scholarly journals Rat Chondrocyte Inflammation and Osteoarthritis Are Ameliorated by Madecassoside

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Safwat Adel Abdo Moqbel ◽  
Yuzhe He ◽  
Langhai Xu ◽  
Chiyuan Ma ◽  
Jisheng Ran ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Cartilage Damage ◽  
Centella Asiatica ◽  
Type Ii Collagen ◽  
Cartilage Degeneration ◽  
Treated Group ◽  
Joint Disease ◽  
Inflammatory Factors ◽  
Protective Effects ◽  
Osteoarthritic Chondrocytes

As a joint disease, osteoarthritis (OA) is caused by the breakdown of subchondral bone and cartilage damage. Inflammatory factors, such as interleukin- (IL-) 1β, mediate the progression of OA. Madecassoside (MA), a triterpenoid component derived from the gotu kola herb (Centella asiatica), exhibits various pharmacological effects, including antioxidative and anti-inflammatory properties. In the present study, the protective effects and possible mechanism of MA on the treatment of OA were investigated. MA was demonstrated to significantly suppress the IL-1β-induced overexpression of matrix metalloproteinase- (MMP-) 3, MMP-13, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) and to decrease the IL-1β-induced degradation of type II collagen and sox9. Additionally, MA was able to reduce the IL-1β-induced phosphorylation of p65 in osteoarthritic chondrocytes. Furthermore, in a rat OA model, MA prevented cartilage degeneration and reduced the OARSI score in the MA-treated group compared with the OA group. The present study showed that MA suppresses the nuclear factor-κB signaling pathway, reducing IL-1β-induced chondrocyte inflammation, which indicates the therapeutic potential of MA in patients with OA.

scholarly journals Conditioned Media from Adipose-Tissue-Derived Mesenchymal Stem Cells Downregulate Degradative Mediators Induced by Interleukin-1βin Osteoarthritic Chondrocytes

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Julia Platas ◽  
Maria Isabel Guillén ◽  
María Dolores Pérez del Caz ◽  
Francisco Gomar ◽  
Vicente Mirabet ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Adipose Tissue ◽  
Type Ii Collagen ◽  
Cartilage Degeneration ◽  
Joint Disease ◽  
Prostaglandin E ◽  
Osteoarthritic Chondrocytes ◽  
Joint Disorder ◽  
Oa Chondrocytes

Osteoarthritis (OA) is the most frequent joint disorder and an important cause of disability. Recent studies have shown the potential of adipose-tissue-derived mesenchymal stem cells (AD-MSC) for cartilage repair. We have investigated whether conditioned medium from AD-MSC (CM) may regulate in OA chondrocytes a number of key mediators involved in cartilage degeneration. CM enhanced type II collagen expression in OA chondrocytes while decreasing matrix metalloproteinase (MMP) activity in cell supernatants as well as the levels of MMP-3 and MMP-13 proteins and mRNA in OA chondrocytes stimulated with interleukin- (IL-) 1β. In addition, CM increased IL-10 levels and counteracted the stimulating effects of IL-1βon the production of tumor necrosis factor-α, IL-6, prostaglandin E2, and NO measured as nitrite and the mRNA expression of these cytokines, CCL-2, CCL-3, CCL-4, CCL-5, CCL-8, CCL-19, CCL-20, CXCL-1, CXCL-2, CXCL-3, CXCL-5, CXCL-8, cyclooxygenase-2, microsomal prostaglandin E synthase-1, and inducible NO synthase. These effects may be dependent on the inhibition of nuclear factor-κB activation by CM. Our data demonstrate the chondroprotective actions of CM and provide support for further studies of this approach in joint disease.

scholarly journals Selonsertib Alleviates the Progression of Rat Osteoarthritis: An in vitro and in vivo Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiyuan Yan ◽  
Yingchi Zhang ◽  
Gaohong Sheng ◽  
Bowei Ni ◽  
Yifan Xiao ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Cartilage Damage ◽  
Cartilage Degradation ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Therapeutic Effects ◽  
Exact Role

Osteoarthritis (OA) is a prevalent degenerative joint disease. Its development is highly associated with inflammatory response and apoptosis in chondrocytes. Selonsertib (Ser), the inhibitor of Apoptosis Signal-regulated kinase-1 (ASK1), has exhibited multiple therapeutic effects in several diseases. However, the exact role of Ser in OA remains unclear. Herein, we investigated the anti-arthritic effects as well as the potential mechanism of Ser on rat OA. Our results showed that Ser could markedly prevent the IL-1β-induced inflammatory reaction, cartilage degradation and cell apoptosis in rat chondrocytes. Meanwhile, the ASK1/P38/JNK and NFκB pathways were involved in the protective roles of Ser. Furthermore, intra-articular injection of Ser could significantly alleviate the surgery induced cartilage damage in rat OA model. In conclusion, our work provided insights into the therapeutic potential of Ser in OA, indicating that Ser might serve as a new avenue in OA treatment.

scholarly journals The P2X7 Receptor in Osteoarthritis

2021 ◽  
Vol 9 ◽  
Author(s):  
Zihao Li ◽  
Ziyu Huang ◽  
Lunhao Bai
Keyword(s):  
Cell Death ◽  
P2x7 Receptor ◽  
Therapeutic Potential ◽  
Purinergic Receptor ◽  
Treatment Options ◽  
Cartilage Degradation ◽  
Joint Disease ◽  
Inflammatory Factors ◽  
Inflammatory Factor ◽  
Inflammatory Reactions

Osteoarthritis (OA) is the most common joint disease. With the increasing aging population, the associated socio-economic costs are also increasing. Analgesia and surgery are the primary treatment options in late-stage OA, with drug treatment only possible in early prevention to improve patients’ quality of life. The most important structural component of the joint is cartilage, consisting solely of chondrocytes. Instability in chondrocyte balance results in phenotypic changes and cell death. Therefore, cartilage degradation is a direct consequence of chondrocyte imbalance, resulting in the degradation of the extracellular matrix and the release of pro-inflammatory factors. These factors affect the occurrence and development of OA. The P2X7 receptor (P2X7R) belongs to the purinergic receptor family and is a non-selective cation channel gated by adenosine triphosphate. It mediates Na+, Ca2+ influx, and K+ efflux, participates in several inflammatory reactions, and plays an important role in the different mechanisms of cell death. However, the relationship between P2X7R-mediated cell death and the progression of OA requires investigation. In this review, we correlate potential links between P2X7R, cartilage degradation, and inflammatory factor release in OA. We specifically focus on inflammation, apoptosis, pyroptosis, and autophagy. Lastly, we discuss the therapeutic potential of P2X7R as a potential drug target for OA.

Inhibition of Long Non-coding RNA CTD-2574D22.4 Alleviates LPS-induced Apoptosis and Inflammatory Injury of Chondrocytes

2019 ◽  
Vol 25 (27) ◽  
pp. 2969-2974 ◽  
Author(s):  
Lisong Li ◽  
Lianfang Zhang ◽  
Yong Zhang ◽  
Dinghua Jiang ◽  
Wu Xu ◽  
...  
Keyword(s):  
Cell Viability ◽  
Inflammatory Cytokines ◽  
Inflammatory Diseases ◽  
Type Ii Collagen ◽  
Cartilage Degeneration ◽  
Joint Disease ◽  
Protein Levels ◽  
Non Coding Rna ◽  
Enhanced Expression ◽  
Induced Apoptosis

Background: Osteoarthritis (OA) is a common joint disease characterized by cartilage degeneration. Long non-coding RNAs (lncRNAs) have been associated with inflammatory diseases, including OA. Here, we investigated the potential molecular role of lncRNAs in OA pathogenesis. Methods: ATDC5 cells were treated with lipopolysaccharides (LPS), and qPCR was used to identify and determine expression of potential lncRNAs involved in LPS-induced chondrocyte injury. Cell viability, apoptosis, and expression of cartilage-related genes and inflammatory cytokines were assessed after CTD-2574D22.4 knockdown. Results: After LPS stimulation, CTD-2574D22.4 was found to be the second highest up-regulated gene, and the enhanced expression was validated in OA chondrocytes. Moreover, CTD-2574D22.4 inhibition significantly rescued cell viability, suppressed by LPS stress, and markedly attenuated LPS-induced apoptosis. The expression of cartilage-degrading enzymes MMP-13 and ADAMTS-5 were increased, while type II collagen was reduced after LPS treatment. This trend was largely reversed by CTD-2574D22.4 knockdown. Additionally, mRNA and protein levels of key inflammatory cytokines (TNF-a, IL-6, and IL-1β) were significantly elevated in the LPS group and partially relieved upon CTD-2574D22.4 knockdown. Conclusion: CTD2574D22.4 knockdown ameliorates LPS-induced cartilage injury by protecting chondrocytes from apoptosis via anti-inflammation and anti- cartilage-degrading pathways. Thus, CTD2574D22.4 might be a potential diagnostic and therapeutic target for OA.

scholarly journals Kelainan Matriks Ekstraseluler Agrekan pada Osteoarthritis

2020 ◽  
Vol 9 (1) ◽  
pp. 67-80
Author(s):  
Umiatin Umiatin ◽  
Jeanne A Diwinata Pawitan
Keyword(s):  
Extracellular Matrix ◽  
Enzyme Activity ◽  
Molecular Mechanisms ◽  
Cartilage Damage ◽  
Type Ii Collagen ◽  
Joint Disease ◽  
Joint Cartilage ◽  
Keywords Osteoarthritis ◽  
A Disintegrin And Metalloproteinase ◽  
Thrombospondin Motif

Abstrak Osteoarthritis (OA) merupakan penyakit sendi dengan prevalensi paling tinggi yang menyebabkan nyeri kronis dan disabilitas. Berbagai faktor antara lain faktor mekanik, biokimia dan faktor enzimatik berperan dalam perkembangan OA. Perkembangan OA dicirikan oleh degradasi berlebihan pada agrekan dalam matriks ekstraseluler tulang rawan sendi. Agrekan berfungsi menyediakan fleksibilitas, viskoelastisitas dan kompresibilitas jaringan. Struktur agrekan tidak konstan sepanjang hidup, namun mengalami perubahan yang disebabkan oleh aktivitas sintesis maupun degradasi. Degradasi agrekan merupakan penanda awal kerusakan tulang rawan sendi pada OA, yang diikuti oleh kerusakan kolagen tipe II. Sejauh ini mekanisme molekulernya belum diketahui pasti, sehingga diperlukan penelitian lebih lanjut mengenai mekanisme dan penyebab kerusakan agrekan. Tulisan ini merupakan suatu kajian naratif berdasarkan artikel dari jurnal nasional dan internasional yang bertujuan untuk memberikan informasi mengenai agrekan meliputi struktur, fungsi, dan faktor-faktor yang berperan pada perubahan struktur agrekan yang menginduksi terjadinya OA. Hasil kajian menunjukkan bahwa perubahan struktur agrekan erat kaitannya dengan perubahan fungsi mekanik tulang rawan sendi. Perubahan ini terjadi terutama karena degradasi yang disebabkan oleh aktivitas enzim, dari keluarga matriks metalloprotease (MMP) dan a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS). Dari kajian ini disimpulkan bahwa degradasi agrekan karena aktivitas enzim berperan penting dalam perkembangan OA, sehingga perlu dilakukan penelitian untuk mencari inhibitor enzim MMP dan ADAMTS sebagai agen terapeutik untuk menghambat perkembangan dan progresivitas OA. Kata kunci: osteoarthritis, matriks ektraseluler, agrekan, degradasi. Abstract Osteoarthritis (OA) is a joint disease with the highest prevalence and a major cause of chronic pain and disability. Many factors such as mechanical, biochemical, and enzymatic factors are involved in OA development. The development of OA is characterized by excessive degradation of aggrecan in the extracellular matrix of articular cartilage, which functions to provide flexibility, viscoelasticity, and tissue compressibility. The structure of aggrecan is not constant throughout life but undergoes changes caused by synthesis and degradation activities. Aggrecan degradation is an early marker of joint cartilage damage in OA, followed by type II collagen damage. However, the molecular mechanisms are not completely understood, so further research is needed on the mechanisms and causes of aggrecan damage. Here we provide a narrative review based on articles from national and international journals to describe the structure, function, and factors that contribute to the degradation of aggrecan. The results of the study show that changes in the structure of aggrecan are closely related to changes in the mechanical function of joint cartilage. This change occurs mainly due to degradation caused by enzyme activity, a family of matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS). The present study concludes that aggrecan degradation caused by enzyme activity was very crucial in the development of OA, it was needed to find MMP and ADAMTS inhibitors as a therapeutic agent to prevent the development and progression of OA. Keywords: osteoarthritis, extracellular matrix, aggrecan, degradation

scholarly journals Sodium Monoiodoacetate Dose-Dependent Changes in Matrix Metalloproteinases and Inflammatory Components as Prognostic Factors for the Progression of Osteoarthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Marta Bryk ◽  
Jakub Chwastek ◽  
Jakub Mlost ◽  
Magdalena Kostrzewa ◽  
Katarzyna Starowicz
Keyword(s):  
Matrix Metalloproteinases ◽  
Synovial Membrane ◽  
Weight Bearing ◽  
Joint Inflammation ◽  
Cartilage Degeneration ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Inflammatory Factors ◽  
Behavioral Studies ◽  
Bone Degradation

Osteoarthritis (OA) is a degenerative joint disease that primarily affects people over 65 years old. During OA progression irreversible cartilage, synovial membrane and subchondral bone degradation is observed, which results in the development of difficult-to-treat chronic pain. One of the most important factors in OA progression is joint inflammation. Both proinflammatory and anti-inflammatory factors, as well as extracellular matrix degradation enzymes (matrix metalloproteinases (MMPs), play an important role in disease development. One of the most widely used animal OA models involves an intra-articular injection of sodium monoiodoacetate (MIA) directly into the joint capsule, which results in glycolysis inhibition in chondrocytes and cartilage degeneration. This model mimics the degenerative changes observed in OA patients. However, the dose of MIA varies in the literature, ranging from 0.5 to 4.8 mg. The aim of our study was to characterize grading changes after injection of 1, 2 or 3 mg of MIA at the behavioral and molecular levels over a 28-day period. In the behavioral studies, MIA injection at all doses resulted in a gradual increase in tactile allodynia and resulted in abnormal weight bearing during free walking sequences. At several days post-OA induction, cartilage, synovial membrane and synovial fluid samples were collected, and qPCR and Western blot analyses were performed. We observed significant dose- and time-dependent changes in both gene expression and protein secretion levels. Inflammatory factors (CCL2, CXCL1, IL-1β, COMP) increased at the beginning of the experiment, indicating a transient inflammatory state connected to the MIA injection and, in more severe OA, also in the advanced stages of the disease. Overall, the results in the 1 mg MIA group were not consistently clear, indicating that the lowest tested dose may not be sufficient to induce long-lasting OA-like changes at the molecular level. In the 2 mg MIA group, significant alterations in the measured factors were observed. In the 3 mg MIA group, MMP-2, MMP-3, MMP-9, and MMP-13 levels showed very strong upregulation, which may cause overly strong reactions in animals. Therefore, a dose of 2 mg appears optimal, as it induces significant but not excessive OA-like changes in a rat model.

scholarly journals Initial Harm Reduction by N-Acetylcysteine Alleviates Cartilage Degeneration after Blunt Single-Impact Cartilage Trauma in Vivo

2019 ◽  
Vol 20 (12) ◽  
pp. 2916 ◽  
Author(s):  
Jana Riegger ◽  
Frank Leucht ◽  
Hans-Georg Palm ◽  
Anita Ignatius ◽  
Rolf E. Brenner
Keyword(s):  
Harm Reduction ◽  
Ex Vivo ◽  
Cluster Formation ◽  
Type Ii Collagen ◽  
Cartilage Degeneration ◽  
Histopathological Analysis ◽  
Protective Effects ◽  
Group B ◽  
Trauma Model

Joint injuries are highly associated with the development of post-traumatic osteoarthritis. Previous studies revealed cell- and matrix-protective effects of N-acetylcysteine (NAC) after ex vivo cartilage trauma, while chondroanabolic stimulation with bone morphogenetic protein 7 (BMP7) enhanced type II collagen (COL2) expression. Here, as a next step, we investigated the combined and individual efficacy of intra-articular antioxidative and chondroanabolic treatment in a rabbit in vivo cartilage trauma model. Animals were randomly divided into group A (right joint: trauma (T); left joint: T+BMP7) and group B (right joint: T+NAC; left joint: T+BMP7+NAC). Condyles were impacted with the use of a spring-loaded impact device to ensure defined, single trauma administration. After 12 weeks, histopathological analysis was performed and the presence of matrix metalloproteinase 13 (MMP-13) and COL2 was assessed. Trauma-induced hypocellularity, MMP-13 expression, and cell cluster formation were reduced in NAC-treated animals. In contrast, BMP7 further increased cluster formation. Moreover, synovial concentrations of COL2 carboxy propeptide (CPII) and proteoglycan staining intensities were enhanced in NAC- and NAC+BMP7-treated joints. For the first time, the efficacy of NAC regarding early harm reduction after blunt cartilage trauma was demonstrated in vivo. However, parallel administration of BMP7 was not significantly superior compared to NAC alone.

scholarly journals Ability of a Urine Assay of Type II Collagen Cleavage by Collagenases to Detect Early Onset and Progression of Articular Cartilage Degeneration: Results from a Population-based Cohort Study

2016 ◽  
Vol 43 (10) ◽  
pp. 1864-1870 ◽  
Author(s):  
A. Robin Poole ◽  
Nhuan Ha ◽  
Suzanne Bourdon ◽  
Eric C. Sayre ◽  
Ali Guermazi ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Competitive Inhibition ◽  
Cartilage Damage ◽  
Type Ii Collagen ◽  
Cartilage Degeneration ◽  
Population Based ◽  
Sandwich Assay ◽  
Radiographic Osteoarthritis ◽  
Collagen Peptide ◽  
Increased Risk

Objective.To evaluate the association of a sandwich assay for cartilage collagenase-mediated degradation, the C2C human urine sandwich assay (IB-C2C-HUSA), with early and late knee cartilage pathology and with progression of cartilage damage.Methods.A population-based cohort with knee pain, age 40–79 years, was evaluated at baseline (n = 253) and after mean 3.3 years (n = 161). We evaluated the IB-C2C-HUSA and a related competitive inhibition assay (C2C). The C2C assay was applied to serum (sC2C) and urine (uC2C). Based on knee radiographs and magnetic resonance imaging (MRI), 3 subgroups [no cartilage pathology, preradiographic cartilage pathology, and radiographic osteoarthritis (ROA)] were evaluated cross-sectionally for association with biomarker levels. Longitudinally, we evaluated whether baseline assays predict subsequent progression of cartilage degeneration, defined by MRI cartilage loss.Results.Cross-sectionally, statistically significant differences were seen in the 3 subgroups for IB-C2C-HUSA (p < 0.001), with the highest levels seen in ROA, and for sC2C (p = 0.023), while no differences were seen for uC2C (p = 0.501). Baseline IB-C2C-HUSA levels were higher in progressors vs nonprogressors (p = 0.003). In logistic regression analysis, only baseline IB-C2C-HUSA was associated with an increased risk of progression of cartilage damage (OR 1.78, 95% CI 1.03–3.09).Conclusion.The IB-C2C-HUSA degradation assay detects the generation of a pathology-related cartilage collagen peptide(s) that increase(s) with onset of degeneration of knee articular cartilage. The baseline values are associated with progression of cartilage degeneration over 3 subsequent years. This assay may have value in clinical OA trials. Further, it points to collagenase activity as a therapeutic target for controlling degeneration of articular cartilage.

scholarly journals Comparison of early-stage changes of osteoarthritis in cartilage and subchondral bone between two different rat models

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8934 ◽  
Author(s):  
Yutao Yang ◽  
Peiran Li ◽  
Songsong Zhu ◽  
Ruiye Bi
Keyword(s):  
Subchondral Bone ◽  
Early Stage ◽  
Cruciate Ligament ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
The Elderly ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Bone Change ◽  
Subchondral Bone Change

Osteoarthritis (OA) is a chronic degenerative joint disease and the major cause of joint pain and disability in the elderly. It is mainly characterized by articular cartilage degradation and subchondral bone remodeling. There are two main types of OA: natural occurring OA and secondary OA, mainly associated with aging and trauma, respectively. In this study, we established two OA models in rat knee joints to simulate the two types of OA, using the type II collagenase injection (CI) and anterior cruciate ligament transection (ACLT), respectively. After intervention for 2–6 weeks, cartilage and subchondral bone changes were detected in histological staining, immunochemistry, and micro-CT. Results showed that both models with typical pathology changes of OA were successfully induced, while the development and severity of OA process in the models were different. In ACLT rats, the cartilage damage was milder, lasted for a shorter time, and subchondral bone reconstruction occurred earlier, compared with the changes in CI rats. The cartilage damage was secondary to subchondral bone change in ACLT rats, while subchondral bone change was secondary to cartilage degeneration in CI rats. In conclusion, the interaction between cartilage and subchondral bone is different between the natural-occurring and secondary OA models. These two models not only suggest potential different mechanisms of the two types of OA, but also provide new directions for OA treatment and prevention.

scholarly journals Hyaluronic Acid versus Alpha-2-Macroglobulin Intra-Articular Injections for Amelioration of Knee Posttraumatic Osteoarthritis: A Rat Model

2020 ◽  
Author(s):  
Shaowei Wang ◽  
Mengbo Zhu ◽  
Yanjing Guo ◽  
Ruijia Yang ◽  
Yaqiong Chang ◽  
...  
Keyword(s):  
Hyaluronic Acid ◽  
Articular Cartilage ◽  
Synovial Fluid ◽  
Rat Model ◽  
Cruciate Ligament ◽  
Cartilage Damage ◽  
Cartilage Degeneration ◽  
Protective Effects ◽  
Significant Difference ◽  
Histological Staining

Abstract Background: The study was performed to evaluate whether intra-articular injection of A2M has better effect than current commonly used Hyaluronic Acid (HA) injection therapy to attenuate cartilage degeneration in a rat anterior cruciate ligament transection (ACLT) osteoarthritis (OA) model.Method: In vivo effects of A2M and HA on cartilage degeneration were evaluated in rat surgery induced ACLT OA models. 100 rats were randomly divided into four groups: (a) Sham surgery + saline (Sham + S), (b) ACLT + A2M, (c) ACLT+HA, or (d) ACLT + saline (ACLT+S). The animals were sacrificed at 12 weeks after surgery. Histological staining was performed to assess cartilage damage. The concentration of MMP-13 and sGAG in synovial fluid lavages was measured using ELISA and spectrophotometric quantitative determination. OA-related gene expression was quantified by qPCR.Result: Indian ink staining showed that articular cartilage surface treated by A2M was relatively intact compared with the animals treated by ACLT with saline or HA injection. Histological staining indicated that early supplemental intra-articular injection of A2M attenuated OA pathogenesis in the rat ACLT model compared with the animals treated with saline and HA. However, supplemental intra-articular injection of HA showed no significant effect on cartilage protection for post traumatic OA compared with saline treatment. Elisa results showed A2M reduced the concentration of MMP-13 in synovial fluid compared with HA treatment group and other groups. RT-qPCR indicated that supplemental intra-articular A2M inhibits catabolism and enhances anabolic metabolism, while there was no significant difference in the expression of OA-related genes between ACLT+HA group and ACLT+S group. Conclusion: In rat model, intra-articular injection of A2M had obvious protective effects on cartilage degeneration compared with HA treatment. Major indexes of joint degeneration decreased, providing strong evidence for its intra-articular inhibitory effect. Meanwhile, we found no significant alleviation of articular cartilage pathogenesis in HA treated group, which suggests that the efficacy of HA is questionable and possibly transient, although it is extensively used to improve syndromes.

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