title: Linking osteopetrosis and pycnodysostosis: regulation of cathepsin K expression by the microphthalmia transcription factor family.
abstract: Various genetic conditions produce dysfunctional osteoclasts resulting in osteopetrosis or osteosclerosis. These include human pycnodysostosis, an autosomal recessive syndrome caused by cathepsin K mutation, cathepsin K-deficient mice, and mitf mutant rodent strains. Cathepsin K is a highly expressed cysteine protease in osteoclasts that plays an essential role in the degradation of protein components of bone matrix. Cathepsin K also is expressed in a significant fraction of human breast cancers where it could contribute to tumor invasiveness. Mitf is a member of a helix-loop-helix transcription factor subfamily, which contains the potential dimerization partners TFE3, TFEB, and TFEC. In mice, dominant negative, but not recessive, mutations of mitf, produce osteopetrosis, suggesting a functional requirement for other family members. Mitf also has been found-and TFE3 has been suggested-to modulate age-dependent changes in osteoclast function. This study identifies cathepsin K as a transcriptional target of Mitf and TFE3 via three consensus elements in the cathepsin K promoter. Additionally, cathepsin K mRNA and protein were found to be deficient in mitf mutant osteoclasts, and overexpression of wild-type Mitf dramatically up-regulated expression of endogenous cathepsin K in cultured human osteoclasts. Cathepsin K promoter activity was disrupted by dominant negative, but not recessive, mouse alleles of mitf in a pattern that closely matches their osteopetrotic phenotypes. This relationship between cathepsin K and the Mitf family helps explain the phenotypic overlap of their corresponding deficiencies in pycnodysostosis and osteopetrosis and identifies likely regulators of cathepsin K expression in bone homeostasis and human malignancy.
authors.affiliation: Division of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: G
authors.initials: G
authors.lastname: Motyckova
authors.forename: K N
authors.initials: KN
authors.lastname: Weilbaecher
authors.forename: M
authors.initials: M
authors.lastname: Horstmann
authors.forename: D J
authors.initials: DJ
authors.lastname: Rieman
authors.forename: D Z
authors.initials: DZ
authors.lastname: Fisher
authors.forename: D E
authors.initials: DE
authors.lastname: Fisher
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D056657:Cathepsin K; D002403:Cathepsins / Q000235:genetics* / Q000378:metabolism; D004247:DNA; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D010022:Osteopetrosis / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D004268:DNA-Binding Proteins; D051739:Microphthalmia-Associated Transcription Factor; C497235:Mitf protein, mouse; D012333:RNA, Messenger; D014157:Transcription Factors; D004247:DNA; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse