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

2016 ◽  
Vol 113 (50) ◽  
pp. 14360-14365 ◽  
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.

scholarly journals Estimation of differences in selected indices of vibroacoustic signals between healthy and osteoarthritic patellofemoral joints as a potential non-invasive diagnostic tool

2021 ◽  
Vol 2130 (1) ◽  
pp. 012009
Author(s):  
R Karpiński ◽  
P Krakowski ◽  
J Jonak ◽  
A Machrowska ◽  
M Maciejewski ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Invasive Procedure ◽  
Superficial Layer ◽  
Degenerative Changes ◽  
Joint Disease ◽  
Control Group ◽  
Kinetic Chain ◽  
Non Invasive ◽  
Joint Surfaces ◽  
Vibroacoustic Signals

Abstract Osteoarthritis (OA) is currently the most generic form of joint disease. It is a complex process in which degenerative changes occur in the articular cartilage [AC], subchondral bone, and synovial membrane and can lead to permanent joint failure. The primary and most commonly used method of diagnosing degenerative changes is classic radiography. Magnetic resonance imaging (MRI) may be used to assess the extent of damage to joint surfaces, but this method is limited by the availability of specialised equipment and the excessive cost of the examination. Arthroscopy, an invasive procedure, is considered the “gold standard” in joint diagnosis. The occurrence of degenerative changes is closely related to the friction and lubrication processes within the joint. The main causes of osteoarthritis are a change or lack of synovial fluid, deformation of the joint bones, local damage to the articular cartilage, and a change in the mechanical properties of the articular cartilage due to water loss from the damaged superficial layer. An alternative, non-invasive method that allows for a delicate assessment of the condition of moving joints is vibroarthrography (VAG). The analysis of vibroacoustic signals generated by moving joint surfaces has an immense potential in the non-invasive assessment of the degree of damage to articular cartilage, meniscus and ligaments and the general diagnosis of degenerative diseases. The purpose of this study is to analyse and statistically compare the basic characteristics of vibroacoustic signals recorded with a CM-01B contact microphone placed on the patella for motion in the 90°–0°–90° range in a closed kinetic chain (CKC) in a control group (HC) and a group of patients diagnosed with osteoarthritis (OA), qualified for the knee alloplasty.

A Fibril Reinforced Poroelastic Model of Articular Cartilage Including Depth Dependent Material Properties

1999 ◽  
Author(s):  
L. P. Li ◽  
M. D. Buschmann ◽  
A. Shirazi-Adl
Keyword(s):  
Articular Cartilage ◽  
Regional Differences ◽  
Articular Surface ◽  
Collagen Fibrils ◽  
Superficial Zone ◽  
Cartilage Surface ◽  
Poroelastic Model ◽  
Oriented Parallel ◽  
Strain Dependent ◽  
Very High

Abstract Articular cartilage is a highly nonhomogeneous, anisotropic and multiphase biomaterial consisting of mainly collagen fibrils, proteoglycans and water. Noncalcified cartilage is morphologically divided into three zones along the depth, i.e. superficial, transitional and radial zones. The thickness, density and alignment of collagen fibrils vary from the superficial zone, where fibrils are oriented parallel to the articular surface, to the radial zone where fibrils are perpendicular to the boundary between bone, and cartilage. The concentration of proteoglycans increases with the depth from the cartilage surface. These regional differences have significant implications to the mechanical function of joints, which is to be explored theoretically in the present work by considering inhomogeneity along the cartilage depth. A nonlinear fibril reinforced poroelastic model is employed as per Li et al. (1999) in which the collagen fibrils were modeled as a distinct constituent whose tensile stiffness was taken to be very high and be strain dependent but whose compressive stiffness was neglected.

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

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 927 ◽  
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.

scholarly journals Wnt/β-catenin signaling contributes to articular cartilage homeostasis through lubricin induction in the superficial zone

2019 ◽  
Vol 21 (1) ◽  
Author(s):  
Fengjun Xuan ◽  
Fumiko Yano ◽  
Daisuke Mori ◽  
Ryota Chijimatsu ◽  
Yuji Maenohara ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Mechanical Loading ◽  
Cartilage Degeneration ◽  
Mrna Levels ◽  
Superficial Zone ◽  
Gain Of Function ◽  
Wnt Ligands ◽  
Signaling Activation ◽  
Signaling Activity

Abstract Background Both loss- and gain-of-function of Wnt/β-catenin signaling in chondrocytes result in exacerbation of osteoarthritis (OA). Here, we examined the activity and roles of Wnt/β-catenin signaling in the superficial zone (SFZ) of articular cartilage. Methods Wnt/β-catenin signaling activity was analyzed using TOPGAL mice. We generated Prg4-CreERT2;Ctnnb1fl/fl and Prg4-CreERT2;Ctnnb1-ex3fl/wt mice for loss- and gain-of-function, respectively, of Wnt/β-catenin signaling in the SFZ. Regulation of Prg4 expression by Wnt/β-catenin signaling was examined in vitro, as were upstream and downstream factors of Wnt/β-catenin signaling in SFZ cells. Results Wnt/β-catenin signaling activity, as determined by the TOPGAL reporter, was high specifically in the SFZ of mouse adult articular cartilage, where Prg4 is abundantly expressed. In SFZ-specific β-catenin-knockout mice, OA development was significantly accelerated, which was accompanied by decreased Prg4 expression and SFZ destruction. In contrast, Prg4 expression was enhanced and cartilage degeneration was suppressed in SFZ-specific β-catenin-stabilized mice. In primary SFZ cells, Prg4 expression was downregulated by β-catenin knockout, while it was upregulated by β-catenin stabilization by exon 3 deletion or treatment with CHIR99021. Among Wnt ligands, Wnt5a, Wnt5b, and Wnt9a were highly expressed in SFZ cells, and recombinant human WNT5A and WNT5B stimulated Prg4 expression. Mechanical loading upregulated expression of these ligands and further promoted Prg4 transcription. Moreover, mechanical loading and Wnt/β-catenin signaling activation increased mRNA levels of Creb1, a potent transcription factor for Prg4. Conclusions We demonstrated that Wnt/β-catenin signaling regulates Prg4 expression in the SFZ of mouse adult articular cartilage, which plays essential roles in the homeostasis of articular cartilage.

scholarly journals Overexpression of Mig-6 in Limb Mesenchyme Leads to Accelerated Osteoarthritis in Mice

2019 ◽  
Author(s):  
Melina Rodrigues Bellini ◽  
Michael Andrew Pest ◽  
Jae-Wook Jeong ◽  
Frank Beier
Keyword(s):  
Articular Cartilage ◽  
Molecular Mechanisms ◽  
Cartilage Degeneration ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Synovial Joint ◽  
Egfr Signaling ◽  
Bone Thickness ◽  
Developmental Effects ◽  
And Control

ABSTRACTBackgroundMitogen-inducible gene 6 (Mig-6) is a tumour suppressor gene that is also associated with the development of osteoarthritis (OA)-like disorder. Recent evidence from our lab and others showed that cartilage-specific Mig-6 knockout (KO) mice develop chondro-osseous nodules, along with increased articular cartilage thickness and enhanced EGFR signaling in the articular cartilage. Here, we evaluate the phenotype of mice with skeletal-specific overexpression of Mig-6.MethodsSynovial joint tissues of the knee were assessed in 12 and 36 weeks-old skeleton-specific Mig-6 overexpressing (Mig-6over/over) and control animals using histological stains, immunohistochemistry, semi-quantitative OARSI scoring, and microCT for skeletal morphometry. Measurement of articular cartilage and subchondral bone thickness were also performed using histomorphometry.ResultsOur results show only subtle developmental effects of Mig-6 overexpression. However, male Mig-6over/over mice show accelerated cartilage degeneration at 36 weeks of age, in both medial and lateral compartments of the knee. Immunohistochemistry for SOX9 and PRG4 showed decreased staining in Mig-6over/over mice relative to controls, providing potential molecular mechanisms for the observed effects.ConclusionOverexpression of Mig-6 in articular cartilage causes no major developmental phenotype but results in accelerated development of OA during aging. These data demonstrate that precise regulation of the Mig-6/EGFR pathway is critical for joint homeostasis.

scholarly journals Recent Advances in Understanding the Role of Cartilage Lubrication in Osteoarthritis

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6122
Author(s):  
Yumei Li ◽  
Zhongrun Yuan ◽  
Hui Yang ◽  
Haijian Zhong ◽  
Weijie Peng ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Essential Role ◽  
Daily Life ◽  
Early Stage ◽  
Joint Disease ◽  
Low Friction ◽  
Cartilage Surface ◽  
Wear And Tear ◽  
Lubrication Properties

The remarkable lubrication properties of normal articular cartilage play an essential role in daily life, providing almost frictionless movements of joints. Alterations of cartilage surface or degradation of biomacromolecules within synovial fluid increase the wear and tear of the cartilage and hence determining the onset of the most common joint disease, osteoarthritis (OA). The irreversible and progressive degradation of articular cartilage is the hallmark of OA. Considering the absence of effective options to treat OA, the mechanosensitivity of chondrocytes has captured attention. As the only embedded cells in cartilage, the metabolism of chondrocytes is essential in maintaining homeostasis of cartilage, which triggers motivations to understand what is behind the low friction of cartilage and develop biolubrication-based strategies to postpone or even possibly heal OA. This review firstly focuses on the mechanism of cartilage lubrication, particularly on boundary lubrication. Then the mechanotransduction (especially shear stress) of chondrocytes is discussed. The following summarizes the recent development of cartilage-inspired biolubricants to highlight the correlation between cartilage lubrication and OA. One might expect that the restoration of cartilage lubrication at the early stage of OA could potentially promote the regeneration of cartilage and reverse its pathology to cure OA.

scholarly journals Functional roles of COMP and TSP-4 in articular cartilage and their relevance in osteoarthritis

2021 ◽  
Author(s):  
◽  
Kathrin Maly
Keyword(s):  
Gene Expression ◽  
Articular Cartilage ◽  
Protein Level ◽  
Functional Role ◽  
Human Articular Cartilage ◽  
Serum Samples ◽  
Superficial Zone ◽  
Ecm Proteins ◽  
Healthy Cartilage

Osteoarthritis (OA) is a slowly progressing disease, resulting in the degradation of cartilage and the loss of joint functionality. The cartilage extracellular matrix (ECM) is degraded and undergoes remodelling in OA progression. Chondrocytes start to express degrading proteases but are also reactivated and synthesise ECM proteins. The spectrum of these newly synthesised proteins and their involvement in OA specific processes and cartilage repair is hardly investigated. Human articular cartilage obtained from OA patients undergoing knee replacement surgery was evaluated according to the OARSI histopathology grading system. Healthy, non-OA cartilage samples were used as controls. The expression and distribution of thrombospondin-4 (TSP-4) and the closely related COMP were analysed on the gene level by PCR and on the protein level by immunohistology and immunoblot assays. The potential of TSP-4 as a diagnostic marker was evaluated by immunoblot assays, using serum samples from OA patients and healthy individuals. The functional role of both proteins was further investigated in in vitro studies using chondrocytes isolated from femoral condyles of healthy pigs. The effect of COMP and TSP-4 on chondrocyte migration and attachment was investigated via transwell and attachment assays, respectively. Moreover, the potential of COMP and TSP-4 to modulate the chondrocyte phenotype by inducing gene expression, ECM protein synthesis and matrix formation was investigated by immunofluorescence staining and qPCR. The activation of cartilage relevant signalling pathways was investigated by immunoblot assays. These results showed for the first time the presence of TSP-4 in articular cartilage. Its amount dramatically increased in OA compared to healthy cartilage and correlated positively with OA severity. In healthy cartilage TSP-4 was primarily found in the superficial zone while it was wider distributed in the middle and deeper zones of OA cartilage. The amount of specific TSP-4 fragments was increased in sera of OA patients compared to healthy controls, indicating a potential to serve as an OA biomarker. COMP was ubiquitously expressed in healthy cartilage but degraded in early as well as re-expressed in late-stage OA. The overall protein levels between OA severity grades were comparable. Contrary to TSP-4, COMP was localised primarily in the upper zone of OA cartilage, in particular in areas with severe damage. COMP could attract chondrocytes and facilitated their attachment, while TSP-4 did not affect these processes. COMP and TSP 4 were generally weak inducers of gene expression, although both could induce COL2A1 and TSP-4 additionally COL12A1 and ACAN after 6 h. Correlating data were obtained on the protein level: COMP and TSP-4 promoted the synthesis and matrix formation of collagen II, collagen IX, collagen XII and proteoglycans. In parallel, both proteins suppressed chondrocyte hypertrophy and dedifferentiation by reducing collagen X and collagen I. By analysing the effect of COMP and TSP-4 on intracellular signalling, both proteins induced Erk1/2 phosphorylation and TSP-4 could further promote Smad2/3 signalling induced by TGF-β1. None of the two proteins had a direct or modulatory effect on Smad1/5/9 dependent signalling. In summary, COMP and TSP-4 contribute to ECM maintenance and repair by inducing the expression of essential ECM proteins and suppressing chondrocyte dedifferentiation. These effects might be mediated by Erk1/2 phosphorylation. The presented data demonstrate an important functional role of COMP and TSP-4 in both healthy and OA cartilage and provide a basis for further studies on their potential in clinical applications for OA diagnosis and treatment.

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

2017 ◽  
Vol 10 (4) ◽  
pp. 440 ◽  
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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