title: Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I.
abstract: Mucopolysaccharidosis-I (MPS-I) is a lysosomal storage disease (LSD) caused by inactivating mutations of IDUA, encoding the glycosaminoglycan-degrading enzyme α-l-iduronidase. Although MPS-I is associated with skeletal abnormalities, the impact of IDUA deficiency on bone remodeling is poorly defined. Here we report that Idua-deficient mice progressively develop a high bone mass phenotype with pathological lysosomal storage in cells of the osteoblast lineage. Histomorphometric quantification identified shortening of bone-forming units and reduced osteoclast numbers per bone surface. This phenotype was not transferable into wild-type mice by bone marrow transplantation (BMT). In contrast, the high bone mass phenotype of Idua-deficient mice was prevented by BMT from wild-type donors. At the cellular level, BMT did not only normalize defects of Idua-deficient osteoblasts and osteocytes but additionally caused increased osteoclastogenesis. Based on clinical observations in an individual with MPS-I, previously subjected to BMT and enzyme replacement therapy (ERT), we treated Idua-deficient mice accordingly and found that combining both treatments normalized all histomorphometric parameters of bone remodeling. Our results demonstrate that BMT and ERT profoundly affect skeletal remodeling of Idua-deficient mice, thereby suggesting that individuals with MPS-I should be monitored for their bone remodeling status, before and after treatment, to avoid long-term skeletal complications.
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Sonja C
authors.initials: SC
authors.lastname: Kuehn
authors.affiliation: Department of Osteology and Biomechanics, Department of Orthodontics.
authors.forename: Till
authors.initials: T
authors.lastname: Koehne
authors.affiliation: Department of Stem Cell Transplantation, Research Department Cell and Gene Therapy.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Cornils
authors.affiliation: Children's Hospital, Department of Biochemistry, and.
authors.forename: Sandra
authors.initials: S
authors.lastname: Markmann
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Christoph
authors.initials: C
authors.lastname: Riedel
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Pestka
authors.affiliation: Center of Molecular Neurobiology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany and.
authors.forename: Michaela
authors.initials: M
authors.lastname: Schweizer
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Christina
authors.initials: C
authors.lastname: Baldauf
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Timur A
authors.initials: TA
authors.lastname: Yorgan
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Matthias
authors.initials: M
authors.lastname: Krause
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Johannes
authors.initials: J
authors.lastname: Keller
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Mona
authors.initials: M
authors.lastname: Neven
authors.affiliation: Children's Hospital Hamburg-Altona, Department of Orthopedics, University Clinic Hamburg, Hamburg 22763, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Breyer
authors.affiliation: Children's Hospital Hamburg-Altona, Department of Orthopedics, University Clinic Hamburg, Hamburg 22763, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Stuecker
authors.affiliation: Children's Hospital, Department of Biochemistry, and.
authors.forename: Nicole
authors.initials: N
authors.lastname: Muschol
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Busse
authors.affiliation: Children's Hospital, Department of Biochemistry, and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Braulke
authors.affiliation: Department of Stem Cell Transplantation, Research Department Cell and Gene Therapy.
authors.forename: Boris
authors.initials: B
authors.lastname: Fehse
authors.affiliation: Department of Osteology and Biomechanics.
authors.forename: Michael
authors.initials: M
authors.lastname: Amling
authors.affiliation: Department of Osteology and Biomechanics, schinke@uke.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schinke
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D016723:Bone Remodeling; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D005260:Female; D006801:Humans; D007068:Iduronidase / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008059:Mucopolysaccharidosis I / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D010010:Osteoclasts / Q000201:enzymology
chemical_list: D007068:Iduronidase