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
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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. / Henriksen, Kim; Gram, Jeppe; Høegh-Andersen, Pernille; Jemtland, Rune; Ueland, Thor; Dziegiel, Morten Hanefeld; Schaller, Sophie; Bollerslev, Jens; Karsdal, Morten A.
In: American Journal of Pathology, Vol. 167, No. 5, 11.2005, p. 1341-8.Research output: Contribution to journal › Journal article › Research › peer-review
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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
VL - 167
SP - 1341
EP - 1348
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 5
ER -
ID: 47557155