Parathyroid hormone-related protein (PTHrP) action in rat articular chondrocytes: comparison of PTH(1–34), PTHrP(1–34), PTHrP(1–141), PTHrP(100–114) and antisense oligonucleotides against PTHrP

1996 ◽  
Vol 150 (3) ◽  
pp. 359-368 ◽  
Author(s):  
T Tsukazaki ◽  
A Ohtsuru ◽  
H Namba ◽  
J Oda ◽  
K Motomura ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Dna Synthesis ◽  
Antisense Oligonucleotides ◽  
Articular Chondrocytes ◽  
Type Ii Collagen ◽  
Type Ii ◽  
Related Protein ◽  
Collagen Mrna ◽  
Parathyroid Hormone Related Protein ◽  
Significant Difference

Abstract Parathyroid hormone-related protein (PTHrP) is thought to be an important autocrine/paracrine factor for chondrocyte metabolism since mice lacking the PTHrP gene exhibit abnormal cartilage development. To determine the biological role of PTHrP in chondrocytes, we first compared the agonist potency of human (h) PTHrP(1–34) with hPTH(1–34) in cultured rat articular chondrocytes. Neither hPTHrP(1–34) nor hPTH(1–34) altered basal DNA synthesis, but attenuated the stimulatory effect of transforming growth factor β (TGF-β). Both agents suppressed the expression of α(1) type II collagen mRNA in a dose–response fashion with the same potency. In addition, the action of exogenously added hPTHrP(1–34) and hPTH(1–34) on intracellular cAMP and [Ca2+]i levels was similar. We next compared the effect of PTHrP within its entire amino acid sequence (1–141). With regard to thymidine incorporation, α(1) type II collagen gene expression and accumulation of cAMP and [Ca2+]i level, there was no significant difference between hPTHrP(1–34) and hPTHrP(1–141). PTHrP C-terminal (100–114) did not show any function. To further investigate PTHrP function, intracellular PTHrP translation was inhibited by a transgene of antisense oligonucleotides against PTHrP. Antisense oligonucleotides decreased PTHrP mRNA translation, specifically inhibited DNA synthesis in control as well as TGF-β-treated chondrocytes and enhanced α(1) type II collagen mRNA expression in TGF-β-treated chondrocytes. These results suggest that there is no significant difference between exogenously added hPTH(1–34), hPTHrP(1–34) and PTHrP(1–141) with regard to the biological action of these agents, including cell growth, differentiation and second messenger pathway. However, the result of DNA synthesis in the antisense PTHrP-inhibition study suggests that intracellular PTHrP may have an as yet unknown biological role, in addition to a classical PTH/PTHrP receptor-mediated function in the rat articular chondrocyte. Journal of Endocrinology (1996) 150, 359–368

Parathyroid Hormone-Related Protein-Induced Hypercalcemia in SCID Mice Engrafted With Adult T-Cell Leukemia Cells

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4747-4751 ◽  
Author(s):  
Akifumi Takaori-Kondo ◽  
Kazunori Imada ◽  
Itsuo Yamamoto ◽  
Akane Kunitomi ◽  
Yasuharu Numata ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
T Cell ◽  
Scid Mice ◽  
T Cell Leukemia ◽  
Related Protein ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Significant Difference

Abstract Parathyroid hormone-related protein (PTHrP) is considered to be one of the main causes of hypercalcemia associated with adult T-cell leukemia (ATL). To clarify the role of PTHrP and bone remodeling in the development of hypercalcemia in ATL, we examined the SCID mouse model of ATL that has previously been shown to mimic the disease in humans. Using this model, we found clear elevations in serum levels of calcium and C-terminal PTHrP (C-PTHrP). PTHrP mRNA was highly expressed in ATL cells proliferating in vivo. After the development of hypercalcemia, ATL mice were killed and bone histomorphometric analysis was performed. Bone volume was clearly decreased in the ATL mice. In comparison to control SCID mice, bone formation indices were very low in the ATL mice. Surprisingly, no significant difference was detected between the ATL mice and the control SCID mice in eroded surface/bone surface (ES/BS), a parameter of bone resorption. To our knowledge, the model presented here is the first animal model of ATL with humoral hypercalcemia. This is in contrast to previously reported, well-characterized animal models of human solid tumors associated with humoral hypercalcemia of malignancy (HHM). Furthermore, this model not only provides us with the opportunity to study the mechanisms underlying development of elevated calcium levels in ATL, but also allows us to test new therapeutic agents designed to treat hypercalcemia.

Parathyroid Hormone-Related Protein-Induced Hypercalcemia in SCID Mice Engrafted With Adult T-Cell Leukemia Cells

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4747-4751 ◽  
Author(s):  
Akifumi Takaori-Kondo ◽  
Kazunori Imada ◽  
Itsuo Yamamoto ◽  
Akane Kunitomi ◽  
Yasuharu Numata ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
T Cell ◽  
Scid Mice ◽  
T Cell Leukemia ◽  
Related Protein ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Humoral Hypercalcemia ◽  
Parathyroid Hormone Related Protein ◽  
Significant Difference

Parathyroid hormone-related protein (PTHrP) is considered to be one of the main causes of hypercalcemia associated with adult T-cell leukemia (ATL). To clarify the role of PTHrP and bone remodeling in the development of hypercalcemia in ATL, we examined the SCID mouse model of ATL that has previously been shown to mimic the disease in humans. Using this model, we found clear elevations in serum levels of calcium and C-terminal PTHrP (C-PTHrP). PTHrP mRNA was highly expressed in ATL cells proliferating in vivo. After the development of hypercalcemia, ATL mice were killed and bone histomorphometric analysis was performed. Bone volume was clearly decreased in the ATL mice. In comparison to control SCID mice, bone formation indices were very low in the ATL mice. Surprisingly, no significant difference was detected between the ATL mice and the control SCID mice in eroded surface/bone surface (ES/BS), a parameter of bone resorption. To our knowledge, the model presented here is the first animal model of ATL with humoral hypercalcemia. This is in contrast to previously reported, well-characterized animal models of human solid tumors associated with humoral hypercalcemia of malignancy (HHM). Furthermore, this model not only provides us with the opportunity to study the mechanisms underlying development of elevated calcium levels in ATL, but also allows us to test new therapeutic agents designed to treat hypercalcemia.

Parathyroid hormone-related protein-(38–64) regulates lung cell proliferation after silica injury

2002 ◽  
Vol 283 (1) ◽  
pp. L12-L21 ◽  
Author(s):  
Randolph H. Hastings ◽  
Angela Asirvatham ◽  
Rick Quintana ◽  
Rebeca Sandoval ◽  
Ruchika Dutta ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Parathyroid Hormone ◽  
Lung Injury ◽  
Nuclear Antigen ◽  
Alveolar Type ◽  
Type Ii Cells ◽  
Type Ii ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Type Ii Cell

Inhalation of silica leads to acute lung injury and alveolar type II cell proliferation. Type II cell proliferation after hyperoxic lung injury is regulated, in part, by parathyroid hormone-related protein (PTHrP). In this study, we investigated lung PTHrP and its effects on epithelial proliferation after injury induced by silica. Lung PTHrP decreased modestly 4 days after we instilled 10 mg of silica into rat lungs and then recovered from 4 to 28 days. The number of proliferating cell nuclear antigen (PCNA)-positive type II cells was increased threefold in silica-injured lungs compared with controls. Subsequently, rats were treated with four exogenous PTHrP peptides in the silica instillate, which were administered subcutaneously daily. One peptide, PTHrP-(38–64), had consistent and significant effects on cell proliferation. PTHrP-(38–64) increased the median number of PCNA-positive cells/field nearly fourfold above controls, 380 vs. 109 ( P < 0.05). Thymidine incorporation was 2.5 times higher in type II cells isolated from rats treated with PTHrP-(38–64) compared with PBS. PTHrP-(38–64) significantly increased the number of cells expressing alkaline phosphatase, a type II cell marker. This study indicates that PTHrP-(38–64) stimulates type II cell growth and may have a role in lung repair in silica-injured rats.

Parathyroid hormone-related protein response to hyperoxic lung injury

2002 ◽  
Vol 282 (6) ◽  
pp. L1198-L1208 ◽  
Author(s):  
Randolph H. Hastings ◽  
Rita M. Ryan ◽  
Carl T. D'Angio ◽  
Bruce A. Holm ◽  
Alka Patel ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Parathyroid Hormone ◽  
Lung Injury ◽  
Growth Inhibitor ◽  
Alveolar Type ◽  
Type Ii ◽  
Related Protein ◽  
Adult Rats ◽  
Parathyroid Hormone Related Protein ◽  
Type Ii Cell

Parathyroid hormone-related protein (PTHrP) is a growth inhibitor for alveolar type II cells. Type II cell proliferation after lung injury from 85% oxygen is regulated, in part, by a fall in lung PTHrP. In this study, we investigated lung PTHrP after injury induced by >95% oxygen in rats and rabbits. In adult rats, lung PTHrP rose 10-fold over controls to 6,356 ± 710 pg/ml (mean ± SE) at 48 h of hyperoxia. Levels fell to 299 ± 78 pg/ml, and staining for PTHrP mRNA was greatly reduced at 60 h ( P < 0.05), the point of most severe injury and greatest pneumocyte proliferation. In adult rabbits, lung PTHrP peaked at 3,289 ± 230 pg/ml after 64 h of hyperoxia with 24 h of normoxic recovery and then dropped to 1,629 ± 153 pg/ml at 48 h of recovery ( P < 0.05). Type II cell proliferation peaked shortly after the fall in PTHrP. In newborn rabbits, lavage PTHrP increased by 50% during the first 8 days of hyperoxia, whereas type II cell growth decreased. PTHrP declined at the LD50, concurrent with increased type II cell division. In summary, lung PTHrP initially rises after injury with >95% hyperoxia and then falls near the peak of injury. Changes in PTHrP are temporally related to type II cell proliferation and may regulate repair of lung injury.

Proapoptotic Effects of Parathyroid Hormone-Related Protein in Type II Pneumocytes

2003 ◽  
Vol 29 (6) ◽  
pp. 733-742 ◽  
Author(s):  
Randolph H. Hastings ◽  
Rick A. Quintana ◽  
Rebeca Sandoval ◽  
Devin Duey ◽  
Yvette Rascon ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Type Ii ◽  
Related Protein ◽  
Parathyroid Hormone Related Protein ◽  
Type Ii Pneumocytes
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