Dataset Information

Accumulation of exogenous activated TGF-? in the superficial zone of articular cartilage.

ABSTRACT: It was recently demonstrated that mechanical shearing of synovial fluid (SF), induced during joint motion, rapidly activates latent transforming growth factor ? (TGF-?). This discovery raised the possibility of a physiological process consisting of latent TGF-? supply to SF, activation via shearing, and transport of TGF-? into the cartilage matrix. Therefore, the two primary objectives of this investigation were to characterize the secretion rate of latent TGF-? into SF, and the transport of active TGF-? across the articular surface and into the cartilage layer. Experiments on tissue explants demonstrate that high levels of latent TGF-?1 are secreted from both the synovium and all three articular cartilage zones (superficial, middle, and deep), suggesting that these tissues are capable of continuously replenishing latent TGF-? to SF. Furthermore, upon exposure of cartilage to active TGF-?1, the peptide accumulates in the superficial zone (SZ) due to the presence of an overwhelming concentration of nonspecific TGF-? binding sites in the extracellular matrix. Although this response leads to high levels of active TGF-? in the SZ, the active peptide is unable to penetrate deeper into the middle and deep zones of cartilage. These results provide strong evidence for a sequential physiologic mechanism through which SZ chondrocytes gain access to active TGF-?: the synovium and articular cartilage secrete latent TGF-? into the SF and, upon activation, TGF-? transports back into the cartilage layer, binding exclusively to the SZ.

SUBMITTER: Albro MB

PROVIDER: S-EPMC3627867 | biostudies-other | 2013 Apr

REPOSITORIES: biostudies-other

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Accumulation of exogenous activated TGF-β in the superficial zone of articular cartilage.

Albro Michael B MB Nims Robert J RJ Cigan Alexander D AD Yeroushalmi Kevin J KJ Alliston Tamara T Hung Clark T CT Ateshian Gerard A GA

Biophysical journal 20130401 8

It was recently demonstrated that mechanical shearing of synovial fluid (SF), induced during joint motion, rapidly activates latent transforming growth factor β (TGF-β). This discovery raised the possibility of a physiological process consisting of latent TGF-β supply to SF, activation via shearing, and transport of TGF-β into the cartilage matrix. Therefore, the two primary objectives of this investigation were to characterize the secretion rate of latent TGF-β into SF, and the transport of act ...[more]

PMID: 23601326

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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/β-catenin signaling is continuously active in SFZ, indicating that it may be essential for SFZ function. Thus, we examined whether Wnt/β-catenin signaling regulates proliferation and phenotypic expression in SFZ cells. Using transgenic mice, we found that acute activation of Wnt/β-catenin signaling increases SFZ thickness, Proteoglycan 4 (Prg4, also called lubricin) expression and the number of slow-cell cycle cells, whereas conditional ablation of β-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 β-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 β-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/β-catenin signaling is a key regulator of SFZ cell phenotype and proliferation, and may be as important for articular cartilage long-term function.

Dataset Information

Accumulation of exogenous activated TGF-? in the superficial zone of articular cartilage.

Publications

Accumulation of exogenous activated TGF-β in the superficial zone of articular cartilage.

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