title: Decreased bone formation and increased osteoclastogenesis cause bone loss in mucolipidosis II.
abstract: 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.
authors.affiliation: Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Kollmann
authors.forename: Jan Malte
authors.initials: JM
authors.lastname: Pestka
authors.forename: Sonja Christin
authors.initials: SC
authors.lastname: Kühn
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schöne
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.forename: Kathrin
authors.initials: K
authors.lastname: Karkmann
authors.forename: Takanobu
authors.initials: T
authors.lastname: Otomo
authors.forename: Philip
authors.initials: P
authors.lastname: Catala-Lehnen
authors.forename: Antonio Virgilio
authors.initials: AV
authors.lastname: Failla
authors.forename: Robert Percy
authors.initials: RP
authors.lastname: Marshall
authors.forename: Matthias
authors.initials: M
authors.lastname: Krause
authors.forename: Rene
authors.initials: R
authors.lastname: Santer
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001846:Bone Development / Q000235:genetics; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D002675:Child, Preschool; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D004164:Diphosphonates / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009081:Mucolipidoses / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D053245:RANK Ligand / Q000378:metabolism; D011859:Radiography; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D015850:Interleukin-6; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D017855:Transferases (Other Substituted Phosphate Groups); C548056:GNPTAB protein, mouse
keywords: alendronate; interleukin-6; mannose 6-phosphate; mucolipidosis II; osteoclastogenesis