Genome-wide Expression Profiles of Subchondral Bone in Osteoarthritis
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE51588 | GEO | 2013/10/24
SECONDARY ACCESSION(S): PRJNA223656
REPOSITORIES: GEO
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Project description:To date, all of the prior osteoarthritic microarray studies in human tissue have focused on the overlying articular cartilage, meniscus, or synovium but not the underlying subchondral bone. In our previous study, our group developed a methodology for high quality RNA isolation from site-matched cartilage and bone from human knee joints, which allowed us to perform candidate gene expression analysis on the subchohndral bone (published on Osteoarthritis and Cartilage on Dec/5/2012 (doi: 10.1016/j.joca.2012.11.016). To the best of our knowledge, the current study is the first to successfully perform whole-genome microarray profiling analyses of human osteoarthritic subchondral bone. We believe our comprehensive microarray results can improve the understanding of the pathogenesis of osteoarthritis and could further contribute to the development of new biomarker and therapeutic strategies in osteoarthritis. Following histological assessment of the integrity of overlying cartilage and the severity of bone abnormality by microcomputed tomography, we isolated total RNA from regions of interest from human OA (n=20) and non-OA (n=5) knee lateral and medial tibial plateaus (LT and MT). A whole-genome profiling study was performed on an Agilent microarray platform and analyzed using Agilent GeneSpring GX11.5. Confirmatory quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis was performed on samples from nine OA individuals to confirm differential expression of 85 genes identified by microarray. Ingenuity Pathway Analysis (IPA) was used to investigate canonical pathways and immunohistochemical staining was performed to validate protein expression levels in samples.
2013-10-24 | E-GEOD-51588 | biostudies-arrayexpress
Project description:Osteoarthritis (OA) is the most common joint disease and this is a major cause of joint pain and disability in the aging population. Its etiology is multifactorial (i.e., age, obesity, joint injury, genetic predisposition), and the pathophysiologic process affects the entirety of the joint (Martel-Pelletier J et al. Osteoarthritis. Nature reviews Disease primers. 2016;2:16072). Although it is not yet clear if it precedes or occurs subsequently to cartilage damage, subchondral bone sclerosis is an important feature in OA pathophysiology (Goldring SR et al. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage-bone crosstalk. Nat Rev Rheumatol. 2016;12:632-44). It is characterized by local bone resorption and the accumulation of weakly mineralized osteoid substance (Bailey AJ et al. Phenotypic expression of osteoblast collagen in osteoarthritic bone: production of type I homotrimer. Int J Biochem Cell Biol. 2002;34:176-82). Subchondral bone sclerosis is suspected to be linked to cartilage degradation, not only by modifying the mechanical stresses transmitted to the cartilage, but also by releasing biochemical factors with an activity on cartilage metabolism (Sanchez C et al. Osteoblasts from the sclerotic subchondral bone downregulate aggrecan but upregulate metalloproteinases expression by chondrocytes. This effect is mimicked by interleukin-6, -1beta and oncostatin M pre-treated non-sclerotic osteoblasts. Osteoarthritis Cartilage. 2005;13:979-87; Sanchez C et al. Subchondral bone osteoblasts induce phenotypic changes in human osteoarthritic chondrocytes. Osteoarthritis Cartilage. 2005;13:988-97; Westacott CI et al J. Alteration of cartilage metabolism by cells from osteoarthritic bone. Arthritis Rheum. 1997;40:1282-91. We have previously demonstrated that osteoblasts isolated from subchondral OA bone exhibited an altered phenotype. More precisely, we showed that osteoblasts coming from the thickening (called sclerotic, SC) of subchondral bone located just below a cartilage lesion produced higher levels of alkaline phosphatase, interleukin (IL)-6, IL-8, prostaglandinE2, vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)-9 and transforming growth factor(TGF)-β1 and type I collagen than osteoblasts coming from the non-thickening neighboring area (called non-sclerotic area, NSC) (Sanchez C et al. Phenotypic characterization of osteoblasts from the sclerotic zones of osteoarthritic subchondral bone. Arthritis Rheum. 2008;58:442-55; Sanchez C et al. Regulation of subchondral bone osteoblast metabolism by cyclic compression. Arthritis Rheum. 2012;64:1193-203.) To compare secretome of cells living in different in vivo conditions is useful, not only to better understand the pathological mechanisms underlying changes in OA subchondral bone, but also to identify soluble biomarkers potentially reflecting these changes. Using our well-characterised human subchondral osteoblast culture model, we compared the secretome of osteoblasts coming from sclerotic and non sclerotic OA subchondral bone. This approach allowed to identify changes in secretome that contribute to explain some subchondral bone abnormalities in OA and to propose osteomodulin and fibulin-3 as potential biomarkers of OA subchondral bone remodelling.
2018-03-20 | PXD008494 | Pride
Project description:Osteoarthritis (OA) is a complex degenerative joint disease, which is not only a cartilage but also a bone disease. A better understanding of the early molecular mechanism changes of subchondral bone in vivo may contribute to elucidating the pathogenesis of OA. We used microarray technology to investigate the time-course molecular changes of subchondral bone just beneath damaged cartilage in early stage of experimental osteoarthritis, and found 2,234 differentially expressed (DE) genes at 1 week, 1,944 at 2 weeks and 1,517 at 4 weeks postsurgery.Further analysis of dysregulated genes indicated that subchondral bone remodeling occurred sequentially and in a time-dependent manner at the gene expression level. Some known dysregulated genes suspected roles in influencing bone development or bone remodeling, such as Alp, Igf1, Tgf β1, Postn, Mmp3, Tnfsf11, Acp5, Bmp5, Aspn and Ihh, were confirmed by real-time PCR, and results indicated that our microarray data could accurately reflect gene expression patterns of early OA. Subsequently, to validate the results of our microarray analysis at protein level, immunohistochemistry staining was introduced to investigate the translational level of genes Mmp3 and Aspn in tissue sections, and results showed that the level of Mmp3 protein expression was totally matched the results of microarray and real-time PCR analysis. Nevertheless, the expression of Aspn protein was not observed differentially expressed at any time point.
2012-12-11 | GSE30322 | GEO
Project description:With an increasing number of affected individuals and a trend towards younger age of onset, research on the treatment of knee osteoarthritis (KOA) is facing significant challenges. The pathogenesis of KOA is complex for being a multifactorial disease affecting the entire joint, and pathological remodeling of subchondral bone may be one of the key factors mediating the degeneration of the overlying cartilage. This study constructed a postmenopausal KOA mice model in bipedal mice to better understand how subchondral bone remodeling and cartilage degeneration interact during KOA development. The femoral condyle tissue, excluding the growth plate, was isolated from the distal epiphyseal line in KOA mice for single cell RNA sequencing and analysis. And a single-cell atlas of the osteochondral composite tissue, including chondrocytes, endothelia cells, osteoblasts, progenitor cells, and so on, was successfully constructed. Furthermore, three novel subtypes of chondrocytes, including Smoc2+ angiogenic chondrocytes, Angptl7+ angiogenic chondrocytes, and Col1a1+ osteogenic chondrocytes, were identified. Angptl7+ chondrocytes activated endothelia cells via the Fgf2-Fgfr2 interaction pathway, and promoted angiogenesis and vascular invasion in subchondral bone of KOA mice. The quantity of H-type vessels, which recruit numerous osterix+ osteoprogenitor cells and stimulate osteogenesis, exhibited an increase within the subchondral bone of mice with KOA. While Sparc+ osteoblast negatively regulated the bone mineralization and osteoblastic differentiation, aggravated the pathological remodeling of subchondral bone and KOA progression. These findings suggest that there are new avenues for potential therapeutic interventions in the treatment of KOA.
2025-02-12 | GSE267616 | GEO
Project description:Osteoarthritis (OA) is a complex degenerative joint disease, which is not only a cartilage but also a bone disease. A better understanding of the early molecular mechanism changes of subchondral bone in vivo may contribute to elucidating the pathogenesis of OA. We used microarray technology to investigate the time-course molecular changes of subchondral bone just beneath damaged cartilage in early stage of experimental osteoarthritis, and found 2,234 differentially expressed (DE) genes at 1 week, 1,944 at 2 weeks and 1,517 at 4 weeks postsurgery.Further analysis of dysregulated genes indicated that subchondral bone remodeling occurred sequentially and in a time-dependent manner at the gene expression level. Some known dysregulated genes suspected roles in influencing bone development or bone remodeling, such as Alp, Igf1, Tgf M-NM-21, Postn, Mmp3, Tnfsf11, Acp5, Bmp5, Aspn and Ihh, were confirmed by real-time PCR, and results indicated that our microarray data could accurately reflect gene expression patterns of early OA. Subsequently, to validate the results of our microarray analysis at protein level, immunohistochemistry staining was introduced to investigate the translational level of genes Mmp3 and Aspn in tissue sections, and results showed that the level of Mmp3 protein expression was totally matched the results of microarray and real-time PCR analysis. Nevertheless, the expression of Aspn protein was not observed differentially expressed at any time point. Ninety 10-week-old male Sprague-Dawley rats, weighing 300-325g, were used in the study. Animals were equally divided into two groups: experimental group (E-Group) and sham-operated group (S-Group). The E-Group rats underwent open surgery, involved in both medial meniscectomy and medial collateral ligament (MCL) transaction with micro-scissors. The S-Group rats were carried out with a sham operation, via a similar incision, without operations of the medial meniscus and the medial collateral ligament.Animals were killed at 1, 2, and 4 weeks postsurgery, and 15 animals were put into use per-timepoint in each treatment group. 5 animals were used for histological analysis and immunohistochemistry, and others were used for microarray study and Real-time polymerase chain reaction (PCR) analysis equally at each timepoint.
2012-12-11 | E-GEOD-30322 | biostudies-arrayexpress
Project description:Objective : To study molecular changes in the articular cartilage and subchondral bone of the tibial plateau from mice deficient in frizzled related protein (Frzb) compared to wild-type mice by transcriptome analysis. Methods : Gene-expression analysis of the articular cartilage and subchondral bone of 3 wild-type and 3 Frzb-/- mice was performed by microarray. Pathway analysis of differentially expressed genes between 3 wild-type and 2 Frzb-/- samples was explored with PANTHER, DAVID and GSEA bioinformatics tools. Activation of the WNT pathway was analyzed using western blot. The effects of Frzb gain and loss of function on chondrogenesis and cell proliferation was examined using ATDC5 micromasses and mouse ribcage chondrocytes. Results : Extracellular matrix-associated integrin and cadherin pathways, as well as WNT pathway genes were upregulated in Frzb-/- samples. Several WNT receptors, target genes, and other antagonists were upregulated, but no difference in active β-catenin was found. Analysis of ATDC5 cell micromasses overexpressing FRZB indicated an upregulation of aggrecan and Col2a1, and downregulation of molecules related to damage and repair in cartilage, Col3a1 and Col5a1. Silencing of Frzb resulted in downregulation of aggrecan and Col2a1. Pathways associated with cell cycle were downregulated. Ribcage chondrocytes derived from Frzb-/- mice showed decreased proliferation compared to wild-type cells. Conclusions : Our analysis provides evidence for tight regulation of WNT signaling, shifts in extracellular matrix components and effects on cell proliferation and differentiation in the articular cartilage - subchondral bone unit in Frzb-/- mice. These data further support an important role for FRZB in joint homeostasis and highlight the complex biology of WNT signaling in the joint. Gene-expression analysis of the articular cartilage and subchondral bone of 3 wild-type and 3 Frzb-/- mice was performed by microarray. Pathway analysis of differentially expressed genes between 3 wild-type and 2 Frzb-/- samples was explored with PANTHER, DAVID and GSEA bioinformatics tools.
2012-01-12 | E-GEOD-33656 | biostudies-arrayexpress
Project description:The composition of subchondral bone cell types in patients with osteoarthritis (OA) and the underlying spatiotemporal transformation processes remain unknown. Here, we identified various subchondral bone cell subsets and investigated the mechanism of subchondral bone microstructure alteration using single-cell RNA sequencing (scRNA-seq).
2022-09-20 | GSE196678 | GEO
Project description:Osteoarthritis is a degenerative joint disease that ranks among the leading causes of pain, adult disability, shortening of working life, and socioeconomic costs worldwide. The mechanisms underlying osteoarthritis pathogenesis are yet to be fully elucidated, thus limiting current disease management and treatment. Galectin-1 is an endogenous carbohydrate-binding protein central to adhesion via glycan-bridging, glycoconjugate-mediated signaling, cell proliferation, differentiation, apoptosis, cancers, and host-pathogen interactions. The chondrocyte glycophenotype, which can act as a system of counter-receptors for galectin binding, is compromised in osteoarthritis. We here investigated Galectin-1 and associated gene network's role in human osteoarthritis pathogenesis. Immunohistochemical analysis showed that Galectin-1 associates with osteoarthritic cartilage and subchondral bone histopathology and severity (p<0.0001, n=29 patients). Glycan-dependent Galectin-1 binding to osteoarthritic chondrocytes' cell surface led to marked upregulation of matrix metalloproteinases and activation of NF-κB. Biochemical, molecular and genome-wide analyses showed that Galectin-1 strongly activates a large inflammatory gene network (p<10-16). Bioinformatic analyses of gene promoters up-regulated by Galectin-1 unveiled an overwhelming NF-κB signaling signature. Inhibition of any of several components of the NF-κB pathway using dedicated inhibitors led to dose-dependent impairment of Galectin-1-mediated transcriptional activation. This study identifies for the first time Galectin-1 as an activator of clinically relevant inflammatory-response genes co-regulated by NF-κB. Since inflammation is critical to cartilage degeneration in osteoarthritis, this report is also first to put glycobiology at the center-stage of osteoarthritic cartilage degeneration. Finally, this is the first report to uncover a Galectin-1 gene signature and associated gene network in any biological setting or species. For microarray experiments, osteoarthritic chondrocytes were isolated from five male patients (47-78 years). Following starvation, cells were incubated in the presence of 50 µg/ml recombinant Galectin-1 for 24 h. For each donor population, untreated cells were included as control. In total, 10 samples were analyzed.
2016-03-01 | E-GEOD-68760 | biostudies-arrayexpress
Project description:Introduction: Emerging evidence suggests long non-coding RNA (lncRNA) H19 is associated with osteoarthritis (OA) pathology. However, how H19 contributes to OA has not been reported. This study aims to investigate the biological function of H19 in OA subchondral bone remodeling and OA progression. Methods: Clinical joint samples and OA animal models induced by medial meniscus destabilization (DMM) surgery were used to verify the causal relationship between osteocyte H19 and OA subchondral bone and cartilage changes. MLO-Y4 osteocyte cells subjected to fluid shear stress were used to verify the mechanism underlying H19-mediated mechano-response. Finally, the antisense oligonucleotide (ASO) against H19 was delivered to mice knee joints by magnetic metal-organic framework (MMOF) nanoparticles in order to develop a site-specific delivery method for targeting osteocyte H19 for OA treatment. Results: Both clinical OA subchondral bone and wildtype mice with DMM-induced OA exhibit aberrant higher subchondral bone mass with more H19 expressing osteocytes. On the contrary, osteocyte-specific deletion of H19 mice is less vulnerable to DMM-induced OA phenotype. In MLO-Y4 cells, H19-mediated osteocyte mechano-response through PI3K/AKT/GSK3 signals activation by EZH2-induced H3K27me3 regulation on PP2A inhibition. Targeted inhibition of H19 (using ASO-loaded MMOF) substantially alleviates subchondral bone remodeling and OA phenotype. Discussion: In summary, our results provide new evidence that the elevated H19 expression in osteocytes may contribute to aberrant subchondral bone remodeling and OA progression. H19 appears to be required for the osteocyte response to mechanical stimulation, and targeting H19 represents a new promising approach for OA treatment.
2025-03-05 | GSE254053 | GEO
Project description:Osteoarthritis (OA) is a chronic disease of the joint characterized by a progressive degradation of articular cartilage and subchondral bone. In healthy tissue, specialized cells called chondrocytes are regulating a balanced cartilage catabolism and anabolism. By contrast osteoarthritic joints are characterized by a dramatic increase of cartilage catabolism, due to changes of gene expression patterns within chondrocytes. To identify potential epigenetic differences regulating this process a genome-wide methylation screening of paired unaffected and osteoarthritic knee cartilage samples was performed. Therefore samples of macroscopic arthritic and non-arthritic cartilage areas of the femoral condyle of five female patients were collected and DNA isolation was performed. For being able to investigate methylation changes on a genome-wide scale using only limited amounts of DNA a specific amplification protocol for mainly methylated DNA has been established, based on combinations of different methylation-sensitive and M-bM-^@M-^Sindependent restriction digestions. The amplified DNA was then labeled and hybridized onto Agilent M-bM-^@M-^\Human Promoter Whole GenomeM-bM-^@M-^] microarrays. A random variance t-test for paired (per patient) samples was performed, identifying 1214 differentially methylated genetic targets between arthritic and non-arthritic samples. The biological relevance of these genes was then further investigated via Gene Ontology (GO) and KEGG pathway analysis. DNA isolated of paired arthritic and non-arthritic knee cartilage samples of five different female osteoarthritis patients (10 samples) was methylation-specifically amplified using combinations of methylation-sensitive and -insensitive restriction enzymes. Amplicons were dye labeled (Cy3) and hybridized onto 2x244k Agilent Human Promoter microarrays.
2014-07-01 | E-GEOD-48422 | biostudies-arrayexpress