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Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage

ABSTRACT: Steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and the intestine. They function as xenobiotic sensors by inducing genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our findings indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging.

ORGANISM(S): Mus musculus

PROVIDER: GSE60401 | GEO | 2015/03/31

SECONDARY ACCESSION(S): PRJNA258189

REPOSITORIES: GEO

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Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage

Project description:Steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and the intestine. They function as xenobiotic sensors by inducing genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our findings indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging. ADC5 cells were infected with adeno-SXR or adeno-DsRed and cultured in phenol red-free DMEM with charcoal/dextran-treated FCS (5%) containing rifampicin (10 μM), vitamin K2 (10 μM), or ethanol. Total RNA was extracted from the cells using the ToTALLY RNA Kit (Ambion, Austin, TX). Profiling of mRNA was performed on Affymetrix Mouse Gene 1.0 ST arrays (Affymetrix Inc., Santa Clara, USA) according to the Gene Chip labeling assay manual version 4.

2015-03-31 | E-GEOD-60401 | biostudies-arrayexpress

Microarray analysis of human articular chondrocytes stimulated with Wnt3a in presence/absence of the CaMKII inhibitor KN93

Project description:The scope of the analysis was to discriminate between CaMKII-dependent and independent targets of Wnt3a stimulation in human articular chondrocytes. Chondrocytes were isolated from preserved areas of the articular cartilage removed from 4 patients affected by osteoarthritis. The samples were stimulated with KN92 (inactive analogue of the CaMKII inhibitor KN93), KN92+Wnt3a and KN93+Wnt3a.

2021-01-01 | GSE162076 | GEO

Contributions of chondrocyte senescence and menopause to the increased incidence of osteoarthritis in older women

Project description:Osteoarthritis (OA) is a degenerative joint disease and a leading cause of disability worldwide. Aging is one of the major risk factors for OA, with the disease prevalence dramatically increasing after age 50. While OA is strongly associated with aging, the specific mechanisms underlying this connection remain unclear. In this pilot study, we performed bulk RNA sequencing on human knee articular chondrocytes to identify transcriptomic changes underlying OA development in the context of aging. We compared the gene expression profiles of chondrocytes isolated from osteoarthritic cartilage of older individuals (age 70-80 years) to those of chondrocytes from the healthy cartilage of a young adult (age 26 years). To model aging in vitro, chondrocytes were serially passaged until they reached the replicative senescence.

2023-11-06 | GSE246425 | GEO

Identification of Sik3-targeting compound, pterosin B, for treatment of osteoarthritis

Project description:Osteoarthritis is a common joint disorder that causes debilitating conditions among the elderly. Risk factors of osteoarthritis include age, which is often associated with the thinning of articular cartilage. We generated conditional knockout mice that lack salt-inducible kinase 3 (Sik3) specifically in chondrocytes after birth by tamoxifen administration. Deletion of Sik3 at 2 or 8 weeks after birth increased the thickness of articular cartilage by increasing the chondrocyte population. Additionally, Sik3 deletion protected cartilage against osteoarthritis development. We identified the edible Pteridium aquilinum ingredient, pterosin B, as a compound that inhibits the Sik3 pathway. Intraarticular injection of pterosin B protected cartilage against osteoarthritis development. Sik3 deletion or pterosin B treatment inhibited activation of the hypertrophic program through the histone deacetylase 4 (Hdac4) pathway, increased Prg4 expression in chondrocytes, and protected cartilage against osteoarthritic attack. Collectively, our results suggest Sik3 is a regulator that regulates homeostasis of articular cartilage thickness and a target for treatment of osteoarthritis, and that pterosin B can be the lead compound for relevant drugs.

2016-03-21 | GSE75995 | GEO

Comparison between articular chondrocytes and mesenchymal stromal cells for the production of articular chondrocyte implants

Project description:Focal lesions of articular cartilage give rise to pain and reduced joint function and may, if left untreated, lead to osteoarthritis. Implantation of in vitro generated, scaffold-free autologous cartilage discs may represent the best treatment option. Here we compare articular chondrocytes (ACs) and bone marrow-derived mesenchymal stromal cells (MSCs) for their ability to make scaffold-free cartilage discs.

2023-02-07 | PXD029434 | Pride

Synovial Cell Cross-talk with Cartilage Plays a Major Role in the Pathogenesis of Osteoarthritis

Project description:We elucidated the molecular cross-talk between knee articular cartilage and paired synovium in n=3 individuals with knee osteoarthritis using the powerful tool of single-cell RNA-sequencing. Multiple cell types were identified based on profiling of 10,640 synoviocytes and 26,192 chondrocytes (11,579 chondrocytes from the diseased medial vs 14,613 chondrocytes from the relatively non-diseased lateral tibial plateau): 12 distinct synovial cell types and 7 distinct articular chondrocyte phenotypes from matched tissues. Intact cartilage was enriched for homeostatic and hypertrophic chondrocytes, while damaged cartilage was enriched for prefibro- and fibro-, regulatory, reparative and prehypertrophic chondrocytes. A total of 61 cytokines and growth factors were predicted to regulate the 7 chondrocyte cell phenotypes. Based on production by >1% of cells, 55% of the cytokines were produced by synovial cells (39% exclusive to synoviocytes and not expressed by chondrocytes) and their presence in osteoarthritic synovial fluid confirmed. The synoviocytes producing IL-1beta (a classic pathogenic cytokine in osteoarthritis), mainly inflammatory macrophages and dendritic cells, were characterized by co-expression of surface proteins corresponding to HLA-DQA1, HLA-DQA2, OLR1 or TLR2. Strategies to deplete these pathogenic intra-articular cell subpopulations could be a therapeutic option for human osteoarthritis.

2020-07-06 | GSE152805 | GEO

Articular cartilage proteome differentiates by zones during osteoarthritis

Project description:Articular cartilage is deprived of blood vessels and nerves, and the only cells residing in this tissue are chondrocytes. The molecular properties of the articular cartilage and the architecture of the extracellular matrix demonstrate a complex structure that differentiates on the depth of tissue. Osteoarthritis (OA) is a degenerative joint disease, the most common form of arthritis, affecting the whole joint. It is associated with ageing and affects the joints that have been continually stressed throughout life including the knees, hips, fingers, and lower spine region. OA is a multifactorial condition of joint characterised by articular cartilage loss, subchondral bone sclerosis, and inflammation leading to progressive joint degradation, structural alterations, loss of mobility and pain. Articular cartilage biology is well studied with a focus on musculoskeletal diseases and cartilage development. However, there are relatively few studies focusing on zonal changes in the cartilage during osteoarthritis.

2022-05-19 | PXD029116 | Pride

Mus musculus

Project description:Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage

| PRJNA258189 | ENA

Periostin induces early articular cartilage degeneration in developmental dysplasia of the hip

Project description:Developmental dysplasia of the hip (DDH) is one of the significant risk factors for hip osteoarthritis. In order to investigate the factors that induce early articular cartilage degeneration of the hip joints that are exposed to reduced dynamic loads arising from hip dislocation , we created rodent models of hip dislocation by swaddling. Notably, expression of periostin (Postn) was increased in the acetabular articular cartilage of the DDH models; Postn was a candidate gene associated with early articular cartilage degeneration. We showed that early articular cartilage degeneration was suppressed in Postn-/- DDH mice. Furthermore, a microgravity environment induced the expression of Postn in chondrocytes through STAT3 signaling. Postn induced catabolic factors, interleukin-6 and matrix metalloproteinase 3, in articular chondrocytes through integrin-nuclear factor κB signaling. Additionally, interleukin-6 stimulated Postn expression through STAT3 signaling. Thus, Postn plays a critical role in early articular cartilage degeneration associated with hip dislocation.

2022-07-20 | GSE173637 | GEO

Identification of chondrocyte subsets during human development

Project description:Joint injury and osteoarthritis affect millions of people worldwide, but attempts to generate articular cartilage using adult stem/progenitor cells have been unsuccessful. We hypothesized that recapitulation of the human developmental chondrogenic program using pluripotent stem cells (PSCs) may represent a superior approach for cartilage restoration. Using laser capture microdissection followed by microarray analysis, we first defined a surface phenotype (CD146low/negCD166low/negCD73+CD44lowBMPR1B+) distinguishing the earliest cartilage committed cells (pre-chondrocytes) at 5-6 weeks of development; pellet assays confirmed these cells as functional, chondrocyte-restricted progenitors. Flow cytometry, qPCR and immunohistochemistry at 17 weeks revealed that the superficial layer of peri-articular chondrocytes was enriched in cells with this surface phenotype. Isolation of cells with a similar immunophenotype from differentiating human PSCs revealed a population of CD166negBMPR1B+ putative pre-chondrocytes. Functional characterization confirmed these cells as cartilage-committed, chondrocyte progenitors. The identification of a specific molecular signature for primary cartilagecommitted progenitors may provide essential knowledge for the generation of purified, clinically relevant cartilage cells from PSCs. A total of 15 samples were analyzed. In the first comparison, there were 6 biological replicates for both the chondrogenic condensations and total limb cells. In the second comparison, three biological replicates of chondrocytes from the articular region were compared to the 6 replicates of the condensations.

2013-12-16 | E-GEOD-51812 | biostudies-arrayexpress

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