Both microRNA-455-5p and -3p repress hypoxia-inducible factor-2α expression and coordinately regulate cartilage homeostasis

AbstractOsteoarthritis (OA), the most common aging-related joint disease, is caused by an imbalance between extracellular matrix synthesis and degradation. Here, we discover that both strands of microRNA-455 (miR-455), -5p and -3p, are up-regulated by Sox9, an essential transcription factor for cartilage differentiation and function. Both miR-455-5p and -3p are highly expressed in human chondrocytes from normal articular cartilage and in mouse primary chondrocytes. We generate miR-455 knockout mice, and find that cartilage degeneration mimicking OA and elevated expression of cartilage degeneration-related genes are observed at 6-months-old. Using a cell-based miRNA target screening system, we identify hypoxia-inducible factor-2α (HIF-2α), a catabolic factor for cartilage homeostasis, as a direct target of both miR-455-5p and -3p. In addition, overexpression of both miR-455-5p and -3p protect cartilage degeneration in a mouse OA model, demonstrating their potential therapeutic value. Furthermore, knockdown of HIF-2α in 6-month-old miR-455 knockout cartilage rescues the elevated expression of cartilage degeneration-related genes. These data demonstrate that both strands of a miRNA target the same gene to regulate articular cartilage homeostasis.

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Noggin Inhibits IL-1β and BMP-2 Expression, and Attenuates Cartilage Degeneration and Subchondral Bone Destruction in Experimental Osteoarthritis

Cells ◽

10.3390/cells9040927 ◽

2020 ◽

Vol 9 (4) ◽

pp. 927 ◽

Cited By ~ 5

Author(s):

Szu-Yu Chien ◽

Chun-Hao Tsai ◽

Shan-Chi Liu ◽

Chien-Chung Huang ◽

Tzu-Hung Lin ◽

...

Keyword(s):

Articular Cartilage ◽

Signaling Pathways ◽

Bone Remodeling ◽

Subchondral Bone ◽

Bone Destruction ◽

Cartilage Degeneration ◽

Cartilage Degradation ◽

Mitogen Activated Protein Kinase ◽

Bone Morphogenetic Protein 2 ◽

Joint Disease

Osteoarthritis (OA) is a chronic inflammatory and progressive joint disease that results in cartilage degradation and subchondral bone remodeling. The proinflammatory cytokine interleukin 1 beta (IL-1β) is abundantly expressed in OA and plays a crucial role in cartilage remodeling, although its role in the activity of chondrocytes in cartilage and subchondral remodeling remains unclear. In this study, stimulating chondrogenic ATDC5 cells with IL-1β increased the levels of bone morphogenetic protein 2 (BMP-2), promoted articular cartilage degradation, and enhanced structural remodeling. Immunohistochemistry staining and microcomputed tomography imaging of the subchondral trabecular bone region in the experimental OA rat model revealed that the OA disease promotes levels of IL-1β, BMP-2, and matrix metalloproteinase 13 (MMP-13) expression in the articular cartilage and enhances subchondral bone remodeling. The intra-articular injection of Noggin protein (a BMP-2 inhibitor) attenuated subchondral bone remodeling and disease progression in OA rats. We also found that IL-1β increased BMP-2 expression by activating the mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase (ERK), and specificity protein 1 (Sp1) signaling pathways. We conclude that IL-1β promotes BMP-2 expression in chondrocytes via the MEK/ERK/Sp1 signaling pathways. The administration of Noggin protein reduces the expression of IL-1β and BMP-2, which prevents cartilage degeneration and OA development.

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Follistatin Alleviates Synovitis and Articular Cartilage Degeneration Induced by Carrageenan

International Journal of Inflammation ◽

10.1155/2014/959271 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 12

Author(s):

Jun Yamada ◽

Kunikazu Tsuji ◽

Kazumasa Miyatake ◽

Yu Matsukura ◽

Kahaer Abula ◽

...

Keyword(s):

Articular Cartilage ◽

Proinflammatory Cytokines ◽

Synovial Membrane ◽

Joint Inflammation ◽

Cartilage Degeneration ◽

Decoy Receptor ◽

Arthritis Model ◽

Cartilage Homeostasis ◽

Articular Cartilage Degeneration ◽

And Cartilage

Activins are proinflammatory cytokines which belong to the TGFβsuperfamily. Follistatin is an extracellular decoy receptor for activins. Since both activins and follistatin are expressed in articular cartilage, we hypothesized that activin-follistatin signaling participates in the process of joint inflammation and cartilage degeneration. To test this hypothesis, we examined the effects of follistatin in a carrageenan-induced mouse arthritis model. Synovitis induced by intra-articular injection of carrageenan was significantly alleviated by preinjection with follistatin. Macrophage infiltration into the synovial membrane was significantly reduced in the presence of follistatin. In addition, follistatin inhibited proteoglycan erosion induced by carrageenan in articular cartilage. These data indicate that activin-follistatin signaling is involved in joint inflammation and cartilage homeostasis. Our data suggest that follistatin can be a new therapeutic target for inflammation-induced articular cartilage degeneration.

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Acetabular Labral Tears

Physical Therapy ◽

10.1093/ptj/86.1.110 ◽

2006 ◽

Vol 86 (1) ◽

pp. 110-121 ◽

Cited By ~ 95

Author(s):

Cara L Lewis ◽

Shirley A Sahrmann

Keyword(s):

Groin Pain ◽

Physical Therapists ◽

Cartilage Degeneration ◽

Hip Pain ◽

Joint Disease ◽

Acetabular Labrum ◽

Duration Of Symptoms ◽

Labral Tears ◽

Long Duration ◽

And Function

Abstract Anterior hip or groin pain is a common complaint for which people are referred for physical therapy, with the hip region being involved in approximately 5% to 9% of injuries in high school athletes.1 Although anterior hip pain is known to result from a number of musculoskeletal and systemic pathologies, a tear of the acetabular labrum is a recent addition to the list that is of particular interest to physical therapists. This mechanically induced pathology is thought to result from excessive forces at the hip joint2,3 and has been proposed as part of a continuum of hip joint disease that may result in articular cartilage degeneration.2 Although the number of recent articles in the orthopedic literature identifying acetabular labral tears as a source of hip pain is increasing, labral tears often evade detection, resulting in a long duration of symptoms, greater than 2 years on average, before diagnosis.4–8 Studies have shown that 22% of athletes with groin pain9 and 55% of patients with mechanical hip pain of unknown etiology2 were found to have a labral tear upon further evaluation. In order to provide the most appropriate intervention for patients with anterior hip or groin pain, physical therapists should be knowledgeable about all of the possible sources and causes of this pain, including a tear of the acetabular labrum and the possible factors contributing to these tears. Therefore, the purpose of this article is to review the anatomy and function of the acetabular labrum and present current concepts on the etiology, clinical characteristics, diagnosis, and treatment of labral tears.

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Knockdown of LSD1 alleviates the IL-1β-induced chondrocyte apoptosis, inflammation and ECM degradation via TRIM32-mediated autophagy

10.21203/rs.3.rs-720497/v1 ◽

2021 ◽

Author(s):

Wenqiang Xu ◽

Xiaofeng Liu ◽

Wenqing Qu ◽

Xin Wang ◽

Hao Su ◽

...

Keyword(s):

Cell Model ◽

Interleukin 1 ◽

Cartilage Degeneration ◽

Joint Disease ◽

Chondrocyte Apoptosis ◽

Interleukin 1 Beta ◽

Chondrocyte Viability ◽

A Cell ◽

Ecm Degradation ◽

Articular Cartilage Degeneration

Abstract Osteoarthritis (OA) is a common joint disease with characteristics of chronic inflammation and articular cartilage degeneration. It has been proved that LSD1 was up-regulated in OA cartilage tissues, but its role and regulatory mechanism in OA are unclear. Herein, interleukin 1 beta (IL-1β)-treated human chondrocytes was performed as a cell model of OA. Then, LSD1 expression was found that up-regulated in OA cartilage tissues and IL-1β-induced chondrocytes. Knockdown of LSD1 increased cell viability, while decreased apoptosis rate and inflammatory cytokines secretion levels in IL-1β-induced chondrocytes. In addition, knockdown of LSD1 reduced the expression of catabolic proteins (MMP-13 and ADAMTS-5) and enhanced the expression of anabolic proteins (Collagen II and Aggrecan) in chondrocytes after IL-1β stimulation. Moreover, overexpression of TRIM32 repressed chondrocyte viability, while promoted IL-1β-induced chondrocyte apoptosis, inflammation and ECM degradation. The expression of LSD1 and TRIM32 in OA cartilage was positively correlated, and knockdown of LSD1 down-regulated TRIM32 expression of chondrocytes. Our data further indicated that LSD1 regulated autophagy of chondrocytes through modulating TRIM32. Overexpression of TRIM32 reduced the effect of LSD1 knockdown on IL-1β-induced chondrocytes, while activating autophagy by Rapamycin further reversed this reduction. Therefore, our study shows that knockdown of LSD1 inhibited IL-1β-induced chondrocyte apoptosis, inflammation and ECM degradation via TRIM32-mediated autophagy.

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INFLUENCE OF STABILIZATION EXERCISES ON ARTICULAR CARTILAGE CHANGES IN DEGENERATIVE TIBIO- FEMORAL JOINT DISEASE- A PILOT STUDY

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2017.v10i4.17026 ◽

2017 ◽

Vol 10 (4) ◽

pp. 440 ◽

Cited By ~ 1

Author(s):

Patchava Apparao ◽

Sudhakar S ◽

Ganapathi Swamy Ch ◽

Ravi Shankar Reddy

Keyword(s):

Articular Cartilage ◽

Muscle Strength ◽

Knee Joint ◽

Cartilage Oligomeric Matrix Protein ◽

Matrix Protein ◽

Cartilage Degeneration ◽

Joint Disease ◽

Post Intervention ◽

Joint Stabilization ◽

Significant Difference

Objectives: To determine the effectiveness of knee joint stabilization exercises in minimizing articular cartilage degeneration and to examine theeffectiveness of knee joint stabilization exercises on decreasing pain, improving range of motion (ROM) and muscle strength.Methods: About 20 volunteer subjects (age 35-65 years) with primary osteoarthritis fulfilled the inclusion criteria given the knee stabilizationexercises for 8 weeks. Pain, muscle strength, functional outcome score, and serum cartilage oligomeric matrix protein (COMP) values were measuredpre- and post-intervention using visual analog scale, dynamometer, and ELISA test. Data were analyzed using a paired t-test with Statistical Packagefor the Social Sciences version 20 to find out the difference between the pre- and post-test.Results: The results of the study have shown that significant difference between pre- and post-test values of pain, ROM, muscle strength and functionaloutcome score with p<0.05, and there is statistical in significance in serum COMP value (p<0.05).Conclusion: Stabilization exercises of knee joint were shown to be beneficial for decreasing pain, improving ROM and muscle strength, and there wasno effect on articular cartilage changes in degenerative tibiofemoral joint disease.Keywords: Serum cartilage oligomeric matrix protein, Knee stabilization exercises, Proprioception exercises, Muscle strength.

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EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1608938113 ◽

2016 ◽

Vol 113 (50) ◽

pp. 14360-14365 ◽

Cited By ~ 35

Author(s):

Haoruo Jia ◽

Xiaoyuan Ma ◽

Wei Tong ◽

Basak Doyran ◽

Zeyang Sun ◽

...

Keyword(s):

Articular Cartilage ◽

High Surface ◽

Cartilage Degeneration ◽

Superficial Layer ◽

Joint Disease ◽

Egfr Signaling ◽

Superficial Zone ◽

Cartilage Surface ◽

Healthy Cartilage ◽

Important Regulator

Osteoarthritis (OA) is the most common joint disease, characterized by progressive destruction of the articular cartilage. The surface of joint cartilage is the first defensive and affected site of OA, but our knowledge of genesis and homeostasis of this superficial zone is scarce. EGFR signaling is important for tissue homeostasis. Immunostaining revealed that its activity is mostly dominant in the superficial layer of healthy cartilage but greatly diminished when OA initiates. To evaluate the role of EGFR signaling in the articular cartilage, we studied a cartilage-specific Egfr-deficient (CKO) mouse model (Col2-Cre EgfrWa5/flox). These mice developed early cartilage degeneration at 6 mo of age. By 2 mo of age, although their gross cartilage morphology appears normal, CKO mice had a drastically reduced number of superficial chondrocytes and decreased lubricant secretion at the surface. Using superficial chondrocyte and cartilage explant cultures, we demonstrated that EGFR signaling is critical for maintaining the number and properties of superficial chondrocytes, promoting chondrogenic proteoglycan 4 (Prg4) expression, and stimulating the lubrication function of the cartilage surface. In addition, EGFR deficiency greatly disorganized collagen fibrils in articular cartilage and strikingly reduced cartilage surface modulus. After surgical induction of OA at 3 mo of age, CKO mice quickly developed the most severe OA phenotype, including a complete loss of cartilage, extremely high surface modulus, subchondral bone plate thickening, and elevated joint pain. Taken together, our studies establish EGFR signaling as an important regulator of the superficial layer during articular cartilage development and OA initiation.

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Miniaturized Water-Jet Ultrasound Indentation System for Quantitative Assessment of Articular Cartilage Degeneration: A Validation Study

BioMed Research International ◽

10.1155/2020/2316369 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Yan-Ping Huang ◽

Yong-Ping Zheng

Keyword(s):

Articular Cartilage ◽

Quantitative Assessment ◽

Large Population ◽

Cartilage Degeneration ◽

The Elderly ◽

Water Jet ◽

Joint Disease ◽

Ultrasound Indentation ◽

Reproducibility Study ◽

Significant Difference

Osteoarthritis is a common joint disease affecting a large population especially the elderly where cartilage degeneration is one of its hallmark symptoms. There is a need to develop new devices and instruments for the early detection and treatment of cartilage degeneration. In this study, we describe the development of a miniaturized water-jet ultrasound indentation probe for this purpose. To evaluate the system, we applied it to characterize the degeneration of articular cartilage with the measurement of its morphologic, acoustic, and mechanical properties, using the enzymatic digestions of cartilage as a model of OA. Fifty cartilage samples were tested with 10 of them used for the reproducibility study and the other 40 for collagenase and trypsin digestions. Thickness, integrated reflection coefficient (IRC), effective stiffness, and energy dissipation ratio (EDR) were used to quantify the change of articular cartilage before and after degeneration. The measurement reproducibility as represented by the standardized coefficient of variation (SCV) was 2.6%, 10.2%, 11.5%, and 12.8% for thickness, IRC, stiffness, and EDR, respectively. A significant change of IRC, stiffness, and EDR was detected after degeneration by the designed probe (p<0.05). There was also a significant difference of IRC, stiffness, and EDR between trypsin and collagenase digestions (p<0.001). In conclusion, a miniaturized water-jet ultrasound indentation probe has been designed, which has been successfully used to detect and differentiate cartilage degeneration simulated by enzymatic digestions. This probe, with future development, can be potentially suitable for quantitative assessment of cartilage degeneration with an arthroscopic operation.

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Osteochondral Regeneration Using Adipose Tissue-Derived Mesenchymal Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21103589 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3589 ◽

Cited By ~ 1

Author(s):

Daiki Murata ◽

Ryota Fujimoto ◽

Koichi Nakayama

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Adipose Tissue ◽

Articular Cartilage ◽

Subchondral Bone ◽

Three Dimensional ◽

Cartilage Regeneration ◽

Joint Disease ◽

And Function ◽

Osteochondral Regeneration

Osteoarthritis (OA) is a major joint disease that promotes locomotor deficiency during the middle- to old-age, with the associated disability potentially decreasing quality of life. Recently, surgical strategies to reconstruct both articular cartilage and subchondral bone for OA have been diligently investigated for restoring joint structure and function. Adipose tissue-derived mesenchymal stem cells (AT-MSCs), which maintain pluripotency and self-proliferation ability, have recently received attention as a useful tool to regenerate osteocartilage for OA. In this review, several studies were described related to AT-MSC spheroids, with scaffold and scaffold-free three-dimensional (3D) constructs produced using “mold” or “Kenzan” methods for osteochondral regeneration. First, several examples of articular cartilage regeneration using AT-MSCs were introduced. Second, studies of osteochondral regeneration (not only cartilage but also subchondral bone) using AT-MSCs were described. Third, examples were presented wherein spheroids were produced using AT-MSCs for cartilage regeneration. Fourth, osteochondral regeneration following autologous implantation of AT-MSC scaffold-free 3D constructs, fabricated using the “mold” or “Kenzan” method, was considered. Finally, prospects of osteochondral regeneration by scaffold-free 3D constructs using AT-MSC spheroids were discussed.

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Potential of Exosomes for Diagnosis and Treatment of Joint Disease: Towards a Point-of-Care Therapy for Osteoarthritis of the Knee

International Journal of Molecular Sciences ◽

10.3390/ijms22052666 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2666

Author(s):

Miki Maehara ◽

Eriko Toyoda ◽

Takumi Takahashi ◽

Masahiko Watanabe ◽

Masato Sato

Keyword(s):

Drug Delivery ◽

Articular Cartilage ◽

Point Of Care ◽

Joint Disease ◽

Cartilage Defects ◽

Osteoarthritis Of The Knee ◽

Fluid Composition ◽

Care Treatment ◽

Articular Cartilage Injury ◽

A Cell

In the knee joint, articular cartilage injury can often lead to osteoarthritis of the knee (OAK). Currently, no point-of-care treatment can completely address OAK symptoms and regenerate articular cartilage to restore original functions. While various cell-based therapies are being developed to address OAK, exosomes containing various components derived from their cells of origin have attracted attention as a cell-free alternative. The potential for exosomes as a novel point-of-care treatment for OAK has been studied extensively, especially in the context of intra-articular treatments. Specific exosomal microRNAs have been identified as possibly effective in treating cartilage defects. Additionally, exosomes have been studied as biomarkers through their differences in body fluid composition between joint disease patients and healthy subjects. Exosomes themselves can be utilized as a drug delivery system through their manipulation and encapsulation of specific contents to be delivered to specific cells. Through the combination of exosomes with tissue engineering, novel sustained release drug delivery systems are being developed. On the other hand, many of the functions and activities of exosomes are unknown and challenges remain for clinical applications. In this review, the possibilities of intra-articular treatments utilizing exosomes and the challenges in using exosomes in therapy are discussed.

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Etiology, pathophysiology and conservative management of degenerative joint disease

Medicinski pregled ◽

10.2298/mpns0202035j ◽

2002 ◽

Vol 55 (1-2) ◽

pp. 35-39

Author(s):

Slavica Jandric

Keyword(s):

Articular Cartilage ◽

Conservative Management ◽

Cartilage Degeneration ◽

Degenerative Joint Disease ◽

Response To Therapy ◽

Joint Disease ◽

Joint Diseases ◽

Joint Stability ◽

The Impact ◽

Degenerative Joint Diseases

Etiology of degenerative joint diseases Etiology of degenerative joint diseases is still not clearly understood and there is no specific management for this group of diseases. Various pathological conditions cause damage of the articular cartilage and lead to clinically and radiographically recognized impairment. Biomechanical, metabolic, genetic factors inflammation and other risk factors contribute to development of osteoarthrosis. Pathophysiology of degenerative joint diseases Osteoarthrosis is characterized by progressive erosion of articular cartilage and bone overgrowth at the joint margins. Cartilage integrity requires balance between synthesis and degradation of matrix components. Chondrocytes react to various mechanical and chemical stresses in order to stabilize and restore the tissue. Failures in stabilizing and restoring the tissue lead to cartilage degeneration that may be irreversibile. For better understanding of conservative management of degenerative joint diseases it is important to know the impact of pathophysiology mechanisms on development of degenerative joint diseases. There is great variability in the rate of progression of erosive processes in articular cartilage in clinical radiographic signs and course of the disease. This is in relation with many factors, as well as with management and response to therapy. Treatment of degenerative joint diseases Treatment should vary depending on the severity of disease and patient's expectations and level of activity. Besides analgesic and anti-inflammatory drugs, conventional and not conventional treatment and techniques can be used for management of osteoarthrosis. Physical therapy and exercises are very important for maintaining muscle strength, joint stability and mobility, but should be closely monitored for optimal efficacy.

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