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Noncanonical frizzled signaling regulates cell polarity of growth plate chondrocytes.

ABSTRACT: Bone growth is driven by cell proliferation and the subsequent hypertrophy of chondrocytes arranged in columns of discoid cells that resemble stacks of coins. However, the molecular mechanisms that direct column formation and the importance of columnar organization to bone morphogenesis are not known. Here, we show in chick that discoid proliferative chondrocytes orient the division plane to generate daughter cells that are initially displaced laterally and then intercalate into the column. Downregulation of frizzled (Fzd) signaling alters the dimensions of long bones and produces cell-autonomous changes in proliferative chondrocyte organization characterized by arbitrary division planes and altered cell stacking. These defects are phenocopied by disruption of noncanonical effector pathways but not by inhibitors of canonical Fzd signaling. These findings demonstrate that the regulation of cell polarity and cell arrangement by noncanonical Fzd signaling plays important roles in generating the unique morphological characteristics that shape individual cartilage elements.

SUBMITTER: Li Y

PROVIDER: S-EPMC2685929 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Noncanonical frizzled signaling regulates cell polarity of growth plate chondrocytes.

Li Yuwei Y Dudley Andrew T AT

Development (Cambridge, England) 20090218 7

Bone growth is driven by cell proliferation and the subsequent hypertrophy of chondrocytes arranged in columns of discoid cells that resemble stacks of coins. However, the molecular mechanisms that direct column formation and the importance of columnar organization to bone morphogenesis are not known. Here, we show in chick that discoid proliferative chondrocytes orient the division plane to generate daughter cells that are initially displaced laterally and then intercalate into the column. Down ...[more]

PMID: 19224985

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Project description:Prostaglandin E2 (PGE2) plays an important role in bone development and metabolism. To interfere therapeutically in the PGE2 pathway, however, knowledge about the involved enzymes (cyclooxygenases) and receptors (PGE2 receptors) is essential. We therefore examined the production of PGE2 in cultured growth plate chondrocytes in vitro and the effects of exogenously added PGE2 on cell proliferation. Furthermore, we analysed the expression and spatial distribution of cyclooxygenase (COX)-1 and COX-2 and PGE2 receptor types EP1, EP2, EP3 and EP4 in the growth plate in situ and in vitro. PGE2 synthesis was determined by mass spectrometry, cell proliferation by DNA [3H]-thymidine incorporation, mRNA expression of cyclooxygenases and EP receptors by RT-PCR on cultured cells and in homogenized growth plates. To determine cellular expression, frozen sections of rat tibial growth plate and primary chondrocyte cultures were stained using immunohistochemistry with polyclonal antibodies directed towards COX-1, COX-2, EP1, EP2, EP3, and EP4. Cultured growth plate chondrocytes transiently secreted PGE2 into the culture medium. Although both enzymes were expressed in chondrocytes in vitro and in vivo, it appears that mainly COX-2 contributed to PGE2-dependent proliferation. Exogenously added PGE2 stimulated DNA synthesis in a dose-dependent fashion and gave a bell-shaped curve with a maximum at 10-8 M. The EP1/EP3 specific agonist sulprostone and the EP1-selective agonist ONO-D1-004 increased DNA synthesis. The effect of PGE2 was suppressed by ONO-8711. The expression of EP1, EP2, EP3, and EP4 receptors in situ and in vitro was observed; EP2 was homogenously expressed in all zones of the growth plate in situ, whereas EP1 expression was inhomogenous, with spared cells in the reserve zone. In cultured cells these four receptors were expressed in a subset of cells only. The most intense staining for the EP1 receptor was found in polygonal cells surrounded by matrix. Expression of receptor protein for EP3 and EP4 was observed also in rat growth plates. In cultured chrondrocytes, however, only weak expression of EP3 and EP4 receptor was detected. We suggest that in growth plate chondrocytes, COX-2 is responsible for PGE2 release, which stimulates cell proliferation via the EP1 receptor.

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Noncanonical frizzled signaling regulates cell polarity of growth plate chondrocytes.

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Noncanonical frizzled signaling regulates cell polarity of growth plate chondrocytes.

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