PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Pycnodysostosis”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources
PubMed1984

Pycnodysostosis.

Explore the source record for details and available documents.

Abnormalities, Multiple↗
PubMed1993

Pycnodysostosis.

Explore the source record for details and available documents.

Bone Diseases, Developmental↗
PubMed2007

High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K.

INTRODUCTION: Pycnodysostosis is typically associated with short stature, multiple fractures without adequate trauma and high bone density on x-ray. The increased bone density is due to a genetic defect of cathepsin K, leading to dysfunctional osteoclastic bone resorption and bone remodeling. We wanted to know how this defect influences the trabecular and cortical volumetric bone mineral density of long bones as measured quantitatively by pQCT. METHODS: Three siblings of a consanguineous family were admitted to our hospital because of multiple fractures. Pycnodysostosis was diagnosed based on the clinical presentation with the characteristic dense appearance of their bones on x-ray. The distal and proximal radius of the patients and of control subjects was scanned using a Stratec XCT-2000 pQCT scanner and data were processed using the software provided by the manufacturer. Genomic DNA was extracted from blood samples of all three patients and their parents. The coding exons of the cathepsin K gene (CTSK) were amplified and sequenced. RESULTS: The patients displayed the typical features of pycnodysostosis: Short stature, delay of closure of the fontanelles, hypoplasia of the maxilla, spondylolysis of the lumbar spine, stubby hands and feet and a history of multiple fractures. Volumetric bone density was much higher in pycnodysostotic bone than in the control bones 686 +/- 28 mg/cm(3) in patients vs. 290 +/- 6 mg/cm(3) in controls; p = 0.001), especially in the trabecular compartment (733 +/- 26 mg/cm(3) in patients vs. 195 +/- 8 mg/cm(3) in controls; p < 0.001), but also in the cortical bone (1108 +/- 22 in patients vs. 1020 +/- 17 in controls; p < 0.01). In contrast to this finding, the patients displayed an elevation of alkaline phosphatase in the serum and free deoxypyridinoline-crosslinks (DPD) in the urine, suggesting osteomalacia. Sequencing of the cathepsin K gene revealed homozygosity for a novel missense mutation in all three patients predicting the amino acid exchange from arginine to tryptophan at position 46 (R46W). CONCLUSION: We present here for the first time quantitative data on the mineral density of bones of pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K. The elevated bone mineral density in the cortex and the changes in the serum markers suggest an effect of cathepsin K not only on bone volume, but also on bone mineralization. This might in part explain the increased susceptibility to fractures of patients with pycnodysostosis.

Absorptiometry, Photon↗
PubMed1997

Structure and chromosomal assignment of the human cathepsin K gene.

Cathepsin K is a recently identified lysosomal cysteine proteinase that is the major protease responsible for bone resorption and remodeling. Mutations in this gene cause the sclerosing osteochondrodysplasia pycnodysostosis. To assess its evolutionary relatedness to other cysteine proteases and to facilitate mutation identification in patients with pycnodysostosis, a genomic clone, 74e16, containing the cathepsin K gene was isolated from a human PAC library, and the cathepsin K genomic structure was determined. The cathepsin K gene contained eight exons and spanned approximately 9 kb. The transcription initiation site, determined by primer extension analysis, was 169 nucleotides upstream from the translation initiation site. The 5'-flanking region lacked a TATA box but contained two AP1 sites. Comparison of genomic and cDNA sequences suggested that this flanking sequence may be the major promoter in osteoclasts and macrophages. Cathepsin K was mapped to chromosome 1q21 by fluorescence in situ hybridization and found to reside within 150 kb of an evolutionarily related cysteine protease, cathepsin S. These findings expand our understanding of the papain family lysosomal cysteine proteases and should facilitate mutation analysis in pycnodysostosis.

Base Sequence↗
PubMed2000

Functions of cathepsin K in bone resorption. Lessons from cathepsin K deficient mice.

Cathepsin K is a cysteine proteinase expressed predominantly in osteoclasts. Cathepsin K cleaves key bone matrix proteins and is believed to play an important role in degrading the organic phase of bone during bone resorption. Pycnodysostosis, an autosomal recessive osteosclerosing skeletal disorder has recently been shown to result from mutations in the cathepsin K gene. Cathepsin K deficient mice generated by targeted disruption of this proteinase phenocopy many aspects of pycnodysostosis. They display an osteopetrotic phenotype with excessive trabeculation of the bone-marrow space accompanied by an altered ultrastructural appearance of the cathepsin K deficient osteoclasts. These cells also demonstrate an impaired resorptive activity in vitro. In contrast to other forms of osteopetrosis, which are due to disrupted osteoclastogenesis, cathepsin K deficiency is associated with an inhibition of osteoclast activity. Taken together the phenotype of cathepsin K knockout mice underlines the importance of this proteinase in bone remodelling.

Animals↗
PubMed2001

Human osteopetrosis and other sclerosing disorders: recent genetic developments.

Osteopetroses are rare human genetic disorders due to markedly decreased bone resorption. To date, the only gene whose inactivation was known to be responsible for human osteopetroses was that encoding carbonic anhydrase type II. Recessive malignant osteopetrosis is linked to decreased osteoclast function, unlike several osteopetroses in rodents that are caused by the inactivation of genes stimulating osteoclast differentiation. Recent advances in genetics have shown that some patients affected with recessive malignant osteopetrosis have inactivating mutations in a subunit of the vacuolar proton pump that is actively produced in the osteoclast brush border, but not in the lysosomes of other cells. The same gene is mutated in osteopetrotic oc/oc mice. The genes responsible for autosomal dominant osteopetrosis (ADO) have not yet been identified. Also, different localizations have been observed for ADO II, the type with sandwich vertebrae, and ADO I, presenting with diffuse osteocondensation. Less data than in malignant osteopetrosis are avaible on the cellular mechanism of decreased bone resorption in ADO but there is also genetic heterogeneity in ADO II. Pycnodysostosis is also due to a decreased resorption, and is quite close to osteopetrosis. Pycnodysostosis is linked to an inactivating mutation in the gene encoding cathepsin K, which is required for osteoclastic resorption. Decreased bone resorption is not the only defect inducing osteosclerosis, and Camurati-Engelmann disease is due to increased bone formation. Recently it has been shown that it is associated with a mutation in the propeptide of TGFbeta1. Thus, human osteosclerosing disorders have a wide range of phenotypes and genotypes and knowledge of them will contribute to a better understanding of the remodeling of normal bone.

Animals↗
PubMed1997

Characterization of the human extracellular matrix protein 1 gene on chromosome 1q21.

Ecm1, the mouse gene encoding extracellular matrix protein 1, is highly expressed in bone and cartilage as well as in osteogenic, preosteoblastic and chondroblastic cell lines. Ecm1 was recently localized to a chromosomal region in mouse syntenic to human chromosome 1q21, establishing this gene as a prime candidate gene for pycnodysostosis, a rare, autosomal recessive sclerosing skeletal dysplasia. Shortly thereafter, it was determined that cathepsin K is the pycnodysostosis gene. We now report the radiation hybrid mapping of human ECM1 to 1q21, and the gene structure and coding sequence of human ECM1.

Amino Acid Sequence↗
PubMedDate not supplied

The role of cathepsin K in normal bone resorption.

Cathepsin K is essential for normal bone resorption; humans lacking cathepsin K exhibit pycnodysostosis, which is characterized by short stature and osteosclerosis. Cathepsin K knockout mice develop osteopetrosis and display features characteristic of pycnodysostosis, and osteoclasts isolated from these mice exhibit impaired bone resorption in vitro. Bone resorption depends upon the synthesis of cathepsin K by osteoclasts and its secretion into the extracellular compartment at the attachment site between osteoclasts and the bone surface, wherein the organic matrix is subsequently degraded by cathepsin K. Factors that directly modulate osteoclastic bone resorption, including cytokines (RANK ligand, tumor necrosis factor-alpha and interferon gamma), hormones (retinoic acid and estrogen) and nuclear transcriptional factors (c-jun and Mitf) also regulate cathepsin K gene expression. Osteoporosis is one of the leading causes of morbidity in the elderly and is characterized by a persistent excess of osteoclastic bone resorption. Therefore, cathepsin K is an attractive target for therapeutic intervention to prevent and ameliorate the significant deleterious impact of osteoporosis.

Animals↗