Increased nerve growth factor expression and osteoclast density are associated with subchondral bone marrow lesions in osteoarthritic knees
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PROVIDER: S-EPMC11340585 | biostudies-literature | 2024 Jul
REPOSITORIES: biostudies-literature
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Project description:Osteoarthritis (OA) is the most common joint disease, where articular cartilage degradation is often accompanied with sclerosis of the subchondral bone. However, the association between OA and tissue mineralization at the nanostructural level is currently not understood. In particular, it is technically challenging to study calcified cartilage, where relevant but poorly understood pathological processes such as tidemark multiplication and advancement occur. Here, we used state-of-the-art microfocus small-angle X-ray scattering with a 5-μm spatial resolution to determine the size and organization of the mineral crystals at the nanostructural level in human subchondral bone and calcified cartilage. Specimens with a wide spectrum of OA severities were acquired from both medial and lateral compartments of medial compartment knee OA patients (n = 15) and cadaver knees (n = 10). Opposing the common notion, we found that calcified cartilage has thicker and more mutually aligned mineral crystals than adjoining bone. In addition, we, for the first time, identified a well-defined layer of calcified cartilage associated with pathological tidemark multiplication, containing 0.32 nm thicker crystals compared to the rest of calcified cartilage. Finally, we found 0.2 nm thicker mineral crystals in both tissues of the lateral compartment in OA compared with healthy knees, indicating a loading-related disease process because the lateral compartment is typically less loaded in medial compartment knee OA. In summary, we report novel changes in mineral crystal thickness during OA. Our data suggest that unloading in the knee might be involved with the growth of mineral crystals, which is especially evident in the calcified cartilage. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
| S-EPMC9540032 | biostudies-literature
Project description:Increase of subchondral bone area (tAB) in OA has been reported, but it remains unclear if this is specific to OA. We investigated differences in knee tAB after one year in healthy subjects and in those with radiographic OA (rOA).MR images of 899 right knees from the OA Initiative were acquired at baseline and one year follow-up (year-1). Medial and lateral tibial cartilage (MT and LT) and weight-bearing femoral cartilage (cMF and cLF) were segmented and tAB computed. Subjects were stratified into: healthy controls, pre-rOA (K&L grades 0 and 1, with OA risk factors), established rOA (K&L grades 2-4), and independently with regards to joint space narrowing (without, with medial, lateral and bilateral JSN). Primary analysis tested if tAB was different between baseline and year-1 in rOA. Exploratory analyses investigated whether: (1) tAB changes differed between healthy controls and those with rOA; (2) tAB differences were greater in higher K&L grades; and (3) tAB was different between baseline and year-1 in JSN. Significance was set at P < 0.0125.Differences in tAB were found in rOA in MT, cMF and cLF (ranging from +0.2% to +0.4%; P < 0.001), but not in healthy controls or pre-rOA. Rates of change did not differ between groups. Within the JSN groups differences of 0.2-0.4% were found in the femur (P < 0.05).We find that knee tABs differ in rOA between baseline and year-1, but the change was not greater than in healthy knees, and is restricted to the femur in JSN.
| S-EPMC5572564 | biostudies-other
Project description:To evaluate the interaction of articular cartilage (AC) and subchondral bone (SB) through analysis of osteoarthritis (OA)-related genes of site-matched tissue.We developed a novel method for isolating site-matched overlying AC and underlying SB from three and four regions of interest respectively from the human knee tibial plateau (n = 50). For each site, the severity of cartilage changes of OA were assessed histologically, and the severity of bone abnormalities were assessed by microcomputed tomography. An RNA isolation procedure was optimized that yielded high quality RNA from site-matched AC and SB tibial regions. Quantitative polymerase chain reaction (Q-PCR) analysis was performed to evaluate gene expression of 61 OA-associated genes for correlation with cartilage integrity and bone structure parameters.A total of 27 (44%) genes were coordinately up- or down-regulated in both tissues. The expression levels of 19 genes were statistically significantly correlated with the severity of AC degeneration and changes of SB structure; these included: ADAMTS1, ASPN, BMP6, BMPER, CCL2, CCL8, COL5A1, COL6A3, COL7A1, COL16A1, FRZB, GDF10, MMP3, OGN, OMD, POSTN, PTGES, TNFSF11 and WNT1.These results provide a strategy for identifying targets whose modification may have the potential to ameliorate pathological alterations and progression of disease in both AC and SB simultaneously. In addition, this is the first study, to our knowledge, to overcome the major difficulties related to isolation of high quality RNA from site-matched joint tissues. We expect this method to facilitate advances in our understanding of the coordinated molecular responses of the whole joint organ.
| S-EPMC3593157 | biostudies-literature
Project description:BackgroundBone marrow lesions (BMLs), common osteoarthritis-related magnetic resonance imaging findings, are associated with osteoarthritis progression and pain. However, there are no articles describing the use of 3-dimensional quantitative assessments to explore the longitudinal relationship between BMLs and hyaline cartilage loss. The purpose of this study was to assess the cross-sectional and longitudinal descriptive characteristics of BMLs with a simple measurement of approximate BML volume, and describe the cross-sectional and longitudinal relationships between BML size and the extent of hyaline cartilage damage.Methods107 participants with baseline and 24-month follow-up magnetic resonance images from a clinical trial were included with symptomatic knee osteoarthritis. An 'index' compartment was identified for each knee defined as the tibiofemoral compartment with greater disease severity. Subsequently, each knee was evaluated in four regions: index femur, index tibia, non-index femur, and non-index tibia. Approximate BML volume, the product of three linear measurements, was calculated for each BML within a region. Cartilage parameters in the index tibia and femur were measured based on manual segmentation.ResultsBML volume changes by region were: index femur (median [95% confidence interval of the median]) 0.1 cm3 (-0.5 to 0.9 cm3), index tibia 0.5 cm3 (-0.3 to 1.7 cm3), non-index femur 0.4 cm3 (-0.2 to 1.6 cm3), and non-index tibia 0.2 cm3 (-0.1 to 1.2 cm3). Among 44 knees with full thickness cartilage loss, baseline tibia BML volume correlated with baseline tibia full thickness cartilage lesion area (r = 0.63, p< 0.002) and baseline femur BML volume with longitudinal change in femoral full thickness cartilage lesion area (r = 0.48 p< 0.002).ConclusionsMany regions had no or small longitudinal changes in approximate BML volume but some knees experienced large changes. Baseline BML size was associated to longitudinal changes in area of full thickness cartilage loss.
| S-EPMC3190349 | biostudies-literature
Project description:Altered subchondral bone and articular cartilage interactions have been implicated in the pathogenesis of osteoarthritis (OA); however, the mechanisms remain unknown. Exosomes are membrane-derived vesicles that have recently been recognized as important mediators of intercellular communication. Herein, we investigated if OA subchondral bone derived exosomes alter transcriptional and bioenergetic signatures of chondrocytes. Exosomes were isolated and purified from osteoblasts of nonsclerotic or sclerotic zones of human OA subchondral bone and their role on the articular cartilage chondrocytes was evaluated by measuring the extent of extracellular matrix production, cellular bioenergetics, and the expression of chondrocyte activity associated marker genes. Exosomal microRNAs were analyzed using RNA sequencing and validated by quantitative real-time PCR and loss-of-function. In coculture studies, chondrocytes internalized OA sclerotic subchondral bone osteoblast derived exosomes and triggered catabolic gene expression and reduced chondrocyte-specific marker expression a phenomenon that is often observed in OA cartilage. RNA sequencing and miRNA profiling have identified miR-210-5p, which is highly enriched in OA sclerotic subchondral bone osteoblast exosomes, triggered the catabolic gene expression in articular cartilage chondrocytes. Importantly, we demonstrate that miR-210-5p suppresses the oxygen consumption rate of chondrocytes, altering their bioenergetic state that is often observed in OA conditions. These effects were markedly inhibited by the addition of a miR-210-5p inhibitor. Our study indicates that exosomes released by OA sclerotic subchondral bone osteoblasts plays a critical role in progression of cartilage degeneration and might be a potential target for therapeutic intervention in OA.
| S-EPMC7911822 | biostudies-literature
Project description:IntroductionBone marrow lesions (BMLs) are frequently identified by MRI in the subchondral bone in knee osteoarthritis (KOA). BMLs are known to be closely associated with joint pain, loss of the cartilage and structural changes in the subchondral trabecular bone (SCTB). Despite this, understanding of the nature of BMLs at the trabecular tissue level is incomplete. Thus, we used Raman microspectroscopy to examine the biochemical properties of SCTB from KOA patients with presence or absence of BMLs (OA-BML, OA No-BML; respectively), in comparison with age-matched cadaveric non-symptomatic controls (Non-OA CTL).MethodsTibial plateau (TP) specimens were collected from 19 KOA arthroplasty patients (6-Male, 13-Female; aged 56-74 years). BMLs were identified ex-vivo by MRI, using PDFS- and T1-weighted sequences. The KOA specimens were then categorized into an OA-BML group (n = 12; containing a BML within the medial condyle only) and an OA No-BML group (n = 7; with no BMLs identified in the TP). The control (CTL) group consisted of Non-OA cadaveric TP samples with no BMLs and no macroscopic or microscopic evidence of OA-related changes (n = 8; 5-Male, 3-Female; aged 44-80 years). Confocal Raman microspectroscopy, with high spatial resolution, was used to quantify the biochemical properties of SCTB tissue of both the medial and the lateral condyle in each group.ResultsThe ratios of peak intensity and integrated area of bone matrix mineral (Phosphate (v1), Phosphate (v2) and Phosphate (v4)), to surrogates of the organic phase of bone matrix (Amide I, Proline and Amide III), were calculated. Within the medial compartment, the mineral:organic matrix ratios were significantly lower for OA-BML, compared to Non-OA CTL. These ratios were also significantly lower for the OA-BML medial compartment, compared to the OA-BML lateral compartment. There were no group or compartmental differences for Carbonate:Phosphate (v1, v2 and v4), Amide III (α-helix):Amide III (random-coil), Hydroxyproline:Proline, or Crystallinity.ConclusionAs measured by Raman microspectroscopy, SCTB tissue in BML zones in KOA is significantly less mineralized than the corresponding zones in individuals without OA. These data are consistent with those obtained using other methods (e.g. Fourier transform infrared spectroscopy; FTIR) and with the increased rate of bone remodeling observed in BML zones. Reduced mineralization may change the biomechanical properties of the trabecular bone in BMLs and the mechanical interaction between subchondral bone and its overlying cartilage, with potential implications for the development and progression of OA.
| S-EPMC7210419 | biostudies-literature
Project description:"Bone marrow lesion" (BML) is a common term used to describe the presence of fluid in the bone marrow. Although various pathologies can cause BMLs seen on magnetic resonance imaging, in this Technical Note we focus on treating the lesions associated with osteoarthritis in the knee joint. The role of the subchondral bone in transferring loads within the knee joint, as well as in cartilage homeostasis, is well established. In addition, cartilage and subchondral bone are increasingly considered as an osteochondral unit, rather than as 2 separate structures. Knee osteoarthritis, along with insufficiency fracture, is one of the main indications for the treatment of painful BMLs. Nowadays, there is a growing interest in this field, and new approaches are being developed. Our technique can be defined as a surgical procedure aimed directly at pathology within the subchondral bone and is named "osteo-core plasty." It consists of 2 parts: The first is decompression of bone marrow to decrease intraosseous pressure, and the second is administration of bone marrow aspirate concentrate for better healing potential and bone autograft to deliver supportive tissue. It should be noted that the cause of BMLs must be known before this kind of treatment is performed.
| S-EPMC7695615 | biostudies-literature
Project description:Bone marrow (BM) and peripheral blood (PB) derived mononuclear cells are precursors of in vitro osteoclast differentiation. However, few studies have compared the phenotypic and functional properties of osteoclasts generated from these sources and the effects of different growth factors on osteoclastogenesis. Both cell types differentiated into functional osteoclasts, but culturing the cells with or without transforming growth factor beta (TGF-β) and dexamethasone revealed differences in their osteoclastogenic capacity. When receptor activator for nuclear factor κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) were used for differentiation, we did not observe differences in bone resorption activity or expression of osteoclastogenic genes calcitonin receptor (CR) and nuclear factor of activated T-cells (NFATc1) between the osteoclasts formed from the two sources. Addition of TGF-β and dexamethasone led to higher number of nuclei in multinuclear cells and increased expression of tartrate resistant acid phosphatase (TRACP) 5a and 5b, CR and NFATc1 in PB- derived osteoclasts depicting the higher osteoclastogenic potential and responsiveness to TGF-β and dexamethasone in PB monocytes. These results conclude that the choice of the osteoclast precursor source as well as the choice of osteoclastogenic growth factors are essential matters in determining the phenotypic characteristics of heterogeneous osteoclast populations.
| S-EPMC6138956 | biostudies-literature
Project description:Bone marrow lesions (BMLs) are localized areas of edema within subchondral bone, which are often due to early chondromalacia changes, subchondral insufficiency stress or microfractures, and/or avascular necrosis. The presence of BMLs worsen outcomes after arthroscopy and arthroplasty, thus making their management important in the preservation of hip function. In recent years, the advent of Subchondroplasty (SCP; Zimmer Knee Creations Incorporated, Exton, PA)-a minimally invasive surgical technique that involves injecting an isothermic calcium phosphate solution to stabilize BMLs-has shown promising results in managing pain from osteoarthritis (OA). The SCP material (AccuFill Bone Substitute Material, Zimmer Knee Creations Incorporated) has a similar physical and chemical structure to native bone mineral. In this Technical Note, we discuss a surgical approach for managing acetabular and femoral head BMLs with SCP. We also review the prior clinical trials reporting on SCP for knee OA. SCP may be a promising technique as part of the treatment algorithm for managing hip OA, and clinical trial enrollment has begun for hip SCP. On the basis of these results, further investigations into this procedure may be warranted.
| S-EPMC7372286 | biostudies-literature
Project description:ObjectiveThis study aims to demonstrate the cellular composition and underlying mechanisms in subchondral bone marrow lesions (BMLs) of knee osteoarthritis (OA).MethodsBMLs were assessed by MRI Osteoarthritis Knee Score (MOAKS)≥2. Bulk RNA-sequencing (bulk-seq) and BML-specific differentially expressed genes (DEGs) analysis were performed among subchondral bone samples (including OA-BML=3, paired OA-NBML=3; non-OA=3). The hub genes of BMLs were identified by verifying in independent datasets and multiple bioinformatic analyses. To further estimate cell-type composition of subchondral bone, we utilized two newly developed deconvolution algorithms (MuSiC, MCP-counter) in transcriptomic datasets, based on signatures from open-accessed single-cell RNA sequencing (scRNA-seq). Finally, competing endogenous RNA (ceRNA) and transcription factor (TF) networks were constructed through multiple predictive databases, and validated by public non-coding RNA profiles.ResultsA total of 86 BML-specific DEGs (up 79, down 7) were identified. IL11 and VCAN were identified as core hub genes. The "has-miR-424-5p/lncRNA PVT1" was determined as crucial network, targeting IL11 and VCAN, respectively. More importantly, two deconvolution algorithms produced approximate estimations of cell-type composition, and the cluster of heterotopic-chondrocyte was discovered abundant in BMLs, and positively correlated with the expression of hub genes.ConclusionIL11 and VCAN were identified as the core hub genes of BMLs, and their molecular networks were determined as well. We profiled the characteristics of subchondral bone at single-cell level and determined that the heterotopic-chondrocyte was abundant in BMLs and was closely linked to IL11 and VCAN. Our study may provide new insights into the microenvironment and pathological molecular mechanism of BMLs, and could lead to novel therapeutic strategies.
| S-EPMC10463447 | biostudies-literature