polymerization, it must then be filled with a material that can support a photonicbandgap. However, many common fillingtechniques (such as chemical vapour deposi-tion of silicon7,8) must be carried out at temperatures that are too high for the polymerized design to survive. Variousgroups are already exploring ways of reinforcing similar polymeric microstruc-tures11, so this problem might soon besolved. If so, after the structure is filled withsilicon (or other similar material), the syn-thetic opal could then be selectively removedto produce a photonic bandgap crystal withan engineered defect. For example, hollowline defects (Fig. 1d) could act as the opticalwires in a future photonic chip.

Although some engineering issues re-main, these results imply that, by adding asimple photopolymerization step, one of themost serious challenges to the application ofself-assembled photonic crystals may soonbe overcome. Lee et al.’s approach could havea technological impact on various applica-tions in photonics, including miniaturizedtelecommunications and Internet devices.But the first effect could be to simplify basicphotonics research: a researcher coulddesign a photonic circuit, make an opal

template by self-assembly, write the circuitusing the multiphoton polymerizationmethod and test the resulting device’s opticalproperties — all in a single day. Like siliconlithography in electronics, defect engineer-ing in photonic crystals suggests a brightfuture for photonics, in which almost every-thing falls naturally into place. ■

T. Andrew Taton is in the Department of Chemistryand David J. Norris is in the Department ofChemical Engineering and Materials Science,University of Minnesota, Minneapolis, Minnesota 55455, USA.e-mails: taton@chem.umn.edudnorris@umn.edu

1. Yablonovitch, E. Phys. Rev. Lett. 58, 2059–2062 (1987).

2. John, S. Phys. Rev. Lett. 58, 2486–2489 (1987).

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386, 143–149 (1997).

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(2002).

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the expression of specific genes, includingthe gene encoding c-Fos5. RANKL is pro-duced by and resides on the surface ofosteoblasts. So, when an osteoclast precur-sor encounters an osteoblast, the resultinginteraction between RANK and RANKLstimulates the osteoclast precursor tomature into a fully differentiated, bone-resorbing osteoclast.

Osteoblasts also produce osteoprotegerin,a soluble ‘decoy’ receptor that binds toRANKL and prevents it from binding toRANK. This effectively inhibits RANKL-mediated osteoclast maturation. Many signals that regulate osteoclast maturation do so indirectly by controlling the productionof RANKL or osteoprotegerin by osteoblasts.The balance between the osteoclast-pro-moting RANKL and osteoclast-inhibitingosteoprotegerin can therefore regulate thenumber and activity of osteoclasts.

It now appears, however, that osteoclastsalso have a say in their own destiny.Takayanagi et al.2 propose a feedback mecha-nism by which osteoclasts control their owndifferentiation and function after beingstimulated by RANKL (Fig. 1). Surprisingly,this signalling pathway involves the osteo-clasts expressing and secreting interferon-b— a protein previously known mainly for its role in cellular responses to viruses. Theproposed pathway is well supported by theauthors’ studies of mice (or cells derivedfrom mice) that had been genetically engineered to lack one or other of the genes encoding various components of thepathway. So even the critical reader shouldbe left in little doubt that this mechanism isat work in vivo.

Specifically, Takayanagi et al. proposethat the activation of RANK by RANKLinduces the expression of interferon-b inosteoclast precursor cells via the transcrip-tion factor c-Fos. Interferon-b is thenreleased from these cells and binds to andactivates its own cell-surface receptor systemon osteoclast precursors, leading to adecrease in c-Fos levels (Fig. 1). Withoutenough c-Fos, osteoclast differentiation isinhibited, bringing this negative-feedbackmechanism full circle.

Several key observations serve as thebasis for this model. First, Takayanagi et al.found that mice lacking the interferon-breceptor have low bone mass and showincreased bone resorption by osteoclasts,implying that the osteoclasts are not beingcontrolled appropriately. Mice that lackinterferon-b have a similar defect. Thesefindings suggest that interferon-b inhibitsthe differentiation or function of osteoclasts.

Next, Takayanagi et al. showed thatRANKL induces the expression of inter-feron-b in cultured osteoclast precursorcells. The authors also provide evidence that c-Fos can directly activate expression of the interferon-b gene. Furthermore, adding

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686 NATURE | VOL 416 | 18 APRIL 2002 | www.nature.com

In adult vertebrates, ten per cent of theskeletal bone mass is replaced every year, amounting to a complete structural

overhaul every decade. This constant re-modelling allows bone to carry out its manyfunctions: to support the body and allowmovement; to incubate developing immunecells; and to act as a reserve of inorganic minerals, especially calcium. Remodellingrepairs bone defects that result from thestress of constant use, and helps to maintainthe optimal levels of calcium in the bloodthat are required for cells to function.

The contractors in this remodelling pro-ject include cells that destroy and resorb oldbone (osteoclasts), and those that depositnew bone in its place (osteoblasts). Theiractivities must be carefully controlled,because a slight imbalance between bonedestruction and formation can have direconsequences, as is seen in osteoporosis. Several molecules have been proposed to co-ordinate the function of osteoclasts with thatof osteoblasts1, but osteoclasts may also keepthemselves under strict control. On page 744of this issue, Takayanagi and colleagues2

show that these cells can do so by drawingupon a molecule — interferon-b — that istraditionally produced by immune cells inresponse to viruses. The authors further suggest that interferon-b might be useful forslowing the excessive bone destruction thatoccurs in some human diseases.

To better understand the details of theseresults2, readers will need to know a littleabout the mechanisms that have alreadybeen found to control osteoclast maturation(differentiation). One of the moleculesrequired is the transcription factor c-Fos,which can bind DNA and drive the ex-pression of genes needed for osteoclasts tofunction3. Accordingly, mice that lack afunctional c-Fos gene develop osteopetrosis— a disease characterized by decreased boneresorption and increased levels of calcifiedbone matrix.

Two cell-surface proteins, RANK and itspartner RANKL (for ‘RANK ligand’), arealso key regulators of osteoclast formationand function4. RANK is present on osteoclastprecursor cells and, when activated, pro-motes osteoclast maturation by increasing

Medicine

Interfering with bone remodellingTamara Alliston and Rik Derynck

As they mature, bone-resorbing cells trigger the production of their own‘off-switch’ — the interferon-b protein — to prevent the runaway bone loss that is seen in diseases such as osteoporosis.

© 2002 Macmillan Magazines Ltd

interferon-b to cultured osteoclast precur-sors prevents the RANKL-induced increasein c-Fos protein levels without affecting other responses to RANKL, and inhibits the RANKL-induced differentiation of thecells into osteoclasts. This inhibition can be overcome by experimentally forcingincreased c-Fos expression. Finally, theauthors reveal that interferon-b reducesosteoclast-mediated bone destruction in amouse model.

Takayanagi et al.’s observations have pro-found implications for our understanding ofbone remodelling. They also reveal a newrole and a new physiological context forinterferon-b, which has not previously beenlinked to osteoclast differentiation6. Andfinally, the authors have uncovered a newmechanism by which the expression of inter-feron-b is activated — c-Fos was not knownto be involved in such activation, and indeedinterferon-b expression in response to viralinfection is induced by other transcription-factor complexes.

In retrospect, we should perhaps not betoo surprised to learn that interferon-b reg-ulates osteoclast differentiation. After all,bone is the site of maturation of certain typesof immune cells, and osteoclasts are derivedfrom the same progenitor cells as someimmune cells. Moreover, RANKL-relatedsignalling pathways are involved in severalimmune responses, and RANKL itself isexpressed by the T cells of the immune sys-tem7. In addition, interferon-g, which is dis-tantly related to interferon-b and signalsthrough a different receptor, also inhibitsRANKL-induced signalling and osteoclastmaturation8, albeit through a differentmechanism (involving degradation of a sig-nalling protein downstream of RANK). As

interferon-g is secreted by T cells but not byosteoclasts, its osteoclast-inhibitory activityis not part of a negative-feedback mecha-nism, but rather illustrates regulatorycrosstalk between the immune system andbone remodelling. These and other studiesreveal the need for more research into theinterplay between immune cells (and theirregulators) and bone.

Finally, the new observations2 suggestthat the targeted use of interferon-b mightbe beneficial for treating diseases such asosteoporosis, rheumatoid arthritis and peri-odontal disease, in which bone resorption isinappropriately high9. Takayanagi et al.’s discovery that interferon-b prevents boneresorption in a mouse model of inflammato-ry arthritis supports this idea. Perhaps muchcould already be learned from a close exami-nation of bone remodelling and metabolismin people, such as those suffering from mul-tiple sclerosis, who are undergoing long-term treatment with interferon-b. Indeed,some such patients have shown improve-ment in their rheumatoid arthritis10. Clearly,Takayanagi et al.’s results will interest scien-tists and physicians alike. ■

Tamara Alliston and Rik Derynck are in theDepartments of Growth and Development, andAnatomy, University of California at San Francisco,San Francisco, California 94143-0640, USA.e-mails: tallist@itsa.ucsf.eduderynck@itsa.ucsf.edu1. Karsenty, G. Genes Dev. 13, 3037–3051 (1999).

2. Takayanagi, H. et al. Nature 416, 744–749 (2002).

3. Grigoriadis, A. E., Wang, Z. Q. & Wagner, E. F. Trends Genet.

11, 436–441 (1995).

4. Suda, T. et al. Endocrinol. Rev. 20, 345–357 (1999).

5. Matsuo, K. et al. Nature Genet. 24, 184–187 (2000).

6. Stark, G. R., Kerr, I. M., Williams, B. R., Silverman, R. H. &

Schreiber, R. D. Annu. Rev. Biochem. 67, 227–264 (1998).

7. Kong, Y. Y., Boyle, W. J. & Penninger, J. M. Immunol. Today

21, 495–502 (2000).

8. Takayanagi, H. et al. Nature 408, 600–605 (2000).

9. Rodan, G. A. & Martin, T. J. Science 289, 1508–1514

(2000).

10.Tak, P. P. et al. Rheumatology 38, 362–369 (1999).

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NATURE | VOL 416 | 18 APRIL 2002 | www.nature.com 687

Figure 1 Balancing bone remodelling. Theactivity of osteoclasts — cells that destroy andresorb bone — is kept in check in several ways.Osteoblasts (cells that make new bone, left)produce the RANKL protein, which activatesRANK on osteoclast precursor cells, stimulatingthese cells to differentiate into mature, bone-resorbing osteoclasts. Activated RANK does thisby inducing the expression of c-Fos, which bindsto DNA and activates expression of several genesneeded for osteoclast function. Takayanagi et al.2

find that c-Fos also activates the expression ofthe interferon-b gene. The interferon-b proteinis then secreted and binds its receptor,presumably on neighbouring osteoclastprecursors, inhibiting osteoclast differentiationby preventing the RANK-induced expression ofc-Fos. ISGF3 and PKR are among the proteinsthat are intermediaries between the interferon-breceptor and c-Fos. Osteoprotegerin is a solubleprotein, released from osteoblasts, that binds toRANKL and prevents it from binding to RANK.

Bone matrix

Bonematrix

Osteoclastprecursors

Mature osteoclast

Osteoblasts

RANK

c-Fos

Osteoclast genes

Osteoclast genes

Interferon-β

RANKL

c-Fos

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PKR & ?

Birds of the cuckoo family show a fasci-nating variety in parental care. Thereare 53 species, called brood parasites,

that lay their eggs in the nests of other birdspecies; the 83 other cuckoo species raisetheir young themselves, although some ofthem may also try to lay eggs in the nests of birds of their own species. The outcome of parasitism is that the offspring of the unfortunate hosts die in one way oranother, cuckoo young being raised instead(Fig. 1, overleaf).

So parasitic cuckoos and their hosts havea conflict of interest, and throughout evolu-tionary history they will have been vying for advantage in a coevolutionary armsrace1,2. For instance, whereas the tendency in parasitic cuckoos will be to make their eggsas much like their hosts’ eggs as possible, so as to fool the prospective step-parents,

many hosts will fight back by recognizing the cuckoo eggs and throwing them out of the nest.

How did this arms race begin? This is aquestion that has been tackled by Krüger andDavies, as they describe in Proceedings of theRoyal Society3. Their starting point is theview that the ancestral cuckoos were non-migratory birds that inhabited tropicalforests and laid big eggs which they cared forthemselves. This view is based on the obser-vation that non-parasitic members of thecuckoo family, and all their close relativesoutside the family, have these characteristics.Krüger and Davies then analysed data on 13 traits related to ecology and life historyfor all 136 cuckoo species, to find out which of these characteristics predated theevolution of parasitism and which evolved as consequences of parasitism. Apart from

Evolutionary biology

The tale of the parasitic cuckoos Arie J. van Noordwijk

These days, investigations of evolutionary events in groups of organismscan be taken well beyond the just-so story. Analysis of how members ofthe cuckoo family became ‘brood parasites’ provides a wonderful example.

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