Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I

TY - JOUR

T1 - Impaired bone remodeling and its correction by combination therapy in a mouse model of mucopolysaccharidosis-I

AU - Kühn, Sonja Christin

AU - Koehne, Till

AU - Cornils, Kerstin

AU - Markmann, Sandra

AU - Riedel , Christoph

AU - Pestka, Jan M

AU - Schweizer, Michaela

AU - Baldauf, Christina

AU - Yorgan, Timur A

AU - Krause, Matthias

AU - Keller, Johannes

AU - Neven, Mona

AU - Breyer, Sandra

AU - Stücker, Ralf

AU - Muschol, Nicole

AU - Busse, Bjoern

AU - Braulke, Thomas

AU - Fehse, Boris

AU - Amling, Michael

AU - Schinke, Thorsten

N1 - © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2015/12/15

Y1 - 2015/12/15

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddv407

DO - 10.1093/hmg/ddv407

M3 - SCORING: Journal article

C2 - 26427607

VL - 24

SP - 7075

EP - 7086

JO - HUM MOL GENET

JF - HUM MOL GENET

SN - 0964-6906

IS - 24

ER -