiota depletion on the progression of osteoarthritis (OA) and osteoporosis (OP). We conducted an experimental mouse model of OA and OP over an 8-week period. The model involved destabilization of the medial meniscus (DMM) and bilateral ovariectomy (OVX). To deplete the gut microbiota, we administered a course of antibiotics for 8 weeks. The severity of OA was assessed through micro-CT scanning, X-rays, and immunohistochemical staining. Microbiome analysis was performed using PCR of 16S DNA on fecal samples, and the levels of serum lipopolysaccharide, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), osteocalcin, and estrogen were measured using enzyme-linked immunosorbent assay (ELISA). We found that in comparison to the OVX+OA group, the OVX+OA+ABT group exhibited increased bone mineral density (BMD) (P<0.0001), bone volume fraction (P=0.0051), and trabecular number (P=0.0023) in the metaphyseal bone. Additionally, cartilage injury and levels of MMP-13 were reduced in the OVX+OA+ABT group compared to the OVX+OA group. Moreover, the OV6X+OA+ABT group demonstrated decreased relative abundance of Bacteroidetes, serum lipopolysaccharide (P=0.0005), TNF-α (P<0.0001), CTX-1 (P=0.0002), and increased expression of bone formation markers. These findings were further supported by correlation network analyses. Depletion of gut microbiota was shown to protect against bone loss and cartilage degradation by modulating the composition of the gut microbiota in osteoporosis and osteoarthritis.
Article
Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease with the cessation of matrix anabolism and aggravation of inflammation, which results in severe pain and impaired joint function. However, the mechanisms are not well understood. Circular RNAs (circRNAs) are reported to have various biological functions and participate in the development, diagnosis, prognosis, and treatment of different diseases. This study aimed to investigate the roles and mechanisms of circ-slain2 in TMJOA. We first established TMJOA mouse models and found circ-slain2 was lowly expressed in the cartilage of TMJOA through sequencing data. We observed that circ-slain2 is predominantly localized in the cytoplasm and downregulated in mouse condylar chondrocytes (mCCs) treated with tumor necrosis factor α (TNFα) and interferon γ (IFNγ). Micro–computed tomography and histological examination showed that intra-articular injection of circ-slain2 overexpressing adeno-associated virus could alleviate cartilage catabolism and synovial inflammation to relieve TMJOA in vivo. In addition, elevated circ-slain2 also showed anticatabolic and anti-inflammatory effects on IFNγ- and TNFα-stimulated mouse condylar chondrocytes (mCCs). Functional enrichment analysis indicated that protein processing in endoplasmic reticulum (ER) was associated with TMJOA, and further functional experiments confirmed that circ-slain2 could suppress ER stress in OA mCCs. RNA binding protein immunoprecipitation assay revealed an overt interaction between activating transcription factor 6 (ATF6) and circ-slain2. Inhibition of the expression of both ATF6 and circ-slain2 resulted in dilation of the ER and enhanced the expression of ER stress markers, whose ER stress level was higher than inhibition of ATF6 but lower than knockdown of circ-slain2 expression. Collectively, our research demonstrated that circ-slain2 could regulate ATF6 to relieve ER stress, reducing temporomandibular joint cartilage degradation and synovial inflammation. These findings provide prospects for developing novel osteoarthritis therapies based on circ-slain2 by focusing on reducing the inflammation of synovium and the imbalance between matrix synthesis and degradation.
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Osteoarthritis (OA), a common joint disorder with articular cartilage degradation as the main pathological change, is the major source of pain and disability worldwide. Despite current treatments, the overall treatment outcome is unsatisfactory. Thus, patients with severe OA often require joint replacement surgery. In recent years, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option for preclinical and clinical palliation of OA. MSC-derived exosomes (MSC-Exos) carrying bioactive molecules of the parental cells, including non-coding RNAs (ncRNAs) and proteins, have demonstrated a significant impact on the modulation of various physiological behaviors of cells in the joint cavity, making them promising candidates for cell-free therapy for OA. This review provides a comprehensive overview of the biosynthesis and composition of MSC-Exos and their mechanisms of action in OA. We also discussed the potential of MSC-Exos as a therapeutic tool for modulating intercellular communication in OA. Additionally, we explored bioengineering approaches to enhance MSC-Exos’ therapeutic potential, which may help to overcome challenges and achieve clinically meaningful OA therapies.
Article
Objectives: Osteoarthritis (OA) causes long-term pain and disorders of lower extremities. Paracetamol is the drug of choice, however, NSAIDs, opioids and steroids are frequently employed in the symptomatic relief of OA. The prescribing of multiple analgesics leads to potential drug-drug interactions (pDDIs). The primary objective of this study was to identify the prevalence and predictors of pDDIs in OA. Materials and methods: A total of three hundred and eighty-six patients, either newly diagnosed or with a history of OA were enrolled for this cross-sectional study. Data regarding patients' demographics, clinical characteristics and prescribed medications were recorded from the prescriptions and examined for the pDDIs using Medscape multi-drug interaction checker. Results: Among 386, most patients were females (53.4%). The most prevalent diagnoses were knee OA (39.7%) and unspecified OA (31.3%). Paracetamol and topical NSAIDs were under-prescribed whereas an oral NSAID, Diclofenac, was the most frequently used drug in OA. Total of 109 pDDIs were found in 386 prescriptions, of which, 63.3% DDIs were categorised as moderate, followed by minor (34.9%) and major (1.8%). Conclusions: This study finds a prevalence of DDIs and polypharmacy among the OA patients. Collaborative efforts among healthcare providers, pharmacists, and patients themselves are essential to optimize medication regimens and minimize the polypharmacy including the associated risks as well as DDIs.
Article
Excessive reactive oxygen species (ROS) in joints could lead to gradual degeneration of the extracellular matrix (ECM) and apoptosis of chondrocytes, contributing to the occurrence and development of osteoarthritis (OA). Mimicking natural enzymes, polydopamine (PDA)-based nanozymes showed great potential in treating various inflammatory diseases. In this work, PDA loaded with ultra-small palladium (PDA-Pd) nanoparticles (NPs) was employed to scavenge ROS for OA therapy. As a result, PDA-Pd effectively declined the intracellular ROS levels and exhibited efficient antioxidative and anti-inflammatory capacity with good biocompatibility in IL-1β stimulated chondrocytes. Significantly, assisted with near-infrared (NIR) irradiation, its therapeutic effect was further enhanced. Further, NIR-stimulated PDA-Pd suppressed the progression of OA after intra-articular injection in the OA rat model. With favorable biocompatibility, PDA-Pd exhibits efficient antioxidative and anti-inflammatory capacity, leading to the alleviation of OA in rats. Our findings may provide new insights into the treatment of various ROS-induced inflammatory diseases.
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Objective This study aimed to determine whether alignment correction by high tibial osteotomy (HTO) can change the biologic intraarticular microenvironment of osteoarthritic (OA) knees. Methods Synovial tissue (ST) and fluid (SF) were collected from the affected knees of 31 OA patients during initial HTO and plate removal surgeries. Changes in gene expression in ST were investigated by microarray and real‐time polymerase chain reaction (PCR). ST specimens were also evaluated histologically using synovitis scores and immunofluorescence staining to determine macrophage polarity. Cytokines and chemokines in SF were analyzed by enzyme‐linked immunosorbent assays. The mechanism of macrophage polarization was investigated in human peripheral blood mononuclear cell–derived macrophages and fibroblast‐like synoviocytes (FLS) stimulated with cartilage fragments. We also evaluated Spearman correlations between Knee Injury and Osteoarthritis Outcome scores (KOOS) and macrophage‐related gene expression. Results The microarray results indicated down‐regulated inflammatory genes and pathways. Real‐time PCR determined that genes expressing proinflammatory IL1B and IL6 were down‐regulated and M2 macrophage–related IL1RA, IL10, CCL18, and CD206 were up‐regulated. Histologic findings revealed attenuated synovitis scores and a shift from M1 to M2 macrophages. Interleukin‐1β (IL‐1β) concentrations in SF decreased after HTO. Cartilage fragments were responsible for M1 macrophage polarization and proinflammatory gene and protein expression in macrophages, whereas cartilage fragments up‐regulated only IL‐6 protein in FLS. Postoperative KOOS positively correlated with the expression of the M2‐related genes CCL18 and CD206. Conclusion Correction of lower limb alignment with HTO attenuated synovial inflammation and changed macrophage polarization from M1 to M2, suggesting an improved intraarticular environment in knee OA.
Article
Osteoarthritis (OA), a chronic degenerative disease, is a major cause of pain, disability, and reduced quality of life among the elderly worldwide. The key to treating it is early prevention and effective intervention. The anti-inflammatory effects of scutellarin (SCU), a flavonoid derived from Erigeron breviscapus, have been increasingly reported. However, the mechanism by which SCU affects OA remains unclear. This study aimed to investigate the therapeutic effects and potential molecular mechanisms of SCU in the development of OA. Here, we found that SCU inhibited interleukin (IL)− 1β-induced degradation of the extracellular matrix (ECM) of cartilage through the NF-kappaB/mitogen-activated protein kinases (NF-κB/MAPK) signaling pathway. In addition, in vivo data showed that SCU significantly reduced cartilage damage in the destabilization of the medial meniscus (DMM) mouse model and ovariectomy (OVX)-induced subchondral bone loss and cartilage degeneration in mice. In summary, our data showed that SCU is expected to become a potentially effective candidate treatment strategy for OA.
Article
Background Knee osteoarthritis (KOA) is one of the most common chronic musculoskeletal disorders worldwide, for which exosomes derived from stem cells may provide an effective treatment. Purpose To assess the effect of exosomes derived from human urine–derived stem cells (hUSCs) overexpressing miR-140-5p (miR means microRNA) on KOA in an in vitro interleukin 1β (IL-1β)–induced osteoarthritis (OA) model and an in vivo rat KOA model. Study Design Controlled laboratory study. Methods Exosomes derived from hUSCs (hUSC-Exos) were isolated and validated. The hUSCs were transfected with miR-140s using lentivirus, and exosomes secreted from such cells (hUSC-140-Exos) were collected. The roles of hUSC-Exos and hUSC-140-Exos in protecting chondrocytes against IL-1β treatment were compared by analyzing the proliferation, migration, apoptosis, and secretion of extracellular matrix (ECM) in chondrocytes. After vascular endothelial growth factor A (VEGFA) was identified as a target of miR-140, the mechanism by which VEGFA can mediate the beneficial effect of miR-140 on OA was investigated using small interfering RNA transfection or chemical drugs. The expression of VEGFA in cartilage and synovial fluid from patients with KOA was measured and compared with that of healthy controls. Surgery for anterior cruciate ligament transection and destabilization of the medial meniscus were performed on the knee joints of Sprague-Dawley rats to establish an animal model of OA, and intra-articular (IA) injection of hUSC-Exos or hUSC-140-Exos was conducted at 4 to 8 weeks after the surgery. Cartilage regeneration and subchondral bone remodeling were evaluated through histological staining and micro–computed tomography analysis. Results Proliferation and migration ability were enhanced and apoptosis was inhibited in chondrocytes treated with IL-1β via hUSC-Exos, with the side effect of decreased ECM secretion. hUSC-140-Exos not only retained the advantages of hUSC-Exos but also increased the secretion of ECM by targeting VEGFA, including collagen II and aggrecan. Increased expression of VEGFA during the progression of KOA was also confirmed in cartilage and synovial fluid samples obtained from patients with OA. In the rat OA model, IA injection of hUSC-140-Exos enhanced cartilage regeneration and subchondral bone remodeling. Conclusion Our results demonstrated the superiority of hUSC-Exos overexpressing miR-140-5p for treating OA compared with the hUSC-Exos. The effect of hUSC-140-Exos for suppressing the progression of KOA is in part mediated by VEGFA. Clinical Relevance Exosomes derived from stem cells may provide a promising treatment for KOA, and our study can advance the related basic research.
Article
Objectives: To investigate the efficacy of fat fraction (FF) and T2* relaxation based on DIXON in the assessment of infrapatellar fat pad (IFP) for knee osteoarthritis (KOA) progression in older adults. Methods: Ninety volunteers (age range 51-70 years, 65 females) were enrolled in this study. Participants were grouped based on the Kellgren-Lawrence grading (KLG). The FF and T2* values were measured based on the 3D-modified DXION technique. Cartilage defects, bone marrow lesions, and synovitis were assessed based on a modified version of whole-organ magnetic resonance imaging score (WORMS). Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index (WOMAC) questionnaire. The differences of FF and T2* measurement and the correlation with WORMS and WOMAC assessments were analyzed. Diagnostic efficiency was analyzed by using receiver operating characteristic (ROC) curves. Results: A total of 60 knees were finally included (n = 20 in each group). The values were 82.6 ± 3.7%, 74.7 ± 5.4%, and 60.5 ± 14.1% for FF is the no OA, mild OA, and advanced OA groups, and were 50.7 ± 6.6 ms, 44.1 ± 6.6 ms, and 39.1 ± 4.2 ms for T2*, respectively (all p values < 0.001). The WORMS assessment and WOMAC pain assessment showed negative correlation with FF and T2* values. The ROC showed the area under the curve (AUC), sensitivity, and specificity for diagnosing OA were 0.93, 77.5%, and 100% using FF, and were 0.86, 75.0%, and 90.0% using T2*, respectively. Conclusions: FF and T2* alternations in IFP are associated with knee structural abnormalities and clinical symptoms cross-sectionally and may have the potential to predict the severity of KOA. Key points: • Fat fraction (FF) and T2* relaxation based on DIXON imaging are novel methods to quantitatively assess the infrapatellar fat pad for knee osteoarthritis (KOA) progression in older adults. • The alterations of FF and T2* using mDIXON technique in IFP were associated with knee structural abnormalities and clinical symptoms. • FF and T2* alternations in IFP can serve as the new imaging biomarkers for fast, simple, and noninvasive assessment in KOA.
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Purpose Recent studies demonstrated a contribution of adrenoceptors (ARs) to osteoarthritis (OA) pathogenesis. Several AR subtypes are expressed in joint tissues and the β2-AR subtype seems to play a major role during OA progression. However, the importance of β2-AR has not yet been investigated in knee OA. Therefore, we examined the development of knee OA in β2-AR-deficient (Adrb2-/- ) mice after surgical OA induction. Methods OA was induced by destabilization of the medial meniscus (DMM) in male wildtype (WT) and Adrb2-/- mice. Cartilage degeneration and synovial inflammation were evaluated by histological scoring. Subchondral bone remodeling was analyzed using micro-CT. Osteoblast (alkaline phosphatase - ALP) and osteoclast (cathepsin K - CatK) activity were analyzed by immunostainings. To evaluate β2-AR deficiency-associated effects, body weight, sympathetic tone (splenic norepinephrine (NE) via HPLC) and serum leptin levels (ELISA) were determined. Expression of the second major AR, the α2-AR, was analyzed in joint tissues by immunostaining. Results WT and Adrb2-/- DMM mice developed comparable changes in cartilage degeneration and synovial inflammation. Adrb2-/- DMM mice displayed elevated calcified cartilage and subchondral bone plate thickness as well as increased epiphyseal BV/TV compared to WTs, while there were no significant differences in Sham animals. In the subchondral bone of Adrb2-/- mice, osteoblasts activity increased and osteoclast activity deceased. Adrb2-/- mice had significantly higher body weight and fat mass compared to WT mice. Serum leptin levels increased in Adrb2-/- DMM compared to WT DMM without any difference between the respective Shams. There was no difference in the development of meniscal ossicles and osteophytes or in the subarticular trabecular microstructure between Adrb2-/- and WT DMM as well as Adrb2-/- and WT Sham mice. Number of α2-AR-positive cells was lower in Adrb2-/- than in WT mice in all analyzed tissues and decreased in both Adrb2-/- and WT over time. Conclusion We propose that the increased bone mass in Adrb2-/- DMM mice was not only due to β2-AR deficiency but to a synergistic effect of OA and elevated leptin concentrations. Taken together, β2-AR plays a major role in OA-related subchondral bone remodeling and is thus an attractive target for the exploration of novel therapeutic avenues.
Article
Objective To explore how systemic factors that modify knee osteoarthritis risk are connected to ‘whole-joint’ structural changes by evaluating the effects of high-fat diet and wheel running exercise on synovial fluid (SF) metabolomics. Methods Male mice were fed a defined control or high-fat (60% kcal fat) diet from 6 to 52 weeks of age, and half the animals were housed with running wheels from 26 to 52 weeks of age (n=9-13 per group). Joint tissue structure and osteoarthritis pathology were evaluated by histology and micro-computed tomography. Systemic metabolic and inflammatory changes were evaluated by body composition, glucose tolerance testing, and serum biomarkers. SF metabolites were analyzed by high performance-liquid chromatography mass spectrometry. We built correlation-based network models to evaluate the connectivity between systemic and local metabolic biomarkers and osteoarthritis structural pathology within each experimental group. Results High-fat diet caused moderate osteoarthritis, including cartilage pathology, synovitis and increased subchondral bone density. In contrast, voluntary exercise had a negligible effect on these joint structure components. 1,412 SF metabolite features were detected, with high-fat sedentary mice being the most distinct. Diet and activity uniquely altered SF metabolites attributed to amino acids, lipids, and steroids. Notably, high-fat diet increased network connections to systemic biomarkers such as interleukin-1β and glucose intolerance. In contrast, exercise increased local joint-level network connections, especially among subchondral bone features and SF metabolites. Conclusion Network mapping showed that obesity strengthened SF metabolite links to blood glucose and inflammation, whereas exercise strengthened SF metabolite links to subchondral bone structure.
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Osteoarthritis (OA) is one of the most common medical conditions affecting > 300 million people globally which represents the formidable public health challenge. Despite its clinical and financial ramifications, there are currently no approved disease modifying OA drugs available and symptom palliation is the only alternative. Currently, the amount of data on the human intestinal microbiome is growing at a high rate, both in health and in various pathological conditions. With an increase in the amount of the accumulated data, there is an expanded understanding that the microbiome provides compelling evidence of a link between the gut microbiome and development of OA. The microbiota management tools of probiotics and/or prebiotics or symbiotic have been developed and indeed, commercialized over the past few decades with the expressed purpose of altering the microbiota within the gastrointestinal tract which could be a potentially novel intervention to tackle or prevent OA. However, the mechanisms how intestinal microbiota affects the OA pathogenesis are still not clear and further research targeting specific gut microbiota or its metabolites is still needed to advance OA treatment strategies from symptomatic management to individualized interventions of OA pathogenesis. This article provides an overview of the various preclinical and clinical studies using probiotics and prebiotics as plausible therapeutic options that can restore the gastrointestinal microbiota and its impact on the OA pathogenesis. May be in the near future the targeted alterations of gut microbiota may pave the way for developing new interventions to prevent and treat OA.
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According to the World Health Organization (WHO), pneumonia is a lung infection, causing an interstitial inflammatory reaction alveolar and bronchial with accumulation of a fibrinous exudate, causing consolidation and degrees of pulmonary dysfunction (1) characterized by cough or dyspnea, with or without fever, refusal of feeding, tachypnea or subcostal drawing, with a duration of less than 14 days. Infants may present with altered consciousness, hypothermia, and seizures. Accompanied by radiological evidence of acute pulmonary infiltrate on chest X-ray (1,2) It is the main cause of mortality in children under five years of age, with an incidence of 156 million new episodes every year worldwide, causing death to 922 000 children under 5 years of age in 2015, which represents 15% of all deaths in the world. (1) In 2014, according to the National Institute of Statistics and Censuses (INEC), Ecuador ranked third in mortality and morbidity in the child population.
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Purpose of the review: Osteoarthritis (OA) is a chronic, painful joint disease that affects approximately 40% of adults over 70 year. Age is the strongest predictor of OA, while obesity is considered the primary preventable risk factor for OA. Both conditions are associated with abnormal innate immune inflammatory responses that contribute to OA progression and are the focus of this review. Recent findings: Recent studies have identified risk factors for OA progression including increased innate immune responses secondary to aging-associated myeloid skewing, obesity-related myeloid activation, and synovial tissue hyperplasia with activated macrophage infiltration. Toll-like receptor (TLR)4-induced catabolic responses also play a significant role in OA. The complex interplay between obesity and aging-associated macrophage activation, pro-inflammatory cytokine production from TLR-driven responses, and adipokines leads to a vicious cycle of synovial hyperplasia, macrophage activation, cartilage catabolism, infrapatellar fat pad fibrosis, and joint destruction.
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The importance of the nociceptive nervous system for maintaining tissue homeostasis has been known for some time, and it has also been suggested that organogenesis and tissue repair are under neuronal control. Changes in peripheral joint innervation are supposed to be partly responsible for degenerative alterations in joint tissues which contribute to development of osteoarthritis. Various resident cell types of the musculoskeletal system express receptors for sensory and sympathetic neurotransmitters, allowing response to peripheral neuronal stimuli. Among them are mesenchymal stem cells, synovial fibroblasts, bone cells and chondrocytes of different origin, which express distinct subtypes of adrenoceptors (AR), receptors for vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP). Some of these cell types synthesize and secrete neuropeptides such as SP, and they are positive for tyrosine-hydroxylase (TH), the rate limiting enzyme for biosynthesis of catecholamines. Sensory and sympathetic neurotransmitters are involved in the pathology of inflammatory diseases such as rheumatoid arthritis (RA) which manifests mainly in the joints. In addition, they seem to play a role in pathogenesis of priori degenerative joint disorders such as osteoarthritis (OA). Altogether it is evident that sensory and sympathetic neurotransmitters have crucial trophic effects which are critical for joint tissue and bone homeostasis. They modulate articular cartilage, subchondral bone and synovial tissue properties in physiological and pathophysiological conditions, in addition to their classical neurological features.
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Systems orientated research offers the possibility of identifying novel therapeutic targets and relevant diagnostic markers for complex diseases such as osteoarthritis. This review demonstrates that the osteoarthritis research community has been slow to incorporate systems orientated approaches into research studies, although a number of key studies reveal novel insights into the regulatory mechanisms that contribute both to joint tissue homeostasis and its dysfunction. The review introduces both top-down and bottom-up approaches employed in the study of osteoarthritis. A holistic and multiscale approach, where clinical measurements may predict dysregulation and progression of joint degeneration, should be a key objective in future research. The review concludes with suggestions for further research and emerging trends not least of which is the coupled development of diagnostic tests and therapeutics as part of a concerted effort by the osteoarthritis research community to meet clinical needs. This article is protected by copyright. All rights reserved
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Osteoarthritis (OA) is the most common joint disorder, is associated with an increasing socioeconomic impact owing to the ageing population and mainly affects the diarthrodial joints. Primary OA results from a combination of risk factors, with increasing age and obesity being the most prominent. The concept of the pathophysiology is still evolving, from being viewed as cartilage-limited to a multifactorial disease that affects the whole joint. An intricate relationship between local and systemic factors modulates its clinical and structural presentations, leading to a common final pathway of joint destruction. Pharmacological treatments are mostly related to relief of symptoms and there is no disease-modifying OA drug (that is, treatment that will reduce symptoms in addition to slowing or stopping the disease progression) yet approved by the regulatory agencies. Identifying phenotypes of patients will enable the detection of the disease in its early stages as well as distinguish individuals who are at higher risk of progression, which in turn could be used to guide clinical decision making and allow more effective and specific therapeutic interventions to be designed. This Primer is an update on the progress made in the field of OA epidemiology, quality of life, pathophysiological mechanisms, diagnosis, screening, prevention and disease management.
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Background: We conducted an exploratory analysis of osteoarthritis progression among medication users in the Osteoarthritis Initiative to identify interventions or pathways that may be associated with disease modification and therefore of interest for future clinical trials. Methods: We used participants from the Osteoarthritis Initiative with annual medication inventory data between the baseline and 36-month follow-up visit (n = 2938). Consistent medication users were defined for each medication classification as a participant reporting at all four annual visits that they were regularly using an oral prescription medication at the time of the visit. The exploratory analysis focused on medication classes with 40 or more users. The primary outcome measures were medial tibiofemoral joint space width change and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) knee pain score change (12-36-month visits). Within each knee, we explored eight comparisons between users and matched or unmatched nonusers (defined two ways). An effect size of each comparison was calculated. Medication classes had potential signals if (a) both knees had less progression among users compared with nonusers, or (b) there was less progression based on structure and symptoms in one knee. Results: We screened 28 medication classes. Six medication classes had signals for fewer structural changes and better knee pain changes: alpha-adrenergic blockers, antilipemic (excluding statins and fibric acid), anticoagulants, selective serotonin reuptake inhibitors, antihistamines, and antineoplastic agents. Four medication classes had signals for structural changes alone: anti-estrogen (median effect size = 0.28; range = -0.41-0.64), angiotensin-converting enzyme inhibitors (median effect size = 0.13; range = -0.08-0.28), beta-adrenergic blockers (median effect size = 0.09; range = 0.01-0.30), and thyroid agents (median effect size = 0.04; range = -0.05-0.14). Thiazide diuretics had evidence for symptom modification (median effect size = -0.12; range = -0.24-0.04). Conclusions: Users of neurovascular, antilipemic, or hormonal interventions may have less disease progression compared with nonusers.
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Despite a technically perfect procedure, surgical stress can determine the success or failure of an operation. Surgical trauma is often referred to as the “neglected step-child” of global health in terms of patient numbers, mortality, morbidity and costs. A staggering 234 million major surgeries are performed every year, and depending upon country and institution, up to 4% of patients will die before leaving hospital, up to 15% will have serious post-operative morbidity, and 5 to 15% will be readmitted within 30 days. These percentages equate to around 1000 deaths and 4000 major complications every hour, and it has been estimated that 50% may be preventable. New frontline drugs are urgently required to make major surgery safer for the patient and more predictable for the surgeon. We review the basic physiology of the stress response from neuroendocrine to genomic systems, and discuss the paucity of clinical data supporting the use of statins, beta-adrenergic blockers and calcium channel blockers. Since cardiac-related complications are the most common, particularly in the elderly, a key strategy would be to improve ventricular-arterial coupling to safeguard the endothelium and maintain tissue oxygenation. Reduced O2 supply is associated with glycocalyx shedding, decreased endothelial barrier function, fluid leakage, inflammation and coagulopathy. A healthy endothelium may prevent these “secondary hit” complications, including possibly immunosuppression. Thus the four pillars of whole body resynchronization during surgical trauma, and targets for new therapies, are: 1) the CNS, 2) the heart, 3) arterial supply and venous return functions, and 4) the endothelium. This is termed the Central-Cardio-Vascular-Endothelium (CCVE) coupling hypothesis. Since similar sterile injury cascades exist in critical illness, accidental trauma, hemorrhage, cardiac arrest, infection and burns, new drugs that improve CCVE coupling may find wide utility in civilian and military medicine.
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Exposure to psychosocial stress is a risk factor for many diseases, including atherosclerosis. Although incompletely understood, interaction between the psyche and the immune system provides one potential mechanism linking stress and disease inception and progression. Known cross-talk between the brain and immune system includes the hypothalamic-pituitary-adrenal axis, which centrally drives glucocorticoid production in the adrenal cortex, and the sympathetic-adrenal-medullary axis, which controls stress-induced catecholamine release in support of the fight-or-flight reflex. It remains unknown, however, whether chronic stress changes hematopoietic stem cell activity. Here we show that stress increases proliferation of these most primitive hematopoietic progenitors, giving rise to higher levels of disease-promoting inflammatory leukocytes. We found that chronic stress induced monocytosis and neutrophilia in humans. While investigating the source of leukocytosis in mice, we discovered that stress activates upstream hematopoietic stem cells. Under conditions of chronic variable stress in mice, sympathetic nerve fibers released surplus noradrenaline, which signaled bone marrow niche cells to decrease CXCL12 levels through the β3-adrenergic receptor. Consequently, hematopoietic stem cell proliferation was elevated, leading to an increased output of neutrophils and inflammatory monocytes. When atherosclerosis-prone Apoe(-/-) mice were subjected to chronic stress, accelerated hematopoiesis promoted plaque features associated with vulnerable lesions that cause myocardial infarction and stroke in humans.
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When chronic alterations in neuronal activity occur, network gain is maintained by global homeostatic scaling of synaptic strength, but the stability of microcircuits can be controlled by unique adaptations that differ from the global changes. It is not understood how specificity of synaptic tuning is achieved. We found that, although a large population of inhibitory synapses was homeostatically scaled down after chronic inactivity, decreased endocannabinoid tone specifically strengthened a subset of GABAergic synapses that express cannabinoid receptors. In rat hippocampal slice cultures, a 3-5-d blockade of neuronal firing facilitated uptake and degradation of anandamide. The consequent reduction in basal stimulation of cannabinoid receptors augmented GABA release probability, fostering rapid depression of synaptic inhibition and on-demand disinhibition. This regulatory mechanism, mediated by activity-dependent changes in tonic endocannabinoid level, permits selective local tuning of inhibitory synapses in hippocampal networks.
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Inhibition of sympathoexcitatory circuits is influenced by cerebral structures and mediated via vagal mechanisms. Studies of pharmacologic blockade of the prefrontal cortex together with neuroimaging studies support the role of the right hemisphere in parasympathetic control of the heart via its connection with the right vagus nerve. Neural mechanisms also regulate inflammation; vagus nerve activity inhibits macrophage activation and the synthesis of tumor necrosis factor in the reticuloendothelial system through the release of acetylcholine. Data suggest an association between heart rate variability and inflammation that may support the concept of a cholinergic anti-inflammatory pathway.
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For humans and animal models alike there is general agreement that the central nervous system processing of gastrointestinal (GI) signals arising from ingested food provides the principal determinant of the size of meals and their frequency. Despite this, relatively few studies are aimed at delineating the brain circuits, neurochemical pathways and intracellular signals that mediate GI-stimulation-induced intake inhibition. Two additional motivations to pursue these circuits and signals have recently arisen. First, the success of gastric-bypass surgery in obesity treatment is highlighting roles for GI signals such as glucagon-like peptide-1 (GLP-1) in intake and energy balance control. Second, accumulating data suggest that the intake-reducing effects of leptin may be mediated through an amplification of the intake-inhibitory effects of GI signals. Experiments reviewed show that: (1) the intake-suppressive effects of a peripherally administered GLP-1 receptor agonist is mediated by caudal brainstem neurons and that forebrain-hypothalamic neural processing is not necessary for this effect; (2) a population of medial nucleus tractus solitarius (NTS) neurons that are responsive to gastric distention is also driven by leptin; (3) caudal brainstem-targeted leptin amplifies the food-intake-inhibitory effects of gastric distention and intestinal nutrient stimulation; (4) adenosine monophosphate-activated protein kinase (AMPK) activity in NTS-enriched brain lysates is elevated by food deprivation and reduced by refeeding and (5) the intake-suppressive effect of hindbrain-directed leptin is reversed by elevating hindbrain AMPK activity. Overall, data support the view that the NTS and circuits within the hindbrain mediate the intake inhibition of GI signals, and that the effects of leptin on food intake result from the amplification of GI signal processing.
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The innervation of skeletal tissues by sensory nerves is poorly understood - especially of nerve fibres which reach into the bony and cartilaginous tissue. Samples of rat cartilaginous tissues from different locations (knee joint, vertebral column, temporomandibular joint) were fixed by perfusion and decalcified. The distribution of protein gene product (PGP) 9.5-, calcitonin gene-related peptide (CGRP)- and tachykinin (TK)-immunoreactive axons was analysed using fluorescence immunohistochemistry. Nerve fibres were detected in the outer regions of the hyaline cartilage of the knee joint, in the hyaline cartilage of the vertebral body, in the fibrocartilage of the intervertebral disc and menisci, and in the articular disc of the temporomandibular joint. Predominantly, they were found to be CGRP-immunoreactive. The neuropeptidergic innervation of the hyaline cartilage in different locations and the presence of nerve fibres in the fibrocartilage might indicate that in addition to the classical neuronal afferent and efferent pathway these fibres may also mediate trophic actions like tissue adaptation and repair.
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Richard von Volkmann (1830-1889), one of the most important surgeons of the 19(th) century, is regarded as one of the fathers of orthopaedic surgery. He was a contemporary of Langenbeck, Esmarch, Lister, Billroth, Kocher, and Trendelenburg. He was head of the Department of Surgery at the University of Halle, Germany (1867-1889). His popularity attracted doctors and patients from all over the world. He was the lead physician for the German military during two wars. From this experience, he compared the mortality of civilian and war injuries and investigated the general poor hygienic conditions in civilian hospitals. This led him to introduce the "antiseptic technique" to Germany that was developed by Lister. His powers of observation and creativity led him to findings and achievements that to this day bear his name: Volkmann's contracture and the Hueter-Volkmann law. Additionally, he was a gifted writer; he published not only scientific literature but also books of children's fairy tales and poems under the pen name of Richard Leander, assuring him a permanent place in the world of literature as well as orthopaedics.
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Sequelae frequently seen in patients with chronic inflammatory diseases, such as fatigue, depressed mood, sleep alterations, loss of appetite, muscle wasting, cachectic obesity, bone loss and hypertension, can be the result of energy shortages caused by an overactive immune system. These sequelae can also be found in patients with chronic inflammatory diseases that are in remission and in ageing individuals, despite the immune system being less active in these situations. This Perspectives article proposes a new way of understanding situations of chronic inflammation (such as rheumatic diseases) and ageing based on the principles of evolutionary medicine, energy regulation and neuroendocrine–immune crosstalk. A conceptual framework is provided to enable physicians and scientists to better understand the signs and symptoms of chronic inflammatory diseases and long-term disease consequences resulting from physical and mental inactivity.
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Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune-mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so-called cholinergic anti-inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL-6 production and improved RA disease severity, even in some patients with therapy-resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.
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Recent studies have revealed that the sensory nervous system is involved in bone metabolism. However, the mechanism of communication between neurons and osteoblasts is yet to be elucidated. In this study, we investigated the signaling pathways between sensory neurons of the dorsal root ganglion (DRG) and the osteoblast-like MC3T3-E1 cells by using an in vitro co-culture system. Our findings indicate that signal transduction from DRG-derived neurons to MC3T3-E1 cells is suppressed by antagonists of the AMPA receptor and the NK1 receptor. Conversely, signal transduction from MC3T3-E1 cells to DRG-derived neurons is suppressed by a P2X7 receptor antagonist. Our results suggest that these cells communicate with each other by exocytosis of glutamate, substance P in the efferent signal, and ATP in the afferent signal. This article is protected by copyright. All rights reserved.
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Purpose of review: Osteoarthritis is a common complex disorder with a strong genetic component. Other identified risk factors such as increasing age and overweight do not fully explain the risk of osteoarthritis. Here, we highlight the main findings from genetic association studies on osteoarthritis to date. Recent findings: Currently, genetic association studies have identified 21 independent susceptibility loci for osteoarthritis. Studies have focused on hip, knee and hand osteoarthritis, as well as posttotal joint replacement and minimum joint space width, a proxy for cartilage thickness. Four distinct loci have recently been identified in a genome-wide association scan on minimum joint space width. The role of mitochondrial DNA variants has been the focus of a recent meta-analysis. Findings have previously been mixed, however, this study suggests a plausible involvement of mitochondrial DNA in the progression of radiographic knee osteoarthritis. Summary: Identifying genetic locations of interest provides a framework upon which to base future studies, for example replication analysis and functional work. Genetic association studies have shaped and will continue to shape research in this field. Improving the understanding of osteoarthritis could improve the diagnosis and treatment of the disease and improve quality of life for many individuals.
Article
Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. Furthermore, we now appreciate that OA pathogenesis involves not only breakdown of cartilage, but also remodelling of the underlying bone, formation of ectopic bone, hypertrophy of the joint capsule, and inflammation of the synovial lining. That is, OA is a disorder of the joint as a whole, with inflammation driving many pathologic changes. The inflammation in OA is distinct from that in rheumatoid arthritis and other autoimmune diseases: it is chronic, comparatively low-grade, and mediated primarily by the innate immune system. Current treatments for OA only control the symptoms, and none has been FDA-approved for the prevention or slowing of disease progression. However, increasing insight into the inflammatory underpinnings of OA holds promise for the development of new, disease-modifying therapies. Indeed, several anti-inflammatory therapies have shown promise in animal models of OA. Further work is needed to identify effective inhibitors of the low-grade inflammation in OA, and to determine whether therapies that target this inflammation can prevent or slow the development and progression of the disease.
Article
[Exctract] In the last hour, 1,000 people died from sepsis around the world and the global burden is increasing at an alarming rate of 8–13% per annum. Opal et al are to be congratulated on their special article in a recent issue of Critical Care Medicine. The five key opinion leaders emphasized that although the underlying pathophysiology of infection and sepsis continues to advance, novel therapeutics to treat the illness has diminished to a trickle.
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Acute inflammatory responses are essential for pathogen control and tissue repair but can also cause severe collateral damage. Tight regulation of the response is required to minimize host injury, but in the face of chronic infections and age-associated immune dysregulation, inflammatory processes may exert multiple detrimental effects on the organism. The signs of low level systemic inflammation commonly detectable in elderly people are associated with many chronic diseases of ageing and may even contribute to their causation. The purpose of this article is to review recent literature from the past two years providing new data on the inter-relationships between inflammatory status and chronic diseases of ageing.
Article
Osteoarthritis has long been considered a"wear and tear" disease leading to loss of cartilage. OA used to be considered the sole consequence of any process leading to increased pressure on one particular joint or fragility of cartilage matrix. Progress in molecular biology in the 1990s has profoundly modified this paradigm. The discovery that many soluble mediators such as cytokines or prostaglandins can increase the production of matrix metalloproteinases by chondrocytes led to the first steps of an "inflammatory" theory. However, it took a decade before synovitis was accepted as a critical feature of OA, and some studies are now opening the way to consider the condition a driver of the OA process. Recent experimental data have shown that subchondral bone may have a substantial role in the OA process, as a mechanical damper, as well as a source of inflammatory mediators implicated in the OA pain process and in the degradation of the deep layer of cartilage. Thus, initially considered cartilage driven, OA is a much more complex disease with inflammatory mediators released by cartilage, bone and synovium. Low-grade inflammation induced by the metabolic syndrome, innate immunity and inflammaging are some of the more recent arguments in favour of the inflammatory theory of OA and highlighted in this review.
Article
Pain is a major clinical problem of osteoarthritis (OA). Recently, OA has been thought to be a disease of the whole joint with both destruction of cartilage and inflammatory components such as synovitis and bone marrow lesions. Clinical studies have documented a significant inflammatory soft tissue contribution to the severity and frequency of OA pain. Both clinical and experimental studies have provided evidence for the sensitization of pain pathways during OA, involving pronounced changes in joint nociceptors and changes of the nociceptive processing in the spinal cord, brainstem, and thalamocortical system. Additionally, evidence has been provided for neuropathic pain components in OA models. Concerning molecular mechanisms of OA pain and potential options for pain therapy, studies on nerve growth factor, cytokines, sodium channel blockers, hyaluronic acid preparations, and others are addressed in this review.
Article
Neural circuits must maintain stable function in the face of many plastic challenges, including changes in synapse number and strength, during learning and development. Recent work has shown that these destabilizing influences are counterbalanced by homeostatic plasticity mechanisms that act to stabilize neuronal and circuit activity. One such mechanism is synaptic scaling, which allows neurons to detect changes in their own firing rates through a set of calcium-dependent sensors that then regulate receptor trafficking to increase or decrease the accumulation of glutamate receptors at synaptic sites. Additional homeostatic mechanisms may allow local changes in synaptic activation to generate local synaptic adaptations, and network-wide changes in activity to generate network-wide adjustments in the balance between excitation and inhibition. The signaling pathways underlying these various forms of homeostatic plasticity are currently under intense scrutiny, and although dozens of molecular pathways have now been implicated in homeostatic plasticity, a clear picture of how homeostatic feedback is structured at the molecular level has not yet emerged. On a functional level, neuronal networks likely use this complex set of regulatory mechanisms to achieve homeostasis over a wide range of temporal and spatial scales.
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Rev. ed. of a thesis, Univ. of London.
Article
Inflammation can cause damage and even death. What controls this primitive and potentially lethal innate immune response to injury and infection? Molecular and neurophysiological studies during the past decade have revealed a pivotal answer: immunity is coordinated by neural circuits that operate reflexively. The afferent arc of the reflex consists of nerves that sense injury and infection. This activates efferent neural circuits, including the cholinergic anti-inflammatory pathway, that modulate immune responses and the progression of inflammatory diseases. It might be possible to develop therapeutics that target neural networks for the treatment of inflammatory disorders.
Article
The history of the nomenclature of rheumatoid arthritis has been traced from antiquity to the present discussion of “rheumatoid disease.” Although Guillaume de Baillou recognized rheumatism as being arthritis in 1611, Augustin Jacob Landré Beauvais was the first to describe clearly rheumatoid arthritis, calling it primary asthenic gout in 1800. Sir Alfred Baring Garrod coined the term rheumatoid arthritis in 1858. The British Ministry of Health adopted this term in 1922, and the American Rheumatism Association replaced atrophic arthritis with rheumatoid arthritis in 1941. Le historia del nomenclatura de arthritis rheumatoide esseva traciate ab le antiquitate usque al presente discussion del termino “morbo rheumatoide.” Ben que Guillaume de Baillou recognosceva in 1611 que rheumatismo es arthritis, Augustin-Jacob Landré Beauvais esseva le prime qui clarmente describeva arthritis rheumatoide. Ille lo designava in 1800 como primari gutta asthenic. Sir Alfred Baring Garrod creava le termino arthritis rheumatoide in 1858. Le Britannic Ministerio de Salute adoptava iste termino in 1922, e in 1941 le Association Rheumatologic American reimplaciava arthritis atrophic per arthritis rheumatoide.
Article
The history of osteoarthritis-osteoarthrosis from antiquity to the present day is elaborated through historical accounts in the literature, paleopathological findings in skeletal remains, visual representations in artwork and new developments in pathophysiological concepts of the disease.
Commentaries on the History and Cure of Diseases. London: Pain and Foss, Pall Mall
  • W Heberden
Heberden W. Commentaries on the History and Cure of Diseases. London: Pain and Foss, Pall Mall; 1816.
  • J Martel-Pelletier
  • A J Barr
  • F M Cicuttini
  • P G Conaghan
  • C Cooper
  • M B Goldring
Martel-Pelletier J, Barr AJ, Cicuttini FM, Conaghan PG, Cooper C, Goldring MB, et al. Osteoarthritis. Nat Rev Dis Primers 2016;13:16072.
Biologic basis of osteoarthritis: state of the evidence
  • Malemud
Malemud CJ. Biologic basis of osteoarthritis: state of the evidence. Curr Opin Rheumatol 2015;27:289e94.
A Treatise of Rheumatism and Rheumatoid Arthritis
  • A E Garrod
Garrod AE. A Treatise of Rheumatism and Rheumatoid Arthritis. London: Griffin; 1890.
The early symptoms and early treatment of osteoarthritis (review of his book)
  • Spender
Spender JK. The early symptoms and early treatment of osteoarthritis (review of his book). Br Med J 1889;1:1232.
Neural regulation of endocrine and autonomic stress responses
  • Ulrich-Lai
Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci 2009;10: 397e409.
Addressing the global burden of sepsis: importance of a systems-based approach
  • Dobson