Interactions between molecules in the synovial fluid and the cartilage surface may play a vital role in the formation of adsorbed films that contribute to the low friction of cartilage boundary lubrication. Osteoarthritis (OA) is the most common degenerative joint disease. Previous studies have shown that in OA-diseased joints, hyaluronan (HA) not only breaks down resulting in a much lower molecular weight (MW), but also its concentration is reduced ten times. Here, we have investigated the structural changes of lipid-HA complexes as a function of HA concentration and MW to simulate the physiologically relevant conditions that exist in healthy and diseased joints. Small angle neutron scattering and dynamic light scattering were used to determine the structure of HA-lipid vesicles in bulk solution, while a combination of atomic force microscopy and quartz crystal microbalance was applied to study their assembly on a gold surface. We infer a significant influence of both MW and HA concentrations on the structure of HA-lipid complexes in bulk and assembled on a gold surface. Our results suggest that low MW HA cannot form an amorphous layer on the gold surface, which is expected to negatively impact the mechanical integrity and longevity of the boundary layer and could contribute to the increased wear of the cartilage that has been reported in joints diseased with OA.
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Nanoscale insight into the degradation mechanisms of the cartilage articulating surface preceding OA
Osteoarthritis (OA) is a degenerative joint disease and a leading cause of disability globally. In OA, the articulating surface of cartilage is compromised by fissures and cracks, and sometimes even worn away completely. Due to its avascular nature, articular cartilage has a poor self-healing ability, and therefore, understanding the mechanisms underlying degradation is key for OA prevention and for optimal design of replacements. In this work, the articulating surface of bovine cartilage was investigated in an environment with enhanced calcium concentration -as often found in cartilage in relation to OA- by combining atomic force microscopy, spectroscopy and an extended surface forces apparatus for the first time. The experimental results reveal that increased calcium concentration irreversibly weakens the cartilage's surface layer, and promotes stiction and high friction. The synergistic effect of calcium on altering the cartilage surface's structural, mechanical and frictional properties is proposed to compromise cartilage integrity at the onset of OA. Furthermore, two mechanisms at the molecular level based on the influence of calcium on lubricin and on the aggregation of the cartilage's matrix, respectively, are identified. The results of this work might not only help prevent OA but also help design better cartilage replacements.
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- Award ID(s):
- 1761696
- NSF-PAR ID:
- 10222946
- Date Published:
- Journal Name:
- Biomaterials Science
- Volume:
- 8
- Issue:
- 14
- ISSN:
- 2047-4830
- Page Range / eLocation ID:
- 3944 to 3955
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Objective To elucidate the role of decorin, a small leucine‐rich proteoglycan, in the degradation of cartilage matrix during the progression of post‐traumatic osteoarthritis (
OA ).Methods Three‐month–old decorin‐null (Dcn−/−) and inducible decorin‐knockout (Dcni
KO ) mice were subjected to surgical destabilization of the medial meniscus (DMM ) to induce post‐traumaticOA . TheOA phenotype that resulted was evaluated by assessing joint morphology and sulfated glycosaminoglycan (sGAG ) staining via histological analysis (n = 6 mice per group), surface collagen fibril nanostructure via scanning electron microscopy (n = 4 mice per group), tissue modulus via atomic force microscopy–nanoindentation (n = 5 or more mice per group) and subchondral bone structure via micro–computed tomography (n = 5 mice per group). Femoral head cartilage explants from wild‐type and Dcn−/−mice were stimulated with the inflammatory cytokine interleukin‐1β (IL ‐1β) in vitro (n = 6 mice per group). The resulting chondrocyte response toIL ‐1β and release ofsGAG s were quantified.Results In both Dcn−/−and Dcni
KO mice, the absence of decorin resulted in acceleratedsGAG loss and formation of highly aligned collagen fibrils on the cartilage surface relative to the control (P < 0.05). Also, Dcn−/−mice developed more salient osteophytes, illustrating more severeOA . In cartilage explants treated withIL ‐1β, loss of decorin did not alter the expression of either anabolic or catabolic genes. However, a greater proportion ofsGAG s was released to the media from Dcn−/−mouse explants, in both live and devitalized conditions (P < 0.05).Conclusion In post‐traumatic
OA , decorin delays the loss of fragmented aggrecan and fibrillation of cartilage surface, and thus, plays a protective role in ameliorating cartilage degeneration. -
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Objective Transforming growth factor β (TGFβ) signaling plays a complex tissue‐specific and nonlinear role in osteoarthritis (OA). This study was conducted to determine the osteocytic contributions of TGFβ signaling to OA.
Methods To identify the role of osteocytic TGFβ signaling in joint homeostasis, we used 16‐week‐old male mice (n = 9–11 per group) and female mice (n = 7–11 per group) with an osteocyte‐intrinsic ablation of TGFβ receptor type II (TβRIIocy−/−mice) and assessed defects in cartilage degeneration, subchondral bone plate (SBP) thickness, and SBP sclerostin expression. To further investigate these mechanisms in 16‐week‐old male mice, we perturbed joint homeostasis by subjecting 8‐week‐old mice to medial meniscal/ligamentous injury (MLI), which preferentially disrupts the mechanical environment of the medial joint to induce OA.
Results In all contexts, independent of sex, genotype, or medial or lateral joint compartment, increased SBP thickness and SBP sclerostin expression were spatially associated with cartilage degeneration. Male TβRIIocy−/−mice, but not female TβRIIocy−/−mice, had increased cartilage degeneration, increased SBP thickness, and higher levels of SBP sclerostin compared with control mice (all
P < 0.05), demonstrating that the role of osteocytic TGFβ signaling on joint homeostasis is sexually dimorphic. With changes in joint mechanics following injury, control mice had increased SBP thickness, subchondral bone volume, and SBP sclerostin expression (allP < 0.05). TβRIIocy−/−mice, however, were insensitive to subchondral bone changes with injury, suggesting that mechanosensation at the SBP requires osteocytic TGFβ signaling.Conclusion Our results provide new evidence that osteocytic TGFβ signaling is required for a mechanosensitive response to injury, and that osteocytes control SBP homeostasis to maintain cartilage health, identifying osteocytic TGFβ signaling as a novel therapeutic target for OA.
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Disorders of cartilage homeostasis and chondrocyte apoptosis are major events in the pathogenesis of osteoarthritis (OA). Herein, we sought to assess the chondroprotective effect and underlying mechanisms of a novel chemically modified curcumin, CMC2.24, in modulating extracellular matrix (ECM) homeostasis and inhibiting chondrocyte apoptosis. Rats underwent the anterior cruciate ligament transection and medial menisci resection were treated by intra-articular injection with CMC2.24. In vitro study, rat chondrocytes were pretreated with CMC2.24 before stimulation with sodium nitroprusside (SNP). The effects of CMC2.24 on cartilage homeostasis and chondrocyte apoptosis were observed. The results from in vivo studies demonstrated that the intra-articular administration of CMC2.24 delayed cartilage degeneration and suppressed chondrocyte apoptosis. CMC2.24 ameliorated osteoarthritic cartilage destruction by promoting collagen 2a1 production and inhibited cartilage degradation and apoptosis by suppressing hypoxia-inducible factor-2a (Hif-2α), matrix metalloproteinase-3 (MMP-3), runt-related transcription factor 2 (RUNX2), cleaved caspase-3, vascular endothelial growth factor (VEGF), and the phosphorylation of IκBα and NF-κB p65. The in vitro results revealed that CMC2.24 exhibited a strong inhibitory effect on SNP-induced chondrocyte catabolism and apoptosis. The SNP-enhanced expression of Hif-2α, catabolic and apoptotic factor, decreased after CMC2.24 treatment in a dose-dependent manner. CMC2.24 pretreatment effectively inhibited SNP-induced IκBα and NF-κB p65 phosphorylation in rat chondrocytes, whereas the pretreatment with NF-κB antagonist BMS-345541 significantly enhanced the effects of CMC2.24. Taken together, these results demonstrated that CMC2.24 attenuates OA progression by modulating ECM homeostasis and chondrocyte apoptosis via suppression of the NF-κB/Hif-2α axis, thus providing a new perspective for the therapeutic strategy of OA.more » « less
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Background Healthy articular cartilage presents structural gradients defined by distinct zonal patterns through the thickness, which may be disrupted in the pathogenesis of several disorders. Analysis of textural patterns using quantitative MRI data may identify structural gradients of healthy or degenerating tissue that correlate with early osteoarthritis (OA).
Purpose To quantify spatial gradients and patterns in MRI data, and to probe new candidate biomarkers for early severity of OA.
Study Type Retrospective study.
Subjects Fourteen volunteers receiving total knee replacement surgery (eight males/two females/four unknown, average age ± standard deviation: 68.1 ± 9.6 years) and 10 patients from the OA Initiative (OAI) with radiographic OA onset (two males/eight females, average age ± standard deviation: 57.7 ± 9.4 years; initial Kellgren‐Lawrence [KL] grade: 0; final KL grade: 3 over the 10‐year study).
Field Strength/Sequence 3.0‐T and 14.1‐T, biomechanics‐based displacement‐encoded imaging, fast spin echo, multi‐slice multi‐echo
T2 mapping.Assessment We studied structure and strain in cartilage explants from volunteers receiving total knee replacement, or structure in cartilage of OAI patients with progressive OA. We calculated spatial gradients of quantitative MRI measures (eg, T2) normal to the cartilage surface to enhance zonal variations. We compared gradient values against histologically OA severity, conventional relaxometry, and/or KL grades.
Statistical Tests Multiparametric linear regression for evaluation of the relationship between residuals of the mixed effects models and histologically determined OA severity scoring, with a significance threshold at
α = 0.05.Results Gradients of individual relaxometry and biomechanics measures significantly correlated with OA severity, outperforming conventional relaxometry and strain metrics. In human explants, analysis of spatial gradients provided the strongest relationship to OA severity (
R 2 = 0.627). Spatial gradients of T2 from OAI data identified variations in radiographic (KL Grade 2) OA severity in single subjects, while conventional T2 alone did not.Data Conclusion Spatial gradients of quantitative MRI data may improve the predictive power of noninvasive imaging for early‐stage degeneration.
Evidence Level 1
Technical Efficacy Stage 1
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1039/d0bm00496k
