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

TY - JOUR

T1 - 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

AU - Henriksen, Kim

AU - Gram, Jeppe

AU - Høegh-Andersen, Pernille

AU - Jemtland, Rune

AU - Ueland, Thor

AU - Dziegiel, Morten Hanefeld

AU - Schaller, Sophie

AU - Bollerslev, Jens

AU - Karsdal, Morten A

PY - 2005/11

Y1 - 2005/11

N2 - 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.

AB - 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.

KW - Adult

KW - Amino Acid Substitution

KW - Antigens, CD14

KW - Bone Resorption

KW - Carrier Proteins

KW - Cell Differentiation

KW - Female

KW - Genes, Dominant

KW - Humans

KW - LDL-Receptor Related Proteins

KW - Low Density Lipoprotein Receptor-Related Protein-5

KW - Macrophage Colony-Stimulating Factor

KW - Male

KW - Membrane Glycoproteins

KW - Middle Aged

KW - Monocytes

KW - Mutation

KW - Osteoclasts

KW - Osteopetrosis

KW - RANK Ligand

KW - Receptor Activator of Nuclear Factor-kappa B

U2 - 10.1016/S0002-9440(10)61221-7

DO - 10.1016/S0002-9440(10)61221-7

M3 - Journal article

C2 - 16251418

SN - 0002-9440

VL - 167

SP - 1341

EP - 1348

JO - American Journal of Pathology

JF - American Journal of Pathology

IS - 5

ER -