Developement: Strong bones: got FZD9?

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  • Frizzled 9 (FZD9), which belongs to a family of receptors involved in WNT signalling, has a role in bone forma-tion, according to a recentstudy.

    Defects in canonical WNT signal-ling were known to cause osteoclast-mediated bone loss through the action of -catenin, and WNT antagonists negatively regulate bone formation invivo. To investigate the molecular mechanism of bone for-mation through WNT signalling, the authors examined gene expression during the early differentiation stages of osteoblasts, the cells that make bone. They found that Fzd9 gene expression increased twofold and, furthermore, that Fzd9 mRNA and protein levels also increased.

    This suggested that FZD9 might play a part in bone formation.

    To examine the role of FZD9 fur-ther, the authors analyzed the skeletal development of Fzd9/ mice. These mice showed decreased trabecular bone mass in the spine, as well as decreased bone formation compared with wild-type mice at 24weeksand reduced osteoblast numbers and bone formation rate. This leads to decreased stability of trabecular bones, making them more fragile. As wild-type and Fzd9/ mice had comparable numbers of osteoclasts, the reduced bone mass was due to a cell-autonomous defect in osteoblasts.

    Next, the authors sought to iden-tify the downstream targets of FZD9. Interestingly, they observed that the expression of genes encoding chem-okines and genes regulated by typeI interferons (IFNs) was reduced in Fzd9/ mice. Furthermore, the chem-okine genes and signal transducer and activator of transcription1 (Stat1; a key regulator of typeI IFN signalling) were expressed following osteoblast treatment with WNT5A. As WNT5A induces non-canonical WNT signal-ling, aberrant bone formation could be the result of defects in thispathway.

    One of the typeI IFN-regulated genes that was decreased in Fzd9/ mice, possibly owing to reduced Stat1 expression, was Isg15, which encodes a ubiquitin-related modifier. Similarly to Fzd9, Isg15 expression during the early stages of osteoblast differentia-tion was increased. Moreover, Isg15/ mice showed decreased bone volume and bone formation at 24weeks compared with wild-type mice, similarly to Fzd9/ mice. Importantly, transduction of Fzd9/ osteoblasts with ISG15 partly rescued their bone formation defects, indicating that ISG15 is a downstream effector ofFZD9.

    So, this study shows that non-canonical WNT signalling through FZD9 has a role in bone formation and that this is partially mediated through the typeI IFN-regulated expression of ISG15. Whether the decreased expression of chemokine genes observed upon loss of Fzd9 is relevant to bone formation waits to be determined.


    ORIGINAL RESEARCH PAPER Albers, J. et al. Control of bone formation by the serpentine receptor Frizzled9. J.Cell Biol. 192, 10571072 (2011)

    D E V E LO P M E N T

    Strong bones: got FZD9?

    Vertebra from 52weekold wildtype (left) and Fzd9/ (right) mice stained for mineralized bone (black). Fzd9/ mice show reduced trabecular bone mass compared with wild-type mice. Image courtesy of J.Albers, University Medical Center HamburgEppendorf,Germany.

    non-canonical WNT signalling through FZD9 has a role in bone formation

    R E S E A R C H H I G H L I G H T S


    Nature Reviews Molecular Cell Biology | AOP, published online 7 April 2011; doi:10.1038/nrm3103

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