title: Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34.
abstract: 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.
authors.affiliation: Calcium Research Laboratory and Department of Medicine, Royal Victoria Hospital of the McGill University Health Centre, Montréal, Québec, Canada.
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
authors.forename: Bin
authors.initials: B
authors.lastname: He
authors.forename: Yebin
authors.initials: Y
authors.lastname: Jiang
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Maria A
authors.initials: MA
authors.lastname: Sorocéanu
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhao
authors.forename: Hanyi
authors.initials: H
authors.lastname: Su
authors.forename: Xinkang
authors.initials: X
authors.lastname: Tong
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.forename: Ajay
authors.initials: A
authors.lastname: Gupta
authors.forename: Harry K
authors.initials: HK
authors.lastname: Genant
authors.forename: Henry M
authors.initials: HM
authors.lastname: Kronenberg
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Karaplis
mesh_terms: 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
chemical_list: D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments