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Bruce D. Gelb - One of the best experts on this subject based on the ideXlab platform.
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mice lacking cathepsin k maintain bone remodeling but develop bone fragility despite high bone mass
Journal of Bone and Mineral Research, 2006Co-Authors: Chao Yang Li, Bruce D. Gelb, Karl J Jepsen, Robert J Majeska, Jian Zhang, Rujing Ni, Mitchell B SchafflerAbstract:Bone microstructural and biomechanical properties were analyzed in mice genetically lacking cathepsin K (CatK). CatK deficiency (CatK−/−) produced mild osteopetrosis, elevated numbers of osteoclasts, regions of disorganized bone microstructure, and increased bone fragility, showing how chronic alteration of enzyme activity during skeletal development dramatically affects bone organization and function. Introduction: Mouse models of CatK deficiency recapitulate the osteopetrosis of human pyknodysostosis and allow study of clinically relevant issues: how inhibition of this enzyme activity affects bone integrity structurally and biomechanically. To address these questions, we generated CatK-deficient mice by targeted disruption of the Ctsk gene and compared their bone structural and mechanical properties with wildtype (WT) controls. Materials and Methods: Standard histomorphometric and biomechanical analyses were performed on femora from C57BL/6J male and female CatK−/−, CatK+/−, and WT mice. Results: CatK−/− femora exhibited the mild metaphyseal osteopetrosis, a greater cortical bone area and thickness, normal bone strength, but a high degree of brittleness (nearly 50–70% decrease in postyield displacement versus WT) and a 30–40% reduction in the work-to-failure. In cancellous bone, osteoclast numbers and resorption surface were increased markedly (∼150% and 50%, respectively), despite the overall decrease in net bone resorption for CatK-deficient mice. Bone formation indices were altered in CatK−/− mice as well, with significant increases in mineral appositional rate, but not in bone formation surface; these data suggest difference in osteoblast work but not in their recruitment in CatK deficiency. CatK-deficient cortical bones had large areas of woven bone and intracortical resorption spaces within the disorganized tissue. Bone phenotype in CatK−/− was similar in males and females. Conclusions: Genetic CatK deficiency in mice results not only in the impairment of osteoclast function and osteopetrosis, but also altered osteoblast function, defective tissue organization, and very brittle bones. Whether this bone fragility in CatK deficiency results entirely from indirect effects of suppressed bone turnover because of impaired osteoclast function or perhaps represents a previously unappreciated more direct role for CatK in bone formation remains to be established.
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decreased bone turnover and deterioration of bone structure in two cases of Pycnodysostosis
The Journal of Clinical Endocrinology and Metabolism, 2004Co-Authors: Nadja Fratzlzelman, Bruce D. Gelb, A Valenta, Paul Roschger, A Nader, Peter Fratzl, Klaus KlaushoferAbstract:Pycnodysostosis is an uncommon human genetic disorder characterized by osteosclerosis of the skeleton, short stature, and bone fragility. The disease results from mutations in the cathepsin K gene, a lysosomal cysteine protease highly expressed in osteoclasts and crucial for the degradation of organic matrix from mineralized bone. Recently, interest has focused on a pharmaceutical inhibition of cathepsin K to prevent bone loss. However, little is known about the cellular activity or material quality of bone in Pycnodysostosis. In the present study, transiliac bone biopsies from two affected individuals, aged 5 and 21 yr, were investigated using light microscopy, quantitative backscattered electron imaging, and small angle x-ray scattering. Results were compared with published age-matched reference data. The mutations in the cathepsin K gene of both patients were identified, including one novel defect. Both individuals had severe osteosclerosis, and their biopsies displayed multinucleated osteoclasts apposed to areas of demineralized matrix as well as bone-lining cells adjacent to this undigested collagen left over by osteoclasts. The homogeneity of the mineralized matrix was markedly disturbed due to large inclusions of mineralized cartilage residues. Histomorphometric evaluation showed a quantitative decrease in static parameters of bone formation. In contrast and despite deficient cathepsin K activity, osteoclastic parameters were close to normal range. At the nanostructural level, there was a marked increase in the mean thickness of the mineral particles, reflecting decreased bone remodeling. Examination of the trabecular structure revealed that the lamellae were highly disordered, which was also apparent from a poor alignment of mineral crystals oriented along the longitudinal axis of collagen fibrils. Taken together, these results strongly suggest that functional cathepsin K is important for balanced bone turnover, and enzyme deficiency results in a profound deterioration of bone quality with respect to trabecular architecture and lamellar arrangement, which is presumably the reason for bone fragility in Pycnodysostosis.
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collagenase activity of cathepsin k depends on complex formation with chondroitin sulfate
Journal of Biological Chemistry, 2002Co-Authors: Zhenqiang Li, Carlos R Escalantetorres, Bruce D. Gelb, Dieter BrommeAbstract:Abstract Bone resorption in balance with bone formation is vital for the maintenance of the skeleton and is mediated by osteoclasts. Cathepsin K is the predominant protease in osteoclasts that degrades the bulk of the major bone forming organic component, type I collagen. Although the potent collagenase activity of cathepsin K is well known, its mechanism of action remains elusive. Here, we report a cathepsin K-specific complex with chondroitin sulfate, which is essential for the collagenolytic activity of the enzyme. The complex is an oligomer consisting of five cathepsin K and five chondroitin sulfate molecules. Only the complex exhibits potent triple helical collagen-degrading activity, whereas monomeric cathepsin K has no collagenase activity. The primary substrate specificity of cathepsin K is not altered by complex formation, suggesting that the protease-chondroitin sulfate complex primarily facilitates the destabilization and/or the specific binding of the triple helical collagen structure. Inhibition of complex formation leads to the loss of collagenolytic activity but does not impair the proteolytic activity of cathepsin K toward noncollagenous substrates. The physiological relevance of cathepsin K complexes is supported by the findings that (i) the content of chondroitin sulfate present in bone and accessible to cathepsin K activity is sufficient for complex formation and (ii) Y212C, a cathepsin K mutant that causes Pycnodysostosis (a bone sclerosing disorder) and that has no collagenase activity but remains potent as a gelatinase, is unable to form complexes. These findings reveal a novel mechanism of bone collagen degradation and suggest that targeting cathepsin K complex formation would be an effective and specific treatment for diseases with excessive bone resorption such as osteoporosis.
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determination of bone markers in Pycnodysostosis effects of cathepsin k deficiency on bone matrix degradation
Journal of Bone and Mineral Research, 1999Co-Authors: Yoshikazu Nishi, Robert J Desnick, Lynn Atley, David E Eyre, Jacob G Edelson, Andrea Supertifurga, Toshiyuki Yasuda, Bruce D. GelbAbstract:Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K. This lysosomal cysteine protease has substantial collagenase activity, is present at high levels in osteoclasts, and is secreted into the subosteoclastic space where bone matrix is degraded. In vitro studies revealed that mutant cathepsin K proteins causing Pycno did not degrade type I collagen, the protein that constitutes 95% of organic bone matrix. To determine the in vivo effects of cathepsin K mutations on bone metabolism in general and osteoclast-mediated bone resorption specifically, several bone metabolism markers were assayed in serum and urine from seven Pycno patients. Two markers of bone synthesis, type I collagen carboxy-terminal propeptide and osteocalcin, were normal in all Pycno patients. Tartrate-resistent acid phosphatase, an osteoclast marker, was also normal in these patients. Two markers that detect type I collagen telopeptide cross-links from the N and C termini, NTX and CTX, respectively, were low in Pycno. A third marker which detects a more proximal portion of the C terminus of type I collagen in serum, ICTP, was elevated in Pycno, a seemingly paradoxical result. The finding of decreased osteoclast-mediated type I collagen degradation as well as the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C-terminal fragments containing the ICTP epitope, established a unique biochemical phenotype for Pycno.
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Paternal Uniparental Disomy for Chromosome 1 Revealed by Molecular Analysis of a Patient with Pycnodysostosis
American Journal of Human Genetics, 1998Co-Authors: Bruce D. Gelb, Teresa M. Dunn, Nataline B. Kardon, Jacques Poncin, Alain Verloes, Judith P Willner, Robert J DesnickAbstract:Molecular analysis of a patient affected by the autosomal recessive skeletal dysplasia, Pycnodysostosis (cathepsin K deficiency; MIM 265800), revealed homozygosity for a novel missense mutation (A277V). Since the A277V mutation was carried by the patient's father but not by his mother, who had two normal cathepsin K alleles, paternal uniparental disomy was suspected. Karyotyping of the patient and of both parents was normal, and high-resolution cytogenetic analyses of chromosome 1, to which cathepsin K is mapped, revealed no abnormalities. Evaluation of polymorphic DNA markers spanning chromosome 1 demonstrated that the patient had inherited two paternal chromosome 1 homologues, whereas alleles for markers from other chromosomes were inherited in a Mendelian fashion. The patient was homoallelic for informative markers mapping near the chromosome 1 centromere, but he was heteroallelic for markers near both telomeres, establishing that the paternal uniparental disomy with partial isodisomy was caused by a meiosis II nondisjunction event. Phenotypically, the patient had normal birth height and weight, had normal psychomotor development at age 7 years, and had only the usual features of Pycnodysostosis. This patient represents the first case of paternal uniparental disomy of chromosome 1 and provides conclusive evidence that paternally derived genes on human chromosome 1 are not imprinted.
David E. Fisher - One of the best experts on this subject based on the ideXlab platform.
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Pycnodysostosis role and regulation of cathepsin k in osteoclast function and human disease
Current Molecular Medicine, 2002Co-Authors: Gabriela Motyckova, David E. FisherAbstract:Abstract Patients with Pycnodysostosis, a rare skeletal dysplasia, present with bone abnormalities such as short stature, acroosteolysis of distal phalanges, and skull deformities. The disease is caused by a deficiency of the cysteine protease cathepsin K which is responsible for degradation of collagen type I and other bone proteins. Osteoclasts, bone cells of hematopoietic origin responsible for bone mineral as well as protein matrix degradation, are dysfunctional in patients with Pycnodysostosis due to mutations in the cathepsin K gene. Cathepsin K deficient osteoclasts can demineralize bone but cannot degrade the protein matrix. Mutations in the cathepsin K gene disrupting wild type cathepsin K activity have been described in patients with Pycnodysostosis. Animal models of cathepsin K deficiency have been created and provide a valuable tool to study osteoclast function and treatment for cathepsin K deficiency. Understanding the regulation and role of cathepsin K in osteoclast function is important for designing future therapies for Pycnodysostosis. Cathepsin K inhibitors will be useful in pathological processes involving excess osteoclast activation and bone resorption such as osteoporosis, bone metastasis and multiple myeloma. This review will discuss the bone remodeling cycle, the human disease Pycnodysostosis caused by cathepsin K deficiency and cathepsin K activity and regulation.
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linking osteopetrosis and Pycnodysostosis regulation of cathepsin k expression by the microphthalmia transcription factor family
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Gabriela Motyckova, David J. Rieman, Daniel Z Fisher, Martin A Horstmann, Katherine N Weilbaecher, David E. FisherAbstract: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.
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linking osteopetrosis and Pycnodysostosis regulation of cathepsin k expression by the microphthalmia transcription factor family
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Gabriela Motyckova, David J. Rieman, Daniel Z Fisher, Martin A Horstmann, Katherine N Weilbaecher, David E. FisherAbstract: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.
Gabriela Motyckova - One of the best experts on this subject based on the ideXlab platform.
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Pycnodysostosis role and regulation of cathepsin k in osteoclast function and human disease
Current Molecular Medicine, 2002Co-Authors: Gabriela Motyckova, David E. FisherAbstract:Abstract Patients with Pycnodysostosis, a rare skeletal dysplasia, present with bone abnormalities such as short stature, acroosteolysis of distal phalanges, and skull deformities. The disease is caused by a deficiency of the cysteine protease cathepsin K which is responsible for degradation of collagen type I and other bone proteins. Osteoclasts, bone cells of hematopoietic origin responsible for bone mineral as well as protein matrix degradation, are dysfunctional in patients with Pycnodysostosis due to mutations in the cathepsin K gene. Cathepsin K deficient osteoclasts can demineralize bone but cannot degrade the protein matrix. Mutations in the cathepsin K gene disrupting wild type cathepsin K activity have been described in patients with Pycnodysostosis. Animal models of cathepsin K deficiency have been created and provide a valuable tool to study osteoclast function and treatment for cathepsin K deficiency. Understanding the regulation and role of cathepsin K in osteoclast function is important for designing future therapies for Pycnodysostosis. Cathepsin K inhibitors will be useful in pathological processes involving excess osteoclast activation and bone resorption such as osteoporosis, bone metastasis and multiple myeloma. This review will discuss the bone remodeling cycle, the human disease Pycnodysostosis caused by cathepsin K deficiency and cathepsin K activity and regulation.
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linking osteopetrosis and Pycnodysostosis regulation of cathepsin k expression by the microphthalmia transcription factor family
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Gabriela Motyckova, David J. Rieman, Daniel Z Fisher, Martin A Horstmann, Katherine N Weilbaecher, David E. FisherAbstract: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.
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linking osteopetrosis and Pycnodysostosis regulation of cathepsin k expression by the microphthalmia transcription factor family
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Gabriela Motyckova, David J. Rieman, Daniel Z Fisher, Martin A Horstmann, Katherine N Weilbaecher, David E. FisherAbstract: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.
Koray Boduroğlu - One of the best experts on this subject based on the ideXlab platform.
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Cathepsin K analysis in a Pycnodysostosis cohort: demographic, genotypic and phenotypic features
Orphanet Journal of Rare Diseases, 2014Co-Authors: Ahmet Arman, Ajda Coker, Pelin Özlem Şimşek Kiper, Tulay Guran, Behzat Özkan, Zeynep Atay, Teoman Akcay, Belma Haliloglu, Abdullah Bereket, Koray BoduroğluAbstract:Background: To characterize cathepsin K (CTSK) mutations in a group of patients with Pycnodysostosis, who presented with either short stature or atypical fractures to pediatric endocrinology or dysmorphic features to pediatric genetics clinics. Methods: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced. Sixteen patients from 14 families with Pycnodysostosis, presenting with typical dysmorphic features, short stature, frequent fractures and osteosclerosis, were included in the study. Results: We identified five missense mutations (M1I, I249T, L7P, D80Y and D169N), one nonsense mutation (R312X) and one 301 bp insertion in intron 7, which is revealed as Alu sequence; among them, only L7P and I249 were described previously. The mutations were homozygous in all cases, and the families mostly originated from the region where consanguineous marriage rate is the highest. Patients with M1I mutation had fractures, at younger ages than the other Pycnodysostosis cases in our cohort which were most probably related to the severity of mutation, since M1I initiates the translation, and mutation might lead to the complete absence of the protein. The typical finding of Pycnodysostosis, acroosteolysis, could not be detected in two patients, although other patients carrying the same mutations had acroosteolysis. Additionally, none of the previously described hot spot mutations were seen in our cohort; indeed, L7P and R312X were the most frequently detected mutations. Conclusions: We described a large cohort of Pycnodysostosis patients with genetic and phenotypic features, and, first Alu sequence insertion in Pycnodysostosis.
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cathepsin k analysis in a Pycnodysostosis cohort demographic genotypic and phenotypic features
Orphanet Journal of Rare Diseases, 2014Co-Authors: Ahmet Arman, Ajda Coker, Pelin Özlem Şimşek Kiper, Tulay Guran, Behzat Özkan, Zeynep Atay, Teoman Akcay, Belma Haliloglu, Abdullah Bereket, Koray BoduroğluAbstract:Background To characterize cathepsin K (CTSK) mutations in a group of patients with Pycnodysostosis, who presented with either short stature or atypical fractures to pediatric endocrinology or dysmorphic features to pediatric genetics clinics.
Robert J Desnick - One of the best experts on this subject based on the ideXlab platform.
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determination of bone markers in Pycnodysostosis effects of cathepsin k deficiency on bone matrix degradation
Journal of Bone and Mineral Research, 1999Co-Authors: Yoshikazu Nishi, Robert J Desnick, Lynn Atley, David E Eyre, Jacob G Edelson, Andrea Supertifurga, Toshiyuki Yasuda, Bruce D. GelbAbstract:Pycnodysostosis (Pycno) is an autosomal recessive osteosclerotic skeletal dysplasia that is caused by the markedly deficient activity of cathepsin K. This lysosomal cysteine protease has substantial collagenase activity, is present at high levels in osteoclasts, and is secreted into the subosteoclastic space where bone matrix is degraded. In vitro studies revealed that mutant cathepsin K proteins causing Pycno did not degrade type I collagen, the protein that constitutes 95% of organic bone matrix. To determine the in vivo effects of cathepsin K mutations on bone metabolism in general and osteoclast-mediated bone resorption specifically, several bone metabolism markers were assayed in serum and urine from seven Pycno patients. Two markers of bone synthesis, type I collagen carboxy-terminal propeptide and osteocalcin, were normal in all Pycno patients. Tartrate-resistent acid phosphatase, an osteoclast marker, was also normal in these patients. Two markers that detect type I collagen telopeptide cross-links from the N and C termini, NTX and CTX, respectively, were low in Pycno. A third marker which detects a more proximal portion of the C terminus of type I collagen in serum, ICTP, was elevated in Pycno, a seemingly paradoxical result. The finding of decreased osteoclast-mediated type I collagen degradation as well as the use of alternative collagen cleavage sites by other proteases, and the accumulation of larger C-terminal fragments containing the ICTP epitope, established a unique biochemical phenotype for Pycno.
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Paternal Uniparental Disomy for Chromosome 1 Revealed by Molecular Analysis of a Patient with Pycnodysostosis
American Journal of Human Genetics, 1998Co-Authors: Bruce D. Gelb, Teresa M. Dunn, Nataline B. Kardon, Jacques Poncin, Alain Verloes, Judith P Willner, Robert J DesnickAbstract:Molecular analysis of a patient affected by the autosomal recessive skeletal dysplasia, Pycnodysostosis (cathepsin K deficiency; MIM 265800), revealed homozygosity for a novel missense mutation (A277V). Since the A277V mutation was carried by the patient's father but not by his mother, who had two normal cathepsin K alleles, paternal uniparental disomy was suspected. Karyotyping of the patient and of both parents was normal, and high-resolution cytogenetic analyses of chromosome 1, to which cathepsin K is mapped, revealed no abnormalities. Evaluation of polymorphic DNA markers spanning chromosome 1 demonstrated that the patient had inherited two paternal chromosome 1 homologues, whereas alleles for markers from other chromosomes were inherited in a Mendelian fashion. The patient was homoallelic for informative markers mapping near the chromosome 1 centromere, but he was heteroallelic for markers near both telomeres, establishing that the paternal uniparental disomy with partial isodisomy was caused by a meiosis II nondisjunction event. Phenotypically, the patient had normal birth height and weight, had normal psychomotor development at age 7 years, and had only the usual features of Pycnodysostosis. This patient represents the first case of paternal uniparental disomy of chromosome 1 and provides conclusive evidence that paternally derived genes on human chromosome 1 are not imprinted.
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Structure and chromosomal assignment of the human cathepsin K gene
Genomics, 1997Co-Authors: Bruce D. Gelb, Matthew Heller, Stanislawa Weremowicz, Cynthia C Morton, Robert J Desnick, Harold A. ChapmanAbstract:Abstract 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.
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Pycnodysostosis a lysosomal disease caused by cathepsin k deficiency
Science, 1996Co-Authors: Bruce D. Gelb, Harold A. Chapman, Robert J DesnickAbstract:Pycnodysostosis, an autosomal recessive osteochondrodysplasia characterized by osteosclerosis and short stature, maps to chromosome 1q21. Cathepsin K, a cysteine protease gene that is highly expressed in osteoclasts, localized to the Pycnodysostosis region. Nonsense, missense, and stop codon mutations in the gene encoding cathepsin K were identified in patients. Transient expression of complementary DNA containing the stop codon mutation resulted in messenger RNA but no immunologically detectable protein. Thus, Pycnodysostosis results from gene defects in a lysosomal protease with highest expression in osteoclasts. These findings suggest that cathepsin K is a major protease in bone resorption, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis.
