Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34.
Mice heterozygous for targeted disruption of Pthrp exhibit, by 3 months of age, diminished bone volume and skeletal microarchitectural changes indicative of advanced osteoporosis. Impaired bone formation arising from decreased BM precursor cell recruitment and increased apoptotic death of osteoblastic cells was identified as the underlying mechanism for low bone mass. The osteoporotic phenotype was recapitulated in mice with osteoblast-specific targeted disruption of Pthrp, generated using Cre-LoxP technology, and defective bone formation was reaffirmed as the underlying etiology. Daily administration of the 1-34 amino-terminal fragment of parathyroid hormone (PTH 1-34) to Pthrp+/- mice resulted in profound improvement in all parameters of skeletal microarchitecture, surpassing the improvement observed in treated WT littermates. These findings establish a pivotal role for osteoblast-derived PTH-related protein (PTHrP) as a potent endogenous bone anabolic factor that potentiates bone formation by altering osteoblast recruitment and survival and whose level of expression in the bone microenvironment influences the therapeutic efficacy of exogenous PTH 1-34.
Miao
Dengshun
D
Calcium Research Laboratory and Department of Medicine, Royal Victoria Hospital of the McGill University Health Centre, Montréal, Québec, Canada.
He
Bin
B
Jiang
Yebin
Y
Kobayashi
Tatsuya
T
Sorocéanu
Maria A
MA
Zhao
Jenny
J
Su
Hanyi
H
Tong
Xinkang
X
Amizuka
Norio
N
Gupta
Ajay
A
Genant
Harry K
HK
Kronenberg
Henry M
HM
Goltzman
David
D
Karaplis
Andrew C
AC
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015519:Bone Density; D001851:Bone Diseases, Metabolic / Q000235:genetics / Q000473:pathology; D001842:Bone and Bones / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism; D018390:Gene Targeting; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology*; D010024:Osteoporosis / Q000473:pathology / Q000503:physiopathology; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use
D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments