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nature genetics • volume 23 • december 1999 379

Changes in commensal oral flora and faunaand a breach in the junctional epitheliumcan lead to periodontitis (deep pockets oflocalized infection adjacent to teeth), thechronic destruction of the periodontal liga-ments and alveolar bone supporting eachtooth, and eventual exfoliation of teeth.

The perils of periodontitisAlthough periodontitis has long beenconsidered a localized infection, it is nowclear that periodontal diseases are linkedto conditions with systemic implicationsand affect more than 30% of the popula-tion. Oral microbial infections are associ-ated with cerebrovascular disease;pregnant women with periodontitis areat greater risk of delivering pretermbabies; and people with periodontitis aremore likely to develop heart disease (forreview, see ref. 2). The impact of thischronic battle against oral microbesincreases with age (see figure; refs 3,4),leading to loss of teeth, compromisednutrition, psychosocial effect and chal-lenges to general health.

Susceptibility to periodontal disease andthe severity of the disease results from theinteractions of genetic mutations and poly-morphisms with numerous environmentalagents. Diseases associated with early-onset(before puberty) periodontitis includePapillon-Lefèvre syndrome (PLS; ref. 5),leukocyte adhesion deficiency, Down syn-drome, leukaemia and early-onset type Idiabetes, among others6. In elucidating thegenetic aetiology of PLS, Toomes et al. pro-vide insight into how periodontal diseasemay arise. The syndrome is a rare autoso-mal recessive disorder characterized bysevere, early-onset periodontitis and pal-moplantar hyperkeratosis (thickening andscaling of the skin of the palms and soles).People with PLS lose their primary teeth bythe age of four years; by age fourteen, mostlose all permanent teeth7.

By analysing samples from eight con-sanguineous families with PLS, Toomes etal. identified loss-of-function mutationsin the gene (CTSC) encoding the papain-like, lysosomal cysteine protease cathepsinC (also known as dipeptidyl peptidase I),which is expressed in a wide range of celltypes. The enzyme processes and activatesa number of granule serine proteases criti-cal to immune and inflammatoryresponses of myeloid and lymphoid cells8.Assays of cathepsin C activity in familymembers with PLS revealed near completeloss in affected individuals, and partialloss of activity in heterozygous carriers.

Cathepsin C functionThe PLS phenotype suggests that cathep-sin C is essential for establishing or main-

taining the structural organization of theepidermis of the extremities and theintegrity or immunologic properties ofthe tissues surrounding the teeth. Severalother syndromes involving palmoplantarhyperkeratosis (but not periodontal dis-ease) are caused by mutations in the ker-atin genes. This suggests that cathepsin Cmay indirectly contribute to the process-ing of proteins such as keratins, that main-tain the structural integrity of epithelia ina way that is unique to the tissues that areaffected in these patients.

The processing and activation ofgranzymes A and B by cathepsin C hasbeen well characterized9–11. Granzymesare serine proteases secreted by cyto-toxic T lymphocytes (CTL) and naturalkiller cells in attempt to destroy theirtargets—other lymphocytes or cellscompromised by infection or disease.

Granzymes enter the target cell and trig-ger apoptosis. In addition to eliminatingtumour cells or infected cells, this mech-anism of cell-mediated cytotoxicity canact to dampen the immune response byeliminating activated lymphocytes—anaction potentially critical to the protec-tion of periodontal tissues from damagedue to inflammation.

Mice deficient in cathepsin C developnormally and seem healthy, but theirCTLs and lymphokine-activated killercells lack cytotoxic activity, owing to thelack of processing of both granzymes Aand B (ref. 12). One wonders whetherthese mice might develop periodontal dis-ease or hyperkeratosis and, if so, underwhat conditions. Notably, human ker-atinocytes in culture secrete granzyme B,which has antimicrobial activity13. It istempting to speculate that the periodonti-

Skeletal development in the zebrafish

A variety of growth and differentiation factors regulate the formation of the verte-brate skeleton by activating or repressing different transcription factors. Among thedifferentiation factors, members of the transforming growth factor-β (TGF-β) super-

family are implicated in bothcartilage and bone-cell differ-entiation and in mediatingthe complex patterning of theskeleton. The bone morpho-genetic proteins (BMPs), asmall family of TGF-β–related proteins, stimulatemesenchymal cells to differ-entiate into chondrocytes andosteoblasts, which deposit thebone matrix and regulate thepattern of skeletal formation.Accordingly, inactivation ormutation of BMP genescauses skeletal malformations

in mice, and some skeletal dis-eases in humans may also

result from mutations or alterations in the levels or activities of BMPs.Several secreted polypeptides, of which noggin and chordin are best characterized,

regulate the extracellular activities of the BMPs. Their ability to associate with BMPsprevents them from binding to cell-surface receptors and thereby inhibits their effecton the cell. Last year, noggin was shown to inhibit BMP activity1 in skeletal morpho-genesis. So, mice deficient in noggin have skeletal defects due to excessive cartilageformation and increased bone formation. Shannon Fisher and Marnie Halpern nowprovide evidence2 (see page 442) that skeletal development is regulated by chordinthrough its ability to block BMP activity. They show that zebrafish lacking chordinexpression have aberrant levels of BMP proteins and abnormalities in fin and caudalskeletal patterning—which can be rescued by injections of chordin mRNA. In sodoing, they underscore the advantages of using genetic screens of zebrafish to identifyregulators of skeletal formation in vertebrates.

—Rik Derynck1. Brunet, L. et al. Science 280, 1455–1457 (1998).2. Fisher, S. & Halpern, M. Nature Genet. 23, 442–446 (1999).

Rik Derynck is a professor in the Departments of Growth and Development, and Anatomy, and thePrograms in Cell biology and Developmental Biology at the University of California in San Francisco.

Achording to the zebrafish . . . a deficiency of chordinresults in aberrant tail development (upper image).

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