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(American Journal of Pathology. 2005;167:1341-1348.)
© 2005 American Society for Investigative Pathology

Osteoclasts from Patients with Autosomal Dominant Osteopetrosis Type I Caused by a T253I Mutation in Low-Density Lipoprotein Receptor-Related Protein 5 Are Normal in Vitro, but Have Decreased Resorption Capacity in Vivo

Kim Henriksen*, Jeppe Gram{dagger}, Pernille Høegh-Andersen*, Rune Jemtland{ddagger}, Thor Ueland§, Morten H. Dziegiel, Sophie Schaller*, Jens Bollerslev{ddagger} and Morten A. Karsdal*

From Pharmos Bioscience,* Nordic Bioscience and Center for Clinical and Basic Research A/S, Herlev, Denmark; Ribe County Hospital,{dagger} Esbjerg, Denmark; Hovedstadens Sygehusfællesskab Blodbank, The University Hospital of Copenhagen, Copenhagen, Denmark; and the Section of Medical Endocrinology{ddagger} and the Department of Medicine,§ Research Institute, National University Hospital, Oslo, Norway

Autosomal dominant osteopetrosis type I (ADOI) is presumably caused by gain-of-function mutations in the LRP5 gene. Patients with a T253I mutation in LRP5 have a high bone mass phenotype, characterized by increased mineralizing surface index but abnormally low numbers of small osteoclasts. To investigate the effect of the T253I mutation in LRP5 on osteoclasts, we isolated CD14+ monocytes from ADOI patients and assessed their ability to generate osteoclasts when treated with RANKL and M-CSF compared to that of age- and sex-matched control osteoclasts. We found normal osteoclastogenesis, expression of osteoclast markers, morphology, and localization of proteins involved in bone resorption, such as ClC-7 and cathepsin K. The ability to resorb bone was also normal. In vivo, we compared the bone resorption and bone formation response to T3 in ADOI patients and age- and sex-matched controls. We found attenuated resorptive response to T3 stimulation, despite a normal bone formation response, in alignment with the reduced number of osteoclasts in vivo. These data demonstrate that ADOI osteoclasts are normal with respect to all aspects investigated in vitro. We speculate that the mutations causing ADOI alter the osteoblastic phenotype toward a smaller potential for supporting osteoclastogenesis.




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S. G. Waguespack, S. L. Hui, L. A. DiMeglio, and M. J. Econs
Autosomal Dominant Osteopetrosis: Clinical Severity and Natural History of 94 Subjects with a Chloride Channel 7 Gene Mutation
J. Clin. Endocrinol. Metab., March 1, 2007; 92(3): 771 - 778.
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