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Zone-specific gene expression patterns in articular cartilage.

ABSTRACT: To identify novel genes and pathways specific to the superficial zone (SZ), middle zone (MZ), and deep zone (DZ) of normal articular cartilage.Articular cartilage was obtained from the knees of 4 normal human donors. The cartilage zones were dissected on a microtome. RNA was analyzed on human genome arrays. The zone-specific DNA array data obtained from human tissue were compared to array data obtained from bovine cartilage. Genes differentially expressed between zones were evaluated using direct annotation for structural or functional features, and by enrichment analysis for integrated pathways or functions.The greatest differences in genome-wide RNA expression data were between the SZ and DZ in both human and bovine cartilage. The MZ, being a transitional zone between the SZ and DZ, thereby shared some of the same pathways as well as structural/functional features of the adjacent zones. Cellular functions and biologic processes that were enriched in the SZ relative to the DZ included, most prominently, extracellular matrix-receptor interactions, cell adhesion molecule functions, regulation of actin cytoskeleton, ribosome-related functions, and signaling aspects such as the IFN, IL4, Cdc42/Rac, and JAK/STAT signaling pathways. Two pathways were enriched in the DZ relative to the SZ, including PPARG and EGFR/SMRTE.These differences in cartilage zonal gene expression identify new markers and pathways that govern the unique differentiation status of chondrocyte subpopulations.

SUBMITTER: Grogan SP

PROVIDER: S-EPMC3558601 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Zone-specific gene expression patterns in articular cartilage.

Grogan Shawn P SP Duffy Stuart F SF Pauli Chantal C Koziol James A JA Su Andrew I AI D'Lima Darryl D DD Lotz Martin K MK

Arthritis and rheumatism 20130201 2

<h4>Objective</h4>To identify novel genes and pathways specific to the superficial zone (SZ), middle zone (MZ), and deep zone (DZ) of normal articular cartilage.<h4>Methods</h4>Articular cartilage was obtained from the knees of 4 normal human donors. The cartilage zones were dissected on a microtome. RNA was analyzed on human genome arrays. The zone-specific DNA array data obtained from human tissue were compared to array data obtained from bovine cartilage. Genes differentially expressed betwee ...[more]

PMID: 23124445

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Project description:The superficial zone (SFZ) of articular cartilage has unique structural and biomechanical features, is thought to promote self-renewal of articular cartilage, and is thus important for joint long-term function, but the mechanisms regulating its properties remain unclear. Previous studies revealed that Wnt/?-catenin signaling is continuously active in SFZ, indicating that it may be essential for SFZ function. Thus, we examined whether Wnt/?-catenin signaling regulates proliferation and phenotypic expression in SFZ cells. Using transgenic mice, we found that acute activation of Wnt/?-catenin signaling increases SFZ thickness, Proteoglycan 4 (Prg4, also called lubricin) expression and the number of slow-cell cycle cells, whereas conditional ablation of ?-catenin causes the opposite. We developed a novel method to isolate SFZ cell-rich populations from the epiphyseal articular cartilage of neonatal mice, and found that the SFZ cells in culture exhibit a fibroblastic cytoarchitecture and higher Prg4 and Ets-related gene (Erg) expression and lower aggrecan expression compared with chondrocyte cultures. Gene array analyses indicated that SFZ cells have distinct gene expression profiles compared with underlying articular chondrocytes. Treatment of Wnt3a strongly stimulated SFZ cell proliferation and maintained strong expression of Prg4 and Erg, whereas ablation of ?-catenin strongly impaired proliferation and phenotypic expression. When the cells were transplanted into athymic mice, they formed Prg4- and aggrecan-expressing cartilaginous masses attesting to their autonomous phenotypic capacity. Ablation of ?-catenin caused a rapid loss of Prg4 gene expression and strong increases in expression of aggrecan and collagen 10, the latter being a trait of hypertrophic chondrocytes. Together, the data reveal that Wnt/?-catenin signaling is a key regulator of SFZ cell phenotype and proliferation, and may be as important for articular cartilage long-term function.

Project description:BackgroundArticular cartilage undergoes an important maturation process from neonate to adult that is reflected by alterations in matrix protein organization and increased heterogeneity of chondrocyte morphology. In the horse, these changes are influenced by exercise during the first five months of postnatal life. Transcriptional profiling was used to evaluate changes in articular chondrocyte gene expression during postnatal growth and development.MethodsTotal RNA was isolated from the articular cartilage of neonatal (0-10 days) and adult (4-5 years) horses, subjected to one round of linear RNA amplification, and then applied to a 9,367-element equine-specific cDNA microarray. Comparisons were made with a dye-swap experimental design. Microarray results for selected genes (COL2A1, COMP, P4HA1, TGFB1, TGFBR3, TNC) were validated by quantitative polymerase chain reaction (qPCR).ResultsFifty-six probe sets, which represent 45 gene products, were up-regulated (p < 0.01) in chondrocytes of neonatal articular cartilage relative to chondrocytes of adult articular cartilage. Conversely, 586 probe sets, which represent 499 gene products, were up-regulated (p < 0.01) in chondrocytes of adult articular cartilage relative to chondrocytes of neonatal articular cartilage. Collagens, matrix-modifying enzymes, and provisional matrix non-collagenous proteins were expressed at higher levels in the articular cartilage of newborn foals. Those genes with increased mRNA abundance in adult chondrocytes included leucine-rich small proteoglycans, matrix assembly, and cartilage maintenance proteins.ConclusionDifferential expression of genes encoding matrix proteins and matrix-modifying enzymes between neonates and adults reflect a cellular maturation process in articular chondrocytes. Up-regulated transcripts in neonatal cartilage are consistent with growth and expansion of the articular surface. Expression patterns in mature articular cartilage indicate a transition from growth to homeostasis, and tissue function related to withstanding shear and weight-bearing stresses.

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Zone-specific gene expression patterns in articular cartilage.

Publications

Zone-specific gene expression patterns in articular cartilage.

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