Subscribe to RSS
DOI: 10.1055/s-0037-1619909
Human recessive osteopetrosis
New understanding of osteoclast function through molecular and functional analysis of a rare genetic bone diseaseHumane rezessive OsteopetroseNeue Erkenntnisse zur Osteoklastenfunktion durch die molekulare und funktionale Analyse einer seltenen genetischen Knochenkrankheit The authors wish to acknowledge funding from the European Calcified Tissue Society (a PhD studentship and exchange grant to BP and a career development award to MH) and from the Chief Scientist Office of the Scottish Executive (grant CZB/4/495 to MH and FC) for their work in this area. We also thank expert technical assistance from John Greenhorn, Kevin Mackenzie and Tabitha Schouten with the microscopical imaging shown.Publication History
received:
22 September 2009
accepted:
30 September 2009
Publication Date:
30 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00034914/200904/lookinside/thumbnails/10-1055-s-0037-1619909_de-1.jpg)
Summary
Osteopetrosis is an inherited high bone mass condition resulting from reduced osteoclast activity. Over the past ten years, many of the genes mutated in the various forms of osteopetrosis have been identified. It has become clear that there are not only dominant and recessive forms, but also that within the recessive forms subsets exist, classified as osteoclast-rich and osteoclast-poor. Here, we review the different genetic mutations that are known to cause osteopetrosis and then focus specifically on recessive types of the disease. We will illustrate how not only genetic analysis is important, but also that functional osteoclast assays in the laboratory, combined with bone histology, can help to come to a precise diagnosis. We then discuss how this rare condition has led to new insights in the complex process of bone resorption by osteoclasts. Our story is one of bedside to bench and back again.
Zusammenfassung
Bei der Osteopetrose handelt es sich um eine erblich bedingte erhebliche Zunahme der Knochenmasse infolge einer verminderten Osteoklastenaktivität. In den vergangenen zehn Jahren wurde eine Reihe von Genmutationen bei den verschiedenen Osteopetrose-Formen identifiziert. Es wurde klar, dass es nicht nur dominant und rezessiv vererbte Formen gibt, sondern dass innerhalb der rezessiven Formen Untergruppen existieren, die als osteoklastenreich und osteoklastenarm klassifiziert werden. In diesem Übersichtsartikel werden die verschiedenen bei Osteopetrose bekannten Genmutationen, mit besonderer Berücksichtigung der rezessiven Erkrankungsformen, dargestellt. Es wird gezeigt, dass nicht nur die genetische Analyse von Bedeutung ist, sondern dass auch ein funktionales Osteoklasten-Assay im Labor, kombiniert mit einer histologischen Untersuchung der Knochen, eine exakte Diagnosestellung erleichtern kann. Anschließend wird diskutiert, wie diese seltene Erkrankung zu neuen Einblicken in den komplexen Prozess der Knochenresorption durch Osteoklasten geführt hat. Es ist die Geschichte einer Entwicklung von der Klinik zur Molekulargenetik und wieder zurück.
-
References
- 1 Steward CG. Neurological aspects of osteopetrosis. Neuropathol Appl Neurobiol 2003; 29: 87-97.
- 2 Benichou OD, Laredo JD, de Vernejoul MC. Type II autosomal dominant osteopetrosis (Albers-Schönberg disease): clinical and radiological manifestations in 42 patients. Bone 2000; 26: 87-93.
- 3 Del Fattore A, Peruzzi B, Rucci N. et al. Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment. J Med Genet 2006; 43: 315-325.
- 4 Balemans W, Patel N, Ebeling M. et al. Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 2002; 39: 91-97.
- 5 Balemans W, Ebeling M, Patel N. et al. Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 2001; 10: 537-543.
- 6 Van Wesenbeeck L, Cleiren E, Gram J. et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet 2003; 72: 763-771.
- 7 Yadav VK, Ryu JH, Suda N. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 2008; 135: 825-837.
- 8 Cleiren E, Benichou O, Van Hul E. et al. Alber-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 2001; 10: 2861-2867.
- 9 Helfrich MH. Osteoclast diseases. Microsc Res Tech 2003; 61: 514-532.
- 10 Villa A, Guerrini MM, Cassani B. et al. Infantile malignant, autosomal recessive osteopetrosis: the rich and the poor. Calcif Tissue Int 2009; 84: 1-12.
- 11 Van Wesenbeeck L, Van Hul W. Lessons from osteopetrotic mutations in animals: impact on our current understanding of osteoclast biology. Crit Rev Eukaryot Gene Expr 2005; 15: 133-162.
- 12 Sly WS, Hewett-Emmett D, Whyte MP. et al. Carbonic anhydrase II deficiency identified as the primary defect in the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. Proc Natl Acad Sci U S A 1983; 80: 2752-2756.
- 13 Roth DE, Venta PJ, Tashian RE, Sly WS. Molecular basis of human carbonic anhydrase II deficiency. Proc Natl Acad Sci U S A 1992; 89: 1804-1808.
- 14 Hu PY, Ernst AR, Sly WS. et al. Carbonic anhydrase II deficiency: single-base deletion in exon 7 is the predominant mutation in Caribbean Hispanic patients. Am J Hum Genet 1994; 54: 602-608.
- 15 Frattini A, Orchard PJ, Sobacchi C. et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 2000; 25: 343-346.
- 16 Kornak U, Schulz A, Friedrich W. et al. Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet 2000; 09: 2059-2063.
- 17 Toyomura T, Oka T, Yamaguchi C. et al. Three subunit a isoforms of mouse vacuolar H(+)-ATPase. Preferential expression of the a3 isoform during osteoclast differentiation. J Biol Chem 2000; 275: 8760-8765.
- 18 Kornak U, Kasper D, Bosl MR. et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 2001; 104: 205-215.
- 19 Chalhoub N, Benachenhou N, Rajapurohitam V. et al. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med 2003; 09: 399-406.
- 20 Pangrazio A, Poliani PL, Megarbane A. et al. Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement. J Bone Miner Res 2006; 21: 1098-1105.
- 21 Lange PF, Wartosch L, Jentsch TJ. ClC-7 requires Ostm1 as a beta-subunit to support bone resorption and lysosomal function. Nature 2006; 440: 220-223.
- 22 Ramirez A, Faupel J, Goebel I. et al. Identification of a novel mutation in the coding region of the greylethal gene OSTM1 in human malignant infantile osteopetrosis. Hum Mutat 2004; 23: 471-476.
- 23 Van Wesenbeeck L, Odgren PR, Coxon FP. et al. Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans. J Clin Invest 2007; 117: 919-930.
- 24 Del Fattore A, Fornari R, Van WL. et al. A new heterozygous mutation (R714C) of the osteopetrosis gene, pleckstrin homolog domain containing family M (with run domain) member 1 (PLEKHM1), impairs vesicular acidification and increases TRACP secretion in osteoclasts. J Bone Miner Res 2008; 23: 380-391.
- 25 Sobacchi C, Frattini A, Guerrini MM. et al. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 2007; 39: 960-962.
- 26 Guerrini MM, Sobacchi C, Cassani B. et al. Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet 2008; 83: 64-76.
- 27 Helfrich MH, Aronson DC, Everts V. et al. Morphologic features of bone in human osteopetrosis. Bone 1991; 12: 411-419.
- 28 Karsdal MA, Martin TJ, Bollerslev J. et al. Are nonresorbing osteoclasts sources of bone anabolic activity?. J Bone Miner Res 2007; 22: 487-494.
- 29 Guerrini MM, Sobacchi C, Cassani B. et al. Human osteoclast-poor osteopetrosis with hypogamm-aglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet 2008; 83: 64-76.
- 30 Del Fattore A, Cappariello A, Teti A. Genetics, pathogenesis and complications of osteopetrosis. Bone 2008; 42: 19-29.
- 31 Teti A, Migliaccio S, Taranta A. et al. Mechanisms of osteoclast dysfunction in human osteopetrosis: abnormal osteoclastogenesis and lack of osteoclastspecific adhesion structures. J Bone Miner Res 1999; 14: 2107-2117.
- 32 Blair HC, Yaroslavskiy BB, Robinson LJ. et al. Osteopetrosis with micro-lacunar resorption because of defective integrin organization. Lab Invest 2009; 89: 1007-1017.
- 33 Walker DG. Osteopetrosis cured by temporary parabiosis. Science 1973; 180: 875.
- 34 Walker DG. Bone resorption restored in osteopetrotic mice by transplants of normal bone marrow and spleen cells. Science 1975; 190: 784-785.
- 35 Coccia PF, Krivit W, Cervenka J. et al. Successful bone-marrow transplantation for infantile malignant osteopetrosis. N Engl J Med 1980; 302: 701-708.
- 36 Gelb BD, Shi GP, Chapman HA, Desnick RJ. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 1996; 273: 1236-1238.
- 37 Gauthier JY, Chauret N, Cromlish W. et al. The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K. Bioorg Med Chem Lett 2008; 18: 923-928.
- 38 Schaller S, Henriksen K, Sorensen MG, Karsdal MA. The role of chloride channels in osteoclasts: ClC-7 as a target for osteoporosis treatment. Drug News Perspect 2005; 18: 489-495.
- 39 Sørensen MG, Henriksen K, Neutzsky-Wulff AV. et al. Diphyllin, a novel and naturally potent V-ATPase inhibitor, abrogates acidification of the osteoclastic resorption lacunae and bone resorption. J Bone Miner Res 2007; 22: 1640-1648.
- 40 Rivollier A, Mazzorana M, Tebib J. et al. Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment. Blood 2004; 104: 4029-4037.