title: 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.
abstract: 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.
authors.affiliation: Pharmos Bioscience A/S, Herlev Hovedgade 207, Herlev, DK-2730, Ribe County Hospital, Esbjerg, and the University Hospital of Copenhagen, Denmark. kh@nordicbioscience.com
authors.forename: Kim
authors.initials: K
authors.lastname: Henriksen
authors.forename: Jeppe
authors.initials: J
authors.lastname: Gram
authors.forename: Pernille
authors.initials: P
authors.lastname: Høegh-Andersen
authors.forename: Rune
authors.initials: R
authors.lastname: Jemtland
authors.forename: Thor
authors.initials: T
authors.lastname: Ueland
authors.forename: Morten H
authors.initials: MH
authors.lastname: Dziegiel
authors.forename: Sophie
authors.initials: S
authors.lastname: Schaller
authors.forename: Jens
authors.initials: J
authors.lastname: Bollerslev
authors.forename: Morten A
authors.initials: MA
authors.lastname: Karsdal
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D001862:Bone Resorption / Q000503:physiopathology*; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics* / Q000502:physiology; D018950:Lipopolysaccharide Receptors / Q000032:analysis; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000494:pharmacology; D008875:Middle Aged; D009000:Monocytes; D009154:Mutation; D010010:Osteoclasts / Q000502:physiology*; D010022:Osteopetrosis / Q000235:genetics / Q000503:physiopathology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B
chemical_list: D002352:Carrier Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D018950:Lipopolysaccharide Receptors; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D016173:Macrophage Colony-Stimulating Factor