The effects of mechanical loading and gadolinium concentration on the change of T1 and quantification of glycosaminoglycans in articular cartilage by microscopic MRI

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.

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Cyclic Mechanical Loading Enhances Transport of Antibodies Into Articular Cartilage

Journal of Biomechanical Engineering ◽

10.1115/1.4035265 ◽

2016 ◽

Vol 139 (1) ◽

Cited By ~ 16

Author(s):

Chris D. DiDomenico ◽

Zhen Xiang Wang ◽

Lawrence J. Bonassar

Keyword(s):

Finite Element ◽

Articular Cartilage ◽

Mechanical Loading ◽

Mechanical Stimulation ◽

Mechanical Load ◽

Linear Trend ◽

Fluid Velocity ◽

Cartilage Tissue ◽

Clinical Value ◽

Maximum Enhancement

The goal of this study was to characterize antibody penetration through cartilage tissue under mechanical loading. Mechanical stimulation aids in the penetration of some proteins, but this effect has not characterized molecules such as antibodies (>100 kDa), which may hold some clinical value for treating osteoarthritis (OA). For each experiment, fresh articular cartilage plugs were obtained and exposed to fluorescently labeled antibodies while under cyclic mechanical load in unconfined compression for several hours. Penetration of these antibodies was quantified using confocal microscopy, and finite element (FE) simulations were conducted to predict fluid flow patterns within loaded samples. Transport enhancement followed a linear trend with strain amplitude (0.25–5%) and a nonlinear trend with frequency (0.25–2.60 Hz), with maximum enhancement found to be at 5% cyclic strain and 1 Hz, respectively. Regions of highest enhancement of transport within the tissue were associated with the regions of highest interstitial fluid velocity, as predicted from finite-element simulations. Overall, cyclic compression-enhanced antibody transport by twofold to threefold. To our knowledge, this is the first study to test how mechanical stimulation affects the diffusion of antibodies in cartilage and suggest further study into other important factors regarding macromolecular transport.

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Intermittent applied mechanical loading induces subchondral bone thickening that may be intensified locally by contiguous articular cartilage lesions

Osteoarthritis and Cartilage ◽

10.1016/j.joca.2015.01.012 ◽

2015 ◽

Vol 23 (6) ◽

pp. 940-948 ◽

Cited By ~ 36

Author(s):

B. Poulet ◽

R. de Souza ◽

A.V. Kent ◽

L. Saxon ◽

O. Barker ◽

...

Keyword(s):

Articular Cartilage ◽

Mechanical Loading ◽

Subchondral Bone ◽

Cartilage Lesions ◽

Articular Cartilage Lesions

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A new pressure chamber to study the biosynthetic response of articular cartilage to mechanical loading

Research in Experimental Medicine ◽

10.1007/bf02576220 ◽

1993 ◽

Vol 193 (1) ◽

pp. 137-142 ◽

Cited By ~ 12

Author(s):

Jürgen Steinmeyer ◽

Peter A. Torzilli ◽

Nancy Burton-Wurster ◽

George Lust

Keyword(s):

Articular Cartilage ◽

Mechanical Loading ◽

Pressure Chamber

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MUSCLE-INDUCED PATELLOFEMORAL JOINT LOADING RAPIDLY AFFECTS CARTILAGE mRNA LEVELS IN A SITE SPECIFIC MANNER

Journal of Musculoskeletal Research ◽

10.1142/s0218957704001223 ◽

2004 ◽

Vol 08 (01) ◽

pp. 1-12 ◽

Cited By ~ 7

Author(s):

Andrea L. Clark ◽

Linda Mills ◽

David A Hart ◽

Walter Herzog

Keyword(s):

Articular Cartilage ◽

Mechanical Loading ◽

Patellofemoral Joint ◽

Mrna Level ◽

Recovery Period ◽

Cartilage Explants ◽

Mrna Levels ◽

Biological Responses

Mechanical loading of articular cartilage affects the synthesis and degradation of matrix macromolecules. Much of the work in this area has involved mechanical loading of articular cartilage explants or cells in vitro and assessing biological responses at the mRNA and protein levels. In this study, we developed a new experimental technique to load an intact patellofemoral joint in vivo using muscle stimulation. The articular cartilages were cyclically loaded for one hour in a repeatable and measurable manner. Cartilage was harvested from central and peripheral regions of the femoral groove and patella, either immediately after loading or after a three hour recovery period. Total RNA was isolated from the articular cartilage and biological responses were assessed on the mRNA level using the reverse transcriptase-polymerase chain reaction. Articular cartilage from intact patellofemoral joints demonstrated heterogeneity at the mRNA level for six of the genes assessed independent of the loading protocol. Cyclical loading of cartilage in its native environment led to alterations in mRNA levels for a subset of molecules when assessed immediately after the loading period. However, the increases in TIMP-1 and decreases in bFGF mRNA levels were transient; being present immediately after load application but not after a three hour recovery period.

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Effect of methylprednisolone and mechanical loading on canine articular cartilage in explant culture

Osteoarthritis and Cartilage ◽

10.1016/s1063-4584(96)80007-0 ◽

1996 ◽

Vol 4 (1) ◽

pp. 55-62 ◽

Cited By ~ 18

Author(s):

Tony Farquhar ◽

Rory J. Todhunter ◽

Susan L. Fubini ◽

Nancy Burton-Wurster ◽

Georeg Lust

Keyword(s):

Articular Cartilage ◽

Mechanical Loading ◽

Explant Culture

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Chondrocyte Death in Articular Cartilage Due to Excessive Mechanical Loading in the Axial and Transverse Directions

Advances in Bioengineering ◽

10.1115/imece2002-32669 ◽

2002 ◽

Cited By ~ 1

Author(s):

Chih-Tung Chen ◽

Peter A. Torzilli

Keyword(s):

Articular Cartilage ◽

Mechanical Loading ◽

Impact Load ◽

Impact Loads ◽

Cyclic Loads ◽

Matrix Degradation ◽

Secondary Osteoarthritis ◽

Load Duration ◽

Chondrocyte Death ◽

Traumatic Impact

Chondrocyte injury and death in articular cartilage can cause matrix degradation and is a risk factor for secondary osteoarthritis [1,3–5]. Chondrocyte death can occur due to excessive mechanical loading, such as with a single high traumatic impact load (≥20 MPa), repeated sub-impact loads (≥5 MPa), or extensive cyclic loads (≥1 MPa) [1–5]. Several recent studies have shown that chondrocyte death depends not only on the stress magnitude [2] but also on the stress rate [3], strain rate [5] and load duration [1–2].

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The Relationship Between Proteoglycan Loss, Overloading-Induced Collagen Damage, and Cyclic Loading in Articular Cartilage

Cartilage ◽

10.1177/1947603519885005 ◽

2019 ◽

pp. 194760351988500

Author(s):

Lorenza Henao-Murillo ◽

Maria-Ioana Pastrama ◽

Keita Ito ◽

Corrinus C. van Donkelaar

Keyword(s):

Articular Cartilage ◽

Cyclic Loading ◽

Mechanical Loading ◽

Mechanical Tests ◽

Repeated Loading ◽

Healthy Cartilage ◽

Before And After ◽

Damage Grades ◽

The Relationship ◽

Phosphate Buffered Saline

Objective The interaction between proteoglycan loss and collagen damage in articular cartilage and the effect of mechanical loading on this interaction remain unknown. The aim of this study was to answer the following questions: (1) Is proteoglycan loss dependent on the amount of collagen damage and does it depend on whether this collagen damage is superficial or internal? (2) Does repeated loading further increase the already enhanced proteoglycan loss in cartilage with collagen damage? Design Fifty-six bovine osteochondral plugs were equilibrated in phosphate-buffered saline for 24 hours, mechanically tested in compression for 8 hours, and kept in phosphate-buffered saline for another 48 hours. The mechanical tests included an overloading step to induce collagen damage, creep steps to determine tissue stiffness, and cyclic loading to induce convection. Proteoglycan release was measured before and after mechanical loading, as well as 48 hours post-loading. Collagen damage was scored histologically. Results Histology revealed different collagen damage grades after the application of mechanical overloading. After 48 hours in phosphate-buffered saline postloading, proteoglycan loss increased linearly with the amount of total collagen damage and was dependent on the presence but not the amount of internal collagen damage. In samples without collagen damage, repeated loading also resulted in increased proteoglycan loss. However, repeated loading did not further enhance the proteoglycan loss induced by damaged collagen. Conclusion Proteoglycan loss is enhanced by collagen damage and it depends on the presence of internal collagen damage. Cyclic loading stimulates proteoglycan loss in healthy cartilage but does not lead to additional loss in cartilage with damaged collagen.

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