Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II

Mucolipidosis type II (MLII) is a severe multi‐systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we re...

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Bibliographic Details
Published in:EMBO molecular medicine 2013-12, Vol.5 (12), p.1871-1886
Main Authors: Kollmann, Katrin, Pestka, Jan Malte, Kühn, Sonja Christin, Schöne, Elisabeth, Schweizer, Michaela, Karkmann, Kathrin, Otomo, Takanobu, Catala‐Lehnen, Philip, Failla, Antonio Virgilio, Marshall, Robert Percy, Krause, Matthias, Santer, Rene, Amling, Michael, Braulke, Thomas, Schinke, Thorsten
Format: Article
Language:English
Subjects:
alendronate
Animals
Bone and Bones - drug effects
Bone and Bones - metabolism
Bone and Bones - pathology
Bone Density Conservation Agents - pharmacology
Bone Development - genetics
Bone growth
Bone loss
Bone mass
Bone resorption
Bones
Cancellous bone
Cells, Cultured
Child, Preschool
Chondrocytes
Chondrocytes - cytology
Chondrocytes - metabolism
Chondrocytes - pathology
Cortical bone
Cytokines
Defects
Diphosphonates - pharmacology
Disease Models, Animal
Enzymes
Experiments
Female
Genetic disorders
Genotype & phenotype
Growth plate
Humans
Interleukin-6 - metabolism
interleukin‐6
Macromolecules
mannose 6‐phosphate
Mice
Mice, Inbred C57BL
Mucolipidoses - diagnostic imaging
Mucolipidoses - genetics
Mucolipidoses - pathology
Mucolipidosis
mucolipidosis II
Mutation
Osteoblasts
Osteoclastogenesis
Osteoclasts
Osteoclasts - cytology
Osteoclasts - metabolism
Osteoclasts - pathology
Osteogenesis
Osteoporosis
Phenotypes
Phenotyping
Porosity
Proteins
Radiography
RANK Ligand - metabolism
Storage diseases
Transferases (Other Substituted Phosphate Groups) - genetics
Transferases (Other Substituted Phosphate Groups) - metabolism
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Summary:Mucolipidosis type II (MLII) is a severe multi‐systemic genetic disorder caused by missorting of lysosomal proteins and the subsequent lysosomal storage of undegraded macromolecules. Although affected children develop disabling skeletal abnormalities, their pathogenesis is not understood. Here we report that MLII knock‐in mice, recapitulating the human storage disease, are runted with accompanying growth plate widening, low trabecular bone mass and cortical porosity. Intralysosomal deficiency of numerous acid hydrolases results in accumulation of storage material in chondrocytes and osteoblasts, and impaired bone formation. In osteoclasts, no morphological or functional abnormalities are detected whereas osteoclastogenesis is dramatically increased in MLII mice. The high number of osteoclasts in MLII is associated with enhanced osteoblastic expression of the pro‐osteoclastogenic cytokine interleukin‐6, and pharmacological inhibition of bone resorption prevented the osteoporotic phenotype of MLII mice. Our findings show that progressive bone loss in MLII is due to the presence of dysfunctional osteoblasts combined with excessive osteoclastogenesis. They further underscore the importance of a deep skeletal phenotyping approach for other lysosomal diseases in which bone loss is a prominent feature. Dysfunctional osteoblasts and the Il‐6‐driven osteoclast increase rather than lysosomal hydrolase missorting underlie the osteoporotic phenotype in a mouse model of mucolipidosis II. Bisphosphonate treatment increased bone density and stabilization.
ISSN:1757-4676
1757-4684
DOI:10.1002/emmm.201302979