Tissue-Specific Targeting of the Pthrp Gene: The Generation of Mice with Floxed Alleles

He, Billy Haitian

doi:10.1210/en.142.5.2070

Cited by 22 publications

(29 citation statements)

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“…In vivo, these sequences were reported to confer nearly exclusive specificity of expression of the transgene in osteoblasts (27). This was confirmed here when the Cre ColI transgenic mice were crossed with double-reporter Z/AP mice (28), which provide a convenient and reliable readout of Cre recombinase activity.…”

Section: Pthrp Haploinsufficiency Causes Osteopenia By Decreasing Bonsupporting

confidence: 62%

“…To generate mice with osteoblasts lacking Pthrp (Pthrp flox/flox ;cre ColI mice), Pthrp +/flox mice (with exon 3 of Pthrp flanked by loxP sites) carrying the Cre recombinase transgene under the control of the 2.3-kb fragment of the murine pro-α1(I) collagen gene promoter (colI) were crossed with mice homozygous for the floxed Pthrp allele (27). To genotype mice, floxed Pthrp and Cre were detected by Southern blot analysis of tail-tip genomic DNA, as previously described (27).…”

Section: Methodsmentioning

confidence: 99%

“…Matings between mice homozygous for a "floxed" Pthrp allele, i.e., exon 3 flanked by 2 loxP sites (Pthrp flox/flox mice) (27), and Cre ColI transgenic mice, gave rise to Pthrp flox/flox animals carrying the Cre ColI transgene (Pthrp flox/flox ;cre ColI mice) ( Figure 2C). The nearly complete absence of PTHrP expression in osteoblasts and osteocytes due to Cre recombinase excisional activity was demonstrated by lack of immunostaining in these cells, while PTHrP immunoreactivity was preserved in growth plate chondrocytes ( Figure 2D).…”

Section: Pthrp Haploinsufficiency Causes Osteopenia By Decreasing Bonmentioning

confidence: 99%

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Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34

Miao

He²,

Jiang³

et al. 2005

Journal of Clinical Investigation

255

192

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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.

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Section: Pthrp Haploinsufficiency Causes Osteopenia By Decreasing Bonsupporting

confidence: 62%

Section: Methodsmentioning

confidence: 99%

Section: Pthrp Haploinsufficiency Causes Osteopenia By Decreasing Bonmentioning

confidence: 99%

See 1 more Smart Citation

Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34

Miao

He²,

Jiang³

et al. 2005

Journal of Clinical Investigation

255

192

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“…To investigate the involvement of PTHrP in breast cancer initiation, progression, and metastasis, we constructed an ME-specific Pthrpknockout animal in the PyMT-MMTV transgenic mouse model of breast tumorigenesis, using mice homozygous for a floxed Pthrp allele (2 loxP sites flanking exon 4, which encodes most of the PTHrP protein) (38). The PyMT mouse is a model with complete penetrance and approximates the 4 identifiable stages of tumor progression observed in human breast tumors (hyperplasia, adenoma, early carcinoma, and late carcinoma).…”

Section: Discussionmentioning

confidence: 99%

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Li¹,

Karaplis²,

Huang³

et al. 2011

J. Clin. Invest.

114

118

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Parathyroid hormone-related protein (PTHrP) is a secreted factor expressed in almost all normal fetal and adult tissues. It is involved in a wide range of developmental and physiological processes, including serum calcium regulation. PTHrP is also associated with the progression of skeletal metastases, and its dysregulated expression in advanced cancers causes malignancy-associated hypercalcemia. Although PTHrP is frequently expressed by breast tumors and other solid cancers, its effects on tumor progression are unclear. Here, we demonstrate in mice pleiotropic involvement of PTHrP in key steps of breast cancer -it influences the initiation and progression of primary tumors and metastases. Pthrp ablation in the mammary epithelium of the PyMT-MMTV breast cancer mouse model caused a delay in primary tumor initiation, inhibited tumor progression, and reduced metastasis to distal sites. Mechanistically, it reduced expression of molecular markers of cell proliferation (Ki67) and angiogenesis (factor VIII), antiapoptotic factor Bcl-2, cell-cycle progression regulator cyclin D1, and survival factor AKT1. PTHrP also influenced expression of the adhesion factor CXCR4, and coexpression of PTHrP and CXCR4 was crucial for metastatic spread. Importantly, PTHrP-specific neutralizing antibodies slowed the progression and metastasis of human breast cancer xenografts. Our data identify what we believe to be new functions for PTHrP in several key steps of breast cancer and suggest that PTHrP may constitute a novel target for therapeutic intervention.

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“…The technology for generating such a conditional knockout could be based on the Cre/LoxP sitespecific recombination system (22). Although mice with floxed PTHrP alleles have recently been generated (23), mouse strains that specifically express Cre-recombinase in vascular cells seem difficult to generate and are not yet available.…”

mentioning

confidence: 99%

Intravenous Delivery of PTH/PTHrP Type 1 Receptor cDNA to Rats Decreases Heart Rate, Blood Pressure, Renal Tone, Renin Angiotensin System, and Stress-Induced Cardiovascular Responses

Fritsch

Lindner²,

Welsch³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. While parathyroid hormone type 1 receptor (PTH1R)-mediated vasodilatory, cardiac stimulatory, and renin-activating effects of exogenous PTH/PTH-related protein (PTHrP) are acknowledged, interactions of endogenous PTHrP with these systems remain unclear, mainly because the unavailability of viable PTHrP/PTH1R knockout mice. Transgenic mice overexpressing PTH1R in smooth muscle strongly have supported the PTHrP/PTH1R system as a cardiovascular system (CVS) regulator, but the consequences on renovascular (RVS) and renin-angiotensin systems (RAS) have not been explored in these studies. The aim was to develop a model in which one could study the consequences on CVS, RVS, and RAS of generalized PTH1R overexpression. Systemic PTH1R cDNA plasmid delivery was used in adult rats, a system that is amenable to studies in isolated perfused kidneys and that minimizes development-induced compensatory mechanisms. Intravenous administration of hPTH1R or green fluorescence protein-tagged hPTH1R in pcDNA3 resulted 3 wk later, in generalized expression of hPTH1R (mRNA and protein), especially in vessels, liver, heart, kidney, and central nervous system, where it is expressed physiologically. As expected, PTH1R overexpression decreased BP and renal tone. Unexpected, however, PTH1R overexpression decreased heart rate. These studies also revealed that endogenous PTHrP actually inhibits renin release and that hPTH1R overexpression tends to increase that effect. Striking, liver production and circulatory level of angiotensinogen and hence plasma renin activity were markedly reduced. Thus, abrupt PTH1R overexpression in adult rats profoundly alters the CVS, RVS, and RAS, strongly supporting the PTH/PTHrP/PTH1R system as crucial for heart and vascular tone regulation. In addition, these results revealed that PTH1R-mediated mechanisms might have protective effects against cardiovascular stress-induced responses, including stimulations in heart rate and RAS.

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Tissue-Specific Targeting of the Pthrp Gene: The Generation of Mice with Floxed Alleles

Cited by 22 publications

References 0 publications

Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34

Osteoblast-derived PTHrP is a potent endogenous bone anabolic agent that modifies the therapeutic efficacy of administered PTH 1-34

PTHrP drives breast tumor initiation, progression, and metastasis in mice and is a potential therapy target

Intravenous Delivery of PTH/PTHrP Type 1 Receptor cDNA to Rats Decreases Heart Rate, Blood Pressure, Renal Tone, Renin Angiotensin System, and Stress-Induced Cardiovascular Responses

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