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Osteoporosis International

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01-05-2007 | Original Article

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

Authors: A. F. Schilling, C. Mülhausen, W. Lehmann, R. Santer, T. Schinke, J. M. Rueger, M. Amling

Published in: Osteoporosis International | Issue 5/2007

Abstract

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/cm³ in patients vs. 290 ± 6 mg/cm³ in controls; p = 0.001), especially in the trabecular compartment (733 ± 26 mg/cm³ in patients vs. 195 ± 8 mg/cm³ 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.

Soliman AT, Rajab A, AlSalmi I, Darwish A, Asfour M (1996) Defective growth hormone secretion in children with pycnodysostosis and improved linear growth after growth hormone treatment. Arch Dis Child 75:242–244PubMed

Darcan S, Akisu M, Taneli B, Kendir G (1996) A case of pycnodysostosis with growth hormone deficiency. Clin Genet 50:422–425PubMedCrossRef

Ho N, Punturieri A, Wilkin D, Szabo J, Johnson M, Whaley J, Davis J, Clark A, Weiss S, Francomano C (1999) Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein. J Bone Miner Res 14:1649–1653PubMedCrossRef

Fujita Y, Nakata K, Yasui N, Matsui Y, Kataoka E, Hiroshima K, Shiba RI, Ochi T (2000) Novel mutations of the cathepsin K gene in patients with pycnodysostosis and their characterization. J Clin Endocrinol Metab 85:425–431PubMedCrossRef

Soliman AT, Ramadan MA, Sherif A, Aziz Bedair ES, Rizk MM (2001) Pycnodysostosis: clinical, radiologic, and endocrine evaluation and linear growth after growth hormone therapy. Metabolism 50:905–911PubMedCrossRef

Zenke MS, Hatori M, Tago S, Hosaka M, Kokubun S (2002) Pycnodysostosis associated with spondylolysis. Arch Orthop Trauma Surg 122:248–250PubMedCrossRef

Karakurt L, Yilmaz E, Belhan O, Serin E (2003) Pycnodysostosis associated with bilateral congenital pseudarthrosis of the clavicle. Arch Orthop Trauma Surg 123:125–127PubMed

Maroteaux P, Lamy M (1962) Pyknodysostosis. Presse Med 70:999–1002PubMed

Maroteaux P, Lamy M (1965) The malady of Toulouse-Lautrec. JAMA 191:715–717PubMed

10.

Saftig P, Hunziker E, Wehmeyer O, Jones S, Boyde A, Rommerskirch W, Moritz JD, Schu P, von Figura K (1998) Impaired osteoclastic bone resorption leads to osteopetrosis in cathepsin-K-deficient mice. Proc Natl Acad Sci USA 95:13453–13458PubMedCrossRef

11.

Gelb BD, Shi GP, Chapman HA, Desnick RJ (1996) Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 273:1236–1238PubMedCrossRef

12.

Gelb BD, Spencer E, Obad S, Edelson GJ, Faure S, Weissenbach J, Desnick RJ (1996) Pycnodysostosis: refined linkage and radiation hybrid analyses reduce the critical region to 2 cM at 1q21 and map two candidate genes. Hum Genet 98:141–144PubMedCrossRef

13.

Bromme D, Okamoto K (1995) Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution. Biol Chem Hoppe Seyler 376:379–384PubMed

14.

Shi GP, Chapman HA, Bhairi SM, DeLeeuw C, Reddy VY, Weiss SJ (1995) Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit OC2. FEBS Lett 357:129–134PubMedCrossRef

15.

Bossard MJ, Tomaszek TA, Thompson SK, Amegadzie BY, Hanning CR, Jones C, Kurdyla JT, McNulty DE, Drake FH, Gowen M, Levy MA (1996) Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification. J Biol Chem 271:12517–12524PubMedCrossRef

16.

Kafienah W, Bromme D, Buttle DJ, Croucher LJ, Hollander AP (1998) Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix. Biochem J 331:727–732PubMed

17.

Garnero P, Borel O, Byrjalsen I, Ferreras M, Drake FH, McQueney MS, Foged NT, Delmas PD, Delaisse JM (1998) The collagenolytic activity of cathepsin K is unique among mammalian proteinases. J Biol Chem 273:32347–32352PubMedCrossRef

18.

Inaoka T, Bilbe G, Ishibashi O, Tezuka K, Kumegawa M, Kokubo T (1995) Molecular cloning of human cDNA for cathepsin K: novel cysteine proteinase predominantly expressed in bone. Biochem Biophys Res Commun 206:89–96PubMedCrossRef

19.

LaLonde JM, Zhao B, Janson CA, D’Alessio KJ, McQueney MS, Orsini MJ, Debouck CM, Smith WW (1999) The crystal structure of human procathepsin K. Biochemistry 38:862–869PubMedCrossRef

20.

McQueney MS, Amegadzie BY, D’Alessio K, Hanning CR, McLaughlin MM, McNulty D, Carr SA, Ijames C, Kurdyla J, Jones CS (1997) Autocatalytic activation of human cathepsin K. J Biol Chem 272:13955–13960PubMedCrossRef

21.

Marquis RW, Ru Y, Yamashita DS, Oh HJ, Yen J, Thompson SK, Carr TJ, Levy MA, Tomaszek TA, Ijames CF, Smith WW, Zhao B, Janson CA, Abdel-Meguid SS, D’Alessio KJ, McQueney MS, Veber DF (1999) Potent dipeptidylketone inhibitors of the cysteine protease cathepsin K. Bioorg Med Chem 7:581–588PubMedCrossRef

22.

Marquis RW, Yamashita DS, Ru Y, LoCastro SM, Oh HJ, Erhard KF, DesJarlais RL, Head MS, Smith WW, Zhao B, Janson CA, Abdel-Meguid SS, Tomaszek TA, Levy MA, Veber DF (1998) Conformationally constrained 1,3-diamino ketones: a series of potent inhibitors of the cysteine protease cathepsin K. J Med Chem 41:3563–3567PubMedCrossRef

23.

Bossard MJ, Tomaszek TA, Levy MA, Ijames CF, Huddleston MJ, Briand J, Thompson S, Halpert S, Veber DF, Carr SA, Meek TD, Tew DG (1999) Mechanism of inhibition of cathepsin K by potent, selective 1, 5-diacylcarbohydrazides: a new class of mechanism-based inhibitors of thiol proteases. Biochemistry 38:15893–15902PubMedCrossRef

24.

Inui T, Ishibashi O, Inaoka T, Origane Y, Kumegawa M, Kokubo T, Yamamura T (1997) Cathepsin K antisense oligodeoxynucleotide inhibits osteoclastic bone resorption. J Biol Chem 272:8109–8112PubMedCrossRef

25.

Stroup GB, Lark MW, Veber DF, Bhattacharyya A, Blake S, Dare LC, Erhard KF, Hoffman SJ, James IE, Marquis RW, Ru Y, Vasko-Moser JA, Smith BR, Tomaszek T, Gowen M (2001) Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a nonhuman primate. J Bone Miner Res 16:1739–1746PubMedCrossRef

26.

Fratzl-Zelman N, Valenta A, Roschger P, Nader A, Gelb BD, Fratzl P, Klaushofer K (2004) Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis. J Clin Endocrinol Metab 89:1538–1547PubMedCrossRef

27.

Schoenau E, Neu CM, Rauch F, Manz F (2002) Gender-specific pubertal changes in volumetric cortical bone mineral density at the proximal radius. Bone 31:110–113PubMedCrossRef

28.

Neu CM, Manz F, Rauch F, Merkel A, Schoenau E (2001) Bone densities and bone size at the distal radius in healthy children and adolescents: a study using peripheral quantitative computed tomography. Bone 28:227–232PubMedCrossRef

29.

Gelb BD, Shi GP, Heller M, Weremowicz S, Morton C, Desnick RJ, Chapman HA (1997) Structure and chromosomal assignment of the human cathepsin K gene. Genomics 41:258–262PubMedCrossRef

30.

Santhanakrishnan BR, Panneerselvam S, Ramesh S, Panchatcharam M (1986) Pycnodysostosis with visceral manifestation and rickets. Clin Pediatr (Phila) 25:416–418CrossRef

31.

Li CY, Jepsen KJ, Majeska RJ, Zhang J, Ni R, Gelb BD, Schaffler MB (2006) Mice lacking cathepsin K maintain bone remodeling but develop bone fragility despite high bone mass. J Bone Miner Res 21:865–875PubMedCrossRef

32.

Nishi Y, Atley L, Eyre DE, Edelson JG, Superti-Furga A, Yasuda T, Desnick RJ, Gelb BD (1999) Determination of bone markers in pycnodysostosis: effects of cathepsin K deficiency on bone matrix degradation. J Bone Miner Res 14:1902–1908PubMedCrossRef

33.

Daniels ED, Pettifor JM, Moodley GP (2000) Serum osteocalcin has limited usefulness as a diagnostic marker for rickets. Eur J Pediatr 159:730–733PubMedCrossRef

34.

Ros I, Alvarez L, Guanabens N, Peris P, Monegal A, Vazquez I, Cerda D, Ballesta AM, Munoz-Gomez J (2005) Hypophosphatemic osteomalacia: a report of five cases and evaluation of bone markers. J Bone Miner Metab 23:266–269PubMedCrossRef

35.

Luftner D, Bollow M, Sturzenbecher A, Kaufmann, Priem F, Richter A, Gunther S, Geppert R, Petrides PE, Wernecke KD, Possinger K (2001) Biomarkers and imaging in non-malignant and malignant osteomalacia. Int J Biol Markers 16:136–141PubMed

36.

Hoshino H, Kushida K, Takahashi M, Kawana K, Denda M, Yamazaki K, Inoue T (1998) Characteristics of biochemical markers in patients with metabolic bone disorders. Endocr Res 24:55–64PubMedCrossRef

37.

Kozlowski K, Yu JS (1972) Pycnodysostosis. A variant form with visceral manifestations. Arch Dis Child 47:804–807PubMedCrossRef

38.

Benz G, Schmid-Ruter E (1977) Pycnodysostosis with Heterozygous beta-thalassemia. Pediatr Radiol 5:164–171PubMedCrossRef

39.

Li F, Iqbal J, Wassif W, Kaddam I, Moniz C (1994) Carboxyterminal propeptide of type I procollagen in osteomalacia. Calcif Tissue Int 55:90–93CrossRef

40.

Robins SP, Black D, Paterson CR, Reid DM, Duncan A, Seibel MJ (1991) Evaluation of urinary hydroxypyridinium crosslink measurements as resorption markers in metabolic bone diseases. Eur J Clin Invest 21:310–315PubMedCrossRef

41.

Cabrejas ML, Fromm GA, Roca JF, Mendez MA, Bur GE, Ferreyra ME, Demarchi C, Schurman L (1976) Pycnodysostosis: some aspects concerning kinetics of calcium metabolism and bone pathology. Am J Med Sci 271:215–220PubMed

42.

Kaplan FS, August CS, Fallon MD, Gannon F, Haddad JG (1993) Osteopetrorickets. The paradox of plenty. Pathophysiology and treatment. Clin Orthop Relat Res :64–78

43.

Currey JD (1990) Physical characteristics affecting the tensile failure properties of compact bone. J Biomech 23:837–844PubMedCrossRef

44.

Turner CH (2002) Biomechanics of bone: determinants of skeletal fragility and bone quality. Osteoporos Int 13:97–104PubMedCrossRef

45.

Haagerup A, Hertz JM, Christensen MF, Binderup H, Kruse TA (2000) Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. Eur J Hum Genet 8:431–436PubMedCrossRef

46.

Hou WS, Bromme D, Zhao Y, Mehler E, Dushey C, Weinstein H, Miranda CS, Fraga C, Greig F, Carey J, Rimoin DL, Desnick RJ, Gelb BD (1999) Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis. J Clin Invest 103:731–738PubMed

47.

Johnson MR, Polymeropoulos MH, Vos HL, Ortiz de Luna RI, Francomano CA (1996) A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis. Genome Res 6:1050–1055PubMed

48.

Votta BJ, Levy MA, Badger A, Bradbeer J, Dodds RA, James IE, Thompson S, Bossard MJ, Carr T, Connor JR, Tomaszek TA, Szewczuk L, Drake FH, Veber DF, Gowen M (1997) Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vitro and in vivo. J Bone Miner Res 12:1396–1406PubMedCrossRef

Title: High bone mineral density in pycnodysostotic patients with a novel mutation in the propeptide of cathepsin K
Authors: A. F. Schilling
C. Mülhausen
W. Lehmann
R. Santer
T. Schinke
J. M. Rueger
M. Amling
Publication date: 01-05-2007
Publisher: Springer-Verlag
Published in: Osteoporosis International / Issue 5/2007
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-006-0311-y

2024 ASCO Annual Meeting

Springer Medicine

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

Abstract

Introduction

Methods

Results

Conclusion

2024 ASCO Annual Meeting

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

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