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D Yoon - One of the best experts on this subject based on the ideXlab platform.
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thymic pth increases after Thyroparathyroidectomy in c57bl kalwrij mice
Endocrinology, 2018Co-Authors: Maurizio Zangari, H Yoo, Ik Jae Shin, Larry J Suva, Bum Jun Kim, Ricky D Edmondson, Gareth J Morgan, D YoonAbstract:We previously reported a substantial correlation between serum parathyroid hormone (PTH) levels and the myeloma response to proteasome inhibition that suggests a crucial role for the PTH receptor 1 system in the control of myeloma tumor growth. While investigating the role of PTH in the antimyeloma effect, we observed the recovery of serum PTH levels after Thyroparathyroidectomy (TPTX). Although the presence of thymus-derived PTH has been reported previously, the existence or role of thymic PTH in the serum remains controversial. Here, TPTX was performed in 8- to 12-week-old C57BL/KaLwRij mice to delineate the potential source(s) for the recovery of serum PTH. Immediately after TPTX, the expected loss of measurable serum PTH was observed. Serum PTH levels recovered 3 to 4 weeks after TPTX. Thirteen endocrine organs from mice with recovered serum PTH were examined. The thymus from control mice expressed measurable and detectable Pth transcripts; however, the Pth transcript level was substantially elevated in tissue from TPTX mice. Western blot analysis of the thymus demonstrated a reproducible and distinct PTH band in thymus tissue that was significantly increased after TPTX. To directly confirm the identity of the distinct PTH band, immunoprecipitated proteins were isolated and subjected to tandem mass spectrometry. After fragmentation and direct peptide sequencing, PTH peptides PTH(1-13) and PTH(54-70), diagnostic for PTH, were identified. These data demonstrate that the murine thymus produces PTH and that after TPTX the thymus becomes the major source of serum PTH, compensating for the loss of the parathyroid glands and returning circulating PTH levels to normal.
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surgical Thyroparathyroidectomy prevents progression of 5tgm1 murine multiple myeloma in vivo
Journal of bone oncology, 2018Co-Authors: Maurizio Zangari, H Yoo, D Yoon, Ik Jae Shin, Larry J SuvaAbstract:The 5TGM1 multiple myeloma transplanted C57BL6/KaLwRij model recapitulates many disease features including monoclonal paraprotein production as well as the development of osteolytic bone lesions. Since a significant association between serum parathyroid hormone PTH variations, bone anabolism and myeloma progression in patients receiving proteasome inhibitors exists, this study investigated the effect of the PTH axis on murine myeloma development in vivo. C57BL6/KaLwRij myeloma-bearing mice underwent Thyroparathyroidectomy (TPTX) before and after 5TGM1 cell transplantation. TPTX significantly and permanently inhibited 5TGM1 myeloma cell engraftment and prevented multiple myeloma growth and progression. These data support the hypothesis that the PTH axis is an important mediator of myeloma bone disease.
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thymus derived pth tpth is increased after Thyroparathyroidectomy in c57bl6 kalwrij mice and modulates mouse sensitivity to 5tgm1 myeloma cell line
Blood, 2015Co-Authors: Maurizio Zangari, Larry J Suva, D YoonAbstract:We have previously reported a significant correlation between serum PTH levels and myeloma responses to proteasome inhibition and have recently demonstrated a crucial role for the parathyroid hormone receptor 1 (PTHR1) in vitro and in vivo. In this study the effect of abrogation of parathyroid-derived PTH was tested in 5TGM1 myeloma transplanted C57BL6/KaLwRij mice. To interrogate PTH activity in vivo, Thyroparathyroidectomy (TX-PTX) was performed on the C57BL6/KaLwRij mice before or after the transplantation of 5TGM1 cells. Surgical success was confirmed by the rapid loss of measureable circulating PTH. In TX-PTX mice bearing transplanted 5TGM1 tumors, serum PTH levels was noted to recover 3-4 weeks after surgery and to achieve levels consistently higher than baseline levels pre TX-PTX. These data raised the compelling possibility of an alternative PTH source. To determine the potential source of the recovered PTH levels, multiple organs were examined. Whole tissue lysates were analyzed by Western blot and revealed a faint but specific band from thymic tissue, as expected with no obvious bands detected in 13 other tissues investigated including the liver, lung, kidney, ovary and testis. In addition, murine PTH mRNA transcripts from thymus RNA were measured by Real-Time PCR, using a specifically designed primer set that spans exons 1 and 2, since intron 1 is >1kb. These primers specifically discriminate mRNA transcripts from genomic DNA and improve the assay sensitivity for the detection of PTH transcripts. Using these custom-designed primers, control thymus expressed measureable PTH mRNA transcripts that was significantly elevated in TX-PTX mice. Since the thymus is considerably bigger than the parathyroid glands, PTH was immunoprecipitated before performing Western blot analysis. Following immunoprecipitation, a distinct PTH protein band was observed from the thymus in both TX-PTX and control mice. These data suggest that the thymus is the major source of serum PTH in TX-PTX mice and that the organ can compensate for the loss of serum PTH from the parathyroid gland. We propose that thymus-derived PTH in the TX-PTX mouse may contribute to the control of the 5TGM1 murine myeloma model. Disclosures Zangari:University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding.
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thymus derived pth tpth is increased after Thyroparathyroidectomy in c57bl6 kalwrij mice and modulates mouse sensitivity to 5tgm1 myeloma cell line
Blood, 2015Co-Authors: Maurizio Zangari, H Yoo, Larry J Suva, D YoonAbstract:Abstract We have previously reported a significant correlation between serum PTH levels and myeloma responses to proteasome inhibition and have recently demonstrated a crucial role for the parathyroid hormone receptor 1 (PTHR1) in vitro and in vivo. In this study the effect of abrogation of parathyroid-derived PTH was tested in 5TGM1 myeloma transplanted C57BL6/KaLwRij mice. To interrogate PTH activity in vivo, Thyroparathyroidectomy (TX-PTX) was performed on the C57BL6/KaLwRij mice before or after the transplantation of 5TGM1 cells. Surgical success was confirmed by the rapid loss of measureable circulating PTH. In TX-PTX mice bearing transplanted 5TGM1 tumors, serum PTH levels was noted to recover 3-4 weeks after surgery and to achieve levels consistently higher than baseline levels pre TX-PTX. These data raised the compelling possibility of an alternative PTH source. To determine the potential source of the recovered PTH levels, multiple organs were examined. Whole tissue lysates were analyzed by Western blot and revealed a faint but specific band from thymic tissue, as expected with no obvious bands detected in 13 other tissues investigated including the liver, lung, kidney, ovary and testis. In addition, murine PTH mRNA transcripts from thymus RNA were measured by Real-Time PCR, using a specifically designed primer set that spans exons 1 and 2, since intron 1 is >1kb. These primers specifically discriminate mRNA transcripts from genomic DNA and improve the assay sensitivity for the detection of PTH transcripts. Using these custom-designed primers, control thymus expressed measureable PTH mRNA transcripts that was significantly elevated in TX-PTX mice. Since the thymus is considerably bigger than the parathyroid glands, PTH was immunoprecipitated before performing Western blot analysis. Following immunoprecipitation, a distinct PTH protein band was observed from the thymus in both TX-PTX and control mice. These data suggest that the thymus is the major source of serum PTH in TX-PTX mice and that the organ can compensate for the loss of serum PTH from the parathyroid gland. We propose that thymus-derived PTH in the TX-PTX mouse may contribute to the control of the 5TGM1 murine myeloma model. Disclosures Zangari: University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding.
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surgical control cure of 5tgm1 murine multiple myeloma model by Thyroparathyroidectomy
Clinical Lymphoma Myeloma & Leukemia, 2014Co-Authors: Maurizio Zangari, H Yoo, D YoonAbstract:The 5TGM1 transplanted C57BL6/KaLwRij mouse is widely used to study murine multiple myeloma development. It recapitulates many features of human multiple myeloma including monoclonal paraprotein as well as bone lesions. Using this mouse model we demonstrated the crucial role of the parathyroid hormone 1 receptor (PTH1R) on the survival of mice exposed to proteasome inhibitor drugs such as bortezomib and carfilzomib; specifically the blockage of the PTH1R function by parathyroid hormone antagonist (PTH 7-34) resulted in significant abrogation of the beneficial survival effect of proteasome inhibitor drugs. To further investigate the effect of the parathyroid hormone (PTH) axis on murine myeloma development we performed Thyroparathyroidectomy on the C57BL6/KaLwRij mouse before or after 5TGM1 transplantation. Thyroparathyroidectomy was performed by trained personnel in general anesthesia with isoflurane; all surgical/postsurgical procedures and animal welfare followed an IACUC approved protocol at the University of Arkansas. To prevent hypocalcaemia at postsurgery, 1M CaCl2 solution in the drinking bottle was supplemented for a week. All tested mice received 0.5X106 5TGM1 cell infusion by intravenous injection; mice were divided into three groups; Group 1 control mice (n=10) received 5TGM1 infusion at day 0; Group 2 included 15 mice which on day 10 post 5TGM1 cell infusion underwent Thyroparathyroidectomy; Group 3 included 15 mice which at 20 days post-surgery received infusion of 5TGM1 cells. 30% of animals experienced post-surgical complications and died in the first 7 days from procedure; those animals were not included in this survival analysis which is based on 10 animals for each cohort. Blood samples were collected at weekly intervals for IgG2 measurements. The survival curves of mice recovered after surgery are shown in the figure. All control mice (group 1) developed myeloma progression and died within 3 weeks post-transplant; 2 mice from group 2 and 5 mice of the third cohort manifested disease. All 7 animal deaths were pathologically and serologically attributed to myeloma progression. Compared to controls thyroparathyroidectomized mice (Group 2 and Group 3) showed significantly longer survival p Disclosures Zangari:Norvartis: Membership on an entity9s Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding.
Maurizio Zangari - One of the best experts on this subject based on the ideXlab platform.
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thymic pth increases after Thyroparathyroidectomy in c57bl kalwrij mice
Endocrinology, 2018Co-Authors: Maurizio Zangari, H Yoo, Ik Jae Shin, Larry J Suva, Bum Jun Kim, Ricky D Edmondson, Gareth J Morgan, D YoonAbstract:We previously reported a substantial correlation between serum parathyroid hormone (PTH) levels and the myeloma response to proteasome inhibition that suggests a crucial role for the PTH receptor 1 system in the control of myeloma tumor growth. While investigating the role of PTH in the antimyeloma effect, we observed the recovery of serum PTH levels after Thyroparathyroidectomy (TPTX). Although the presence of thymus-derived PTH has been reported previously, the existence or role of thymic PTH in the serum remains controversial. Here, TPTX was performed in 8- to 12-week-old C57BL/KaLwRij mice to delineate the potential source(s) for the recovery of serum PTH. Immediately after TPTX, the expected loss of measurable serum PTH was observed. Serum PTH levels recovered 3 to 4 weeks after TPTX. Thirteen endocrine organs from mice with recovered serum PTH were examined. The thymus from control mice expressed measurable and detectable Pth transcripts; however, the Pth transcript level was substantially elevated in tissue from TPTX mice. Western blot analysis of the thymus demonstrated a reproducible and distinct PTH band in thymus tissue that was significantly increased after TPTX. To directly confirm the identity of the distinct PTH band, immunoprecipitated proteins were isolated and subjected to tandem mass spectrometry. After fragmentation and direct peptide sequencing, PTH peptides PTH(1-13) and PTH(54-70), diagnostic for PTH, were identified. These data demonstrate that the murine thymus produces PTH and that after TPTX the thymus becomes the major source of serum PTH, compensating for the loss of the parathyroid glands and returning circulating PTH levels to normal.
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surgical Thyroparathyroidectomy prevents progression of 5tgm1 murine multiple myeloma in vivo
Journal of bone oncology, 2018Co-Authors: Maurizio Zangari, H Yoo, D Yoon, Ik Jae Shin, Larry J SuvaAbstract:The 5TGM1 multiple myeloma transplanted C57BL6/KaLwRij model recapitulates many disease features including monoclonal paraprotein production as well as the development of osteolytic bone lesions. Since a significant association between serum parathyroid hormone PTH variations, bone anabolism and myeloma progression in patients receiving proteasome inhibitors exists, this study investigated the effect of the PTH axis on murine myeloma development in vivo. C57BL6/KaLwRij myeloma-bearing mice underwent Thyroparathyroidectomy (TPTX) before and after 5TGM1 cell transplantation. TPTX significantly and permanently inhibited 5TGM1 myeloma cell engraftment and prevented multiple myeloma growth and progression. These data support the hypothesis that the PTH axis is an important mediator of myeloma bone disease.
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thymus derived pth tpth is increased after Thyroparathyroidectomy in c57bl6 kalwrij mice and modulates mouse sensitivity to 5tgm1 myeloma cell line
Blood, 2015Co-Authors: Maurizio Zangari, Larry J Suva, D YoonAbstract:We have previously reported a significant correlation between serum PTH levels and myeloma responses to proteasome inhibition and have recently demonstrated a crucial role for the parathyroid hormone receptor 1 (PTHR1) in vitro and in vivo. In this study the effect of abrogation of parathyroid-derived PTH was tested in 5TGM1 myeloma transplanted C57BL6/KaLwRij mice. To interrogate PTH activity in vivo, Thyroparathyroidectomy (TX-PTX) was performed on the C57BL6/KaLwRij mice before or after the transplantation of 5TGM1 cells. Surgical success was confirmed by the rapid loss of measureable circulating PTH. In TX-PTX mice bearing transplanted 5TGM1 tumors, serum PTH levels was noted to recover 3-4 weeks after surgery and to achieve levels consistently higher than baseline levels pre TX-PTX. These data raised the compelling possibility of an alternative PTH source. To determine the potential source of the recovered PTH levels, multiple organs were examined. Whole tissue lysates were analyzed by Western blot and revealed a faint but specific band from thymic tissue, as expected with no obvious bands detected in 13 other tissues investigated including the liver, lung, kidney, ovary and testis. In addition, murine PTH mRNA transcripts from thymus RNA were measured by Real-Time PCR, using a specifically designed primer set that spans exons 1 and 2, since intron 1 is >1kb. These primers specifically discriminate mRNA transcripts from genomic DNA and improve the assay sensitivity for the detection of PTH transcripts. Using these custom-designed primers, control thymus expressed measureable PTH mRNA transcripts that was significantly elevated in TX-PTX mice. Since the thymus is considerably bigger than the parathyroid glands, PTH was immunoprecipitated before performing Western blot analysis. Following immunoprecipitation, a distinct PTH protein band was observed from the thymus in both TX-PTX and control mice. These data suggest that the thymus is the major source of serum PTH in TX-PTX mice and that the organ can compensate for the loss of serum PTH from the parathyroid gland. We propose that thymus-derived PTH in the TX-PTX mouse may contribute to the control of the 5TGM1 murine myeloma model. Disclosures Zangari:University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding.
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thymus derived pth tpth is increased after Thyroparathyroidectomy in c57bl6 kalwrij mice and modulates mouse sensitivity to 5tgm1 myeloma cell line
Blood, 2015Co-Authors: Maurizio Zangari, H Yoo, Larry J Suva, D YoonAbstract:Abstract We have previously reported a significant correlation between serum PTH levels and myeloma responses to proteasome inhibition and have recently demonstrated a crucial role for the parathyroid hormone receptor 1 (PTHR1) in vitro and in vivo. In this study the effect of abrogation of parathyroid-derived PTH was tested in 5TGM1 myeloma transplanted C57BL6/KaLwRij mice. To interrogate PTH activity in vivo, Thyroparathyroidectomy (TX-PTX) was performed on the C57BL6/KaLwRij mice before or after the transplantation of 5TGM1 cells. Surgical success was confirmed by the rapid loss of measureable circulating PTH. In TX-PTX mice bearing transplanted 5TGM1 tumors, serum PTH levels was noted to recover 3-4 weeks after surgery and to achieve levels consistently higher than baseline levels pre TX-PTX. These data raised the compelling possibility of an alternative PTH source. To determine the potential source of the recovered PTH levels, multiple organs were examined. Whole tissue lysates were analyzed by Western blot and revealed a faint but specific band from thymic tissue, as expected with no obvious bands detected in 13 other tissues investigated including the liver, lung, kidney, ovary and testis. In addition, murine PTH mRNA transcripts from thymus RNA were measured by Real-Time PCR, using a specifically designed primer set that spans exons 1 and 2, since intron 1 is >1kb. These primers specifically discriminate mRNA transcripts from genomic DNA and improve the assay sensitivity for the detection of PTH transcripts. Using these custom-designed primers, control thymus expressed measureable PTH mRNA transcripts that was significantly elevated in TX-PTX mice. Since the thymus is considerably bigger than the parathyroid glands, PTH was immunoprecipitated before performing Western blot analysis. Following immunoprecipitation, a distinct PTH protein band was observed from the thymus in both TX-PTX and control mice. These data suggest that the thymus is the major source of serum PTH in TX-PTX mice and that the organ can compensate for the loss of serum PTH from the parathyroid gland. We propose that thymus-derived PTH in the TX-PTX mouse may contribute to the control of the 5TGM1 murine myeloma model. Disclosures Zangari: University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding.
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surgical control cure of 5tgm1 murine multiple myeloma model by Thyroparathyroidectomy
Clinical Lymphoma Myeloma & Leukemia, 2014Co-Authors: Maurizio Zangari, H Yoo, D YoonAbstract:The 5TGM1 transplanted C57BL6/KaLwRij mouse is widely used to study murine multiple myeloma development. It recapitulates many features of human multiple myeloma including monoclonal paraprotein as well as bone lesions. Using this mouse model we demonstrated the crucial role of the parathyroid hormone 1 receptor (PTH1R) on the survival of mice exposed to proteasome inhibitor drugs such as bortezomib and carfilzomib; specifically the blockage of the PTH1R function by parathyroid hormone antagonist (PTH 7-34) resulted in significant abrogation of the beneficial survival effect of proteasome inhibitor drugs. To further investigate the effect of the parathyroid hormone (PTH) axis on murine myeloma development we performed Thyroparathyroidectomy on the C57BL6/KaLwRij mouse before or after 5TGM1 transplantation. Thyroparathyroidectomy was performed by trained personnel in general anesthesia with isoflurane; all surgical/postsurgical procedures and animal welfare followed an IACUC approved protocol at the University of Arkansas. To prevent hypocalcaemia at postsurgery, 1M CaCl2 solution in the drinking bottle was supplemented for a week. All tested mice received 0.5X106 5TGM1 cell infusion by intravenous injection; mice were divided into three groups; Group 1 control mice (n=10) received 5TGM1 infusion at day 0; Group 2 included 15 mice which on day 10 post 5TGM1 cell infusion underwent Thyroparathyroidectomy; Group 3 included 15 mice which at 20 days post-surgery received infusion of 5TGM1 cells. 30% of animals experienced post-surgical complications and died in the first 7 days from procedure; those animals were not included in this survival analysis which is based on 10 animals for each cohort. Blood samples were collected at weekly intervals for IgG2 measurements. The survival curves of mice recovered after surgery are shown in the figure. All control mice (group 1) developed myeloma progression and died within 3 weeks post-transplant; 2 mice from group 2 and 5 mice of the third cohort manifested disease. All 7 animal deaths were pathologically and serologically attributed to myeloma progression. Compared to controls thyroparathyroidectomized mice (Group 2 and Group 3) showed significantly longer survival p Disclosures Zangari:Norvartis: Membership on an entity9s Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding.
H Yoo - One of the best experts on this subject based on the ideXlab platform.
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thymic pth increases after Thyroparathyroidectomy in c57bl kalwrij mice
Endocrinology, 2018Co-Authors: Maurizio Zangari, H Yoo, Ik Jae Shin, Larry J Suva, Bum Jun Kim, Ricky D Edmondson, Gareth J Morgan, D YoonAbstract:We previously reported a substantial correlation between serum parathyroid hormone (PTH) levels and the myeloma response to proteasome inhibition that suggests a crucial role for the PTH receptor 1 system in the control of myeloma tumor growth. While investigating the role of PTH in the antimyeloma effect, we observed the recovery of serum PTH levels after Thyroparathyroidectomy (TPTX). Although the presence of thymus-derived PTH has been reported previously, the existence or role of thymic PTH in the serum remains controversial. Here, TPTX was performed in 8- to 12-week-old C57BL/KaLwRij mice to delineate the potential source(s) for the recovery of serum PTH. Immediately after TPTX, the expected loss of measurable serum PTH was observed. Serum PTH levels recovered 3 to 4 weeks after TPTX. Thirteen endocrine organs from mice with recovered serum PTH were examined. The thymus from control mice expressed measurable and detectable Pth transcripts; however, the Pth transcript level was substantially elevated in tissue from TPTX mice. Western blot analysis of the thymus demonstrated a reproducible and distinct PTH band in thymus tissue that was significantly increased after TPTX. To directly confirm the identity of the distinct PTH band, immunoprecipitated proteins were isolated and subjected to tandem mass spectrometry. After fragmentation and direct peptide sequencing, PTH peptides PTH(1-13) and PTH(54-70), diagnostic for PTH, were identified. These data demonstrate that the murine thymus produces PTH and that after TPTX the thymus becomes the major source of serum PTH, compensating for the loss of the parathyroid glands and returning circulating PTH levels to normal.
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surgical Thyroparathyroidectomy prevents progression of 5tgm1 murine multiple myeloma in vivo
Journal of bone oncology, 2018Co-Authors: Maurizio Zangari, H Yoo, D Yoon, Ik Jae Shin, Larry J SuvaAbstract:The 5TGM1 multiple myeloma transplanted C57BL6/KaLwRij model recapitulates many disease features including monoclonal paraprotein production as well as the development of osteolytic bone lesions. Since a significant association between serum parathyroid hormone PTH variations, bone anabolism and myeloma progression in patients receiving proteasome inhibitors exists, this study investigated the effect of the PTH axis on murine myeloma development in vivo. C57BL6/KaLwRij myeloma-bearing mice underwent Thyroparathyroidectomy (TPTX) before and after 5TGM1 cell transplantation. TPTX significantly and permanently inhibited 5TGM1 myeloma cell engraftment and prevented multiple myeloma growth and progression. These data support the hypothesis that the PTH axis is an important mediator of myeloma bone disease.
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thymus derived pth tpth is increased after Thyroparathyroidectomy in c57bl6 kalwrij mice and modulates mouse sensitivity to 5tgm1 myeloma cell line
Blood, 2015Co-Authors: Maurizio Zangari, H Yoo, Larry J Suva, D YoonAbstract:Abstract We have previously reported a significant correlation between serum PTH levels and myeloma responses to proteasome inhibition and have recently demonstrated a crucial role for the parathyroid hormone receptor 1 (PTHR1) in vitro and in vivo. In this study the effect of abrogation of parathyroid-derived PTH was tested in 5TGM1 myeloma transplanted C57BL6/KaLwRij mice. To interrogate PTH activity in vivo, Thyroparathyroidectomy (TX-PTX) was performed on the C57BL6/KaLwRij mice before or after the transplantation of 5TGM1 cells. Surgical success was confirmed by the rapid loss of measureable circulating PTH. In TX-PTX mice bearing transplanted 5TGM1 tumors, serum PTH levels was noted to recover 3-4 weeks after surgery and to achieve levels consistently higher than baseline levels pre TX-PTX. These data raised the compelling possibility of an alternative PTH source. To determine the potential source of the recovered PTH levels, multiple organs were examined. Whole tissue lysates were analyzed by Western blot and revealed a faint but specific band from thymic tissue, as expected with no obvious bands detected in 13 other tissues investigated including the liver, lung, kidney, ovary and testis. In addition, murine PTH mRNA transcripts from thymus RNA were measured by Real-Time PCR, using a specifically designed primer set that spans exons 1 and 2, since intron 1 is >1kb. These primers specifically discriminate mRNA transcripts from genomic DNA and improve the assay sensitivity for the detection of PTH transcripts. Using these custom-designed primers, control thymus expressed measureable PTH mRNA transcripts that was significantly elevated in TX-PTX mice. Since the thymus is considerably bigger than the parathyroid glands, PTH was immunoprecipitated before performing Western blot analysis. Following immunoprecipitation, a distinct PTH protein band was observed from the thymus in both TX-PTX and control mice. These data suggest that the thymus is the major source of serum PTH in TX-PTX mice and that the organ can compensate for the loss of serum PTH from the parathyroid gland. We propose that thymus-derived PTH in the TX-PTX mouse may contribute to the control of the 5TGM1 murine myeloma model. Disclosures Zangari: University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding.
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surgical control cure of 5tgm1 murine multiple myeloma model by Thyroparathyroidectomy
Clinical Lymphoma Myeloma & Leukemia, 2014Co-Authors: Maurizio Zangari, H Yoo, D YoonAbstract:The 5TGM1 transplanted C57BL6/KaLwRij mouse is widely used to study murine multiple myeloma development. It recapitulates many features of human multiple myeloma including monoclonal paraprotein as well as bone lesions. Using this mouse model we demonstrated the crucial role of the parathyroid hormone 1 receptor (PTH1R) on the survival of mice exposed to proteasome inhibitor drugs such as bortezomib and carfilzomib; specifically the blockage of the PTH1R function by parathyroid hormone antagonist (PTH 7-34) resulted in significant abrogation of the beneficial survival effect of proteasome inhibitor drugs. To further investigate the effect of the parathyroid hormone (PTH) axis on murine myeloma development we performed Thyroparathyroidectomy on the C57BL6/KaLwRij mouse before or after 5TGM1 transplantation. Thyroparathyroidectomy was performed by trained personnel in general anesthesia with isoflurane; all surgical/postsurgical procedures and animal welfare followed an IACUC approved protocol at the University of Arkansas. To prevent hypocalcaemia at postsurgery, 1M CaCl2 solution in the drinking bottle was supplemented for a week. All tested mice received 0.5X106 5TGM1 cell infusion by intravenous injection; mice were divided into three groups; Group 1 control mice (n=10) received 5TGM1 infusion at day 0; Group 2 included 15 mice which on day 10 post 5TGM1 cell infusion underwent Thyroparathyroidectomy; Group 3 included 15 mice which at 20 days post-surgery received infusion of 5TGM1 cells. 30% of animals experienced post-surgical complications and died in the first 7 days from procedure; those animals were not included in this survival analysis which is based on 10 animals for each cohort. Blood samples were collected at weekly intervals for IgG2 measurements. The survival curves of mice recovered after surgery are shown in the figure. All control mice (group 1) developed myeloma progression and died within 3 weeks post-transplant; 2 mice from group 2 and 5 mice of the third cohort manifested disease. All 7 animal deaths were pathologically and serologically attributed to myeloma progression. Compared to controls thyroparathyroidectomized mice (Group 2 and Group 3) showed significantly longer survival p Disclosures Zangari:Norvartis: Membership on an entity9s Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding.
Tatsuo Suda - One of the best experts on this subject based on the ideXlab platform.
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parathyroid hormone inhibits 25 hydroxyvitamin d3 24 hydroxylase mrna expression stimulated by 1 alpha 25 dihydroxyvitamin d3 in rat kidney but not in intestine
Journal of Biological Chemistry, 1992Co-Authors: Toshimasa Shinki, Cheng He Jin, A Nishimura, Y Nagai, Y Ohyama, M Noshiro, K Okuda, Tatsuo SudaAbstract:Using a cDNA probe for rat renal 24-hydroxylase, expression of its mRNA was compared in the rat kidney and intestine. Vitamin D-deficient rats received a single injection of 1 alpha,25-dihydroxyvitamin D3. Expression of 24-hydroxylase mRNA was first detected in the kidney at 3-h post-injection and increased thereafter. Similarly, 24-hydroxylase mRNA was expressed in the intestine after 1 alpha,25-dihydroxyvitamin D3 injection. However, the dose level of 1 alpha,25-dihydroxyvitamin D3 required to induce the intestinal 24-hydroxylase mRNA expression was only 1/100 the amount required to induce renal 24-hydroxylase mRNA. Induction of intestinal 24-hydroxylase mRNA expression by 1 alpha,25-dihydroxyvitamin D3 was far more rapid than that of renal 24-hydroxylase mRNA. Thyroparathyroidectomy shortened the time required to induce expression of renal, but not intestinal, 24-hydroxylase mRNA. Administration of either parathyroid hormone or cAMP to vitamin D-deficient rats greatly reduced the expression of 24-hydroxylase mRNA in the kidney but not in the intestine. When rats were fed a vitamin D-repleted diet containing 0.7% (adequate) or 0.03% (low) calcium for 2 weeks, intestinal expression of 24-hydroxylase mRNA could be induced only in the low calcium group. In contrast, renal mRNA expression was preferentially stimulated in the adequate calcium group. These results clearly demonstrate that the expression of 24-hydroxylase mRNA is down-regulated by parathyroid hormone in the kidney but not in the intestine.
Larry J Suva - One of the best experts on this subject based on the ideXlab platform.
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thymic pth increases after Thyroparathyroidectomy in c57bl kalwrij mice
Endocrinology, 2018Co-Authors: Maurizio Zangari, H Yoo, Ik Jae Shin, Larry J Suva, Bum Jun Kim, Ricky D Edmondson, Gareth J Morgan, D YoonAbstract:We previously reported a substantial correlation between serum parathyroid hormone (PTH) levels and the myeloma response to proteasome inhibition that suggests a crucial role for the PTH receptor 1 system in the control of myeloma tumor growth. While investigating the role of PTH in the antimyeloma effect, we observed the recovery of serum PTH levels after Thyroparathyroidectomy (TPTX). Although the presence of thymus-derived PTH has been reported previously, the existence or role of thymic PTH in the serum remains controversial. Here, TPTX was performed in 8- to 12-week-old C57BL/KaLwRij mice to delineate the potential source(s) for the recovery of serum PTH. Immediately after TPTX, the expected loss of measurable serum PTH was observed. Serum PTH levels recovered 3 to 4 weeks after TPTX. Thirteen endocrine organs from mice with recovered serum PTH were examined. The thymus from control mice expressed measurable and detectable Pth transcripts; however, the Pth transcript level was substantially elevated in tissue from TPTX mice. Western blot analysis of the thymus demonstrated a reproducible and distinct PTH band in thymus tissue that was significantly increased after TPTX. To directly confirm the identity of the distinct PTH band, immunoprecipitated proteins were isolated and subjected to tandem mass spectrometry. After fragmentation and direct peptide sequencing, PTH peptides PTH(1-13) and PTH(54-70), diagnostic for PTH, were identified. These data demonstrate that the murine thymus produces PTH and that after TPTX the thymus becomes the major source of serum PTH, compensating for the loss of the parathyroid glands and returning circulating PTH levels to normal.
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surgical Thyroparathyroidectomy prevents progression of 5tgm1 murine multiple myeloma in vivo
Journal of bone oncology, 2018Co-Authors: Maurizio Zangari, H Yoo, D Yoon, Ik Jae Shin, Larry J SuvaAbstract:The 5TGM1 multiple myeloma transplanted C57BL6/KaLwRij model recapitulates many disease features including monoclonal paraprotein production as well as the development of osteolytic bone lesions. Since a significant association between serum parathyroid hormone PTH variations, bone anabolism and myeloma progression in patients receiving proteasome inhibitors exists, this study investigated the effect of the PTH axis on murine myeloma development in vivo. C57BL6/KaLwRij myeloma-bearing mice underwent Thyroparathyroidectomy (TPTX) before and after 5TGM1 cell transplantation. TPTX significantly and permanently inhibited 5TGM1 myeloma cell engraftment and prevented multiple myeloma growth and progression. These data support the hypothesis that the PTH axis is an important mediator of myeloma bone disease.
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thymus derived pth tpth is increased after Thyroparathyroidectomy in c57bl6 kalwrij mice and modulates mouse sensitivity to 5tgm1 myeloma cell line
Blood, 2015Co-Authors: Maurizio Zangari, Larry J Suva, D YoonAbstract:We have previously reported a significant correlation between serum PTH levels and myeloma responses to proteasome inhibition and have recently demonstrated a crucial role for the parathyroid hormone receptor 1 (PTHR1) in vitro and in vivo. In this study the effect of abrogation of parathyroid-derived PTH was tested in 5TGM1 myeloma transplanted C57BL6/KaLwRij mice. To interrogate PTH activity in vivo, Thyroparathyroidectomy (TX-PTX) was performed on the C57BL6/KaLwRij mice before or after the transplantation of 5TGM1 cells. Surgical success was confirmed by the rapid loss of measureable circulating PTH. In TX-PTX mice bearing transplanted 5TGM1 tumors, serum PTH levels was noted to recover 3-4 weeks after surgery and to achieve levels consistently higher than baseline levels pre TX-PTX. These data raised the compelling possibility of an alternative PTH source. To determine the potential source of the recovered PTH levels, multiple organs were examined. Whole tissue lysates were analyzed by Western blot and revealed a faint but specific band from thymic tissue, as expected with no obvious bands detected in 13 other tissues investigated including the liver, lung, kidney, ovary and testis. In addition, murine PTH mRNA transcripts from thymus RNA were measured by Real-Time PCR, using a specifically designed primer set that spans exons 1 and 2, since intron 1 is >1kb. These primers specifically discriminate mRNA transcripts from genomic DNA and improve the assay sensitivity for the detection of PTH transcripts. Using these custom-designed primers, control thymus expressed measureable PTH mRNA transcripts that was significantly elevated in TX-PTX mice. Since the thymus is considerably bigger than the parathyroid glands, PTH was immunoprecipitated before performing Western blot analysis. Following immunoprecipitation, a distinct PTH protein band was observed from the thymus in both TX-PTX and control mice. These data suggest that the thymus is the major source of serum PTH in TX-PTX mice and that the organ can compensate for the loss of serum PTH from the parathyroid gland. We propose that thymus-derived PTH in the TX-PTX mouse may contribute to the control of the 5TGM1 murine myeloma model. Disclosures Zangari:University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding.
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thymus derived pth tpth is increased after Thyroparathyroidectomy in c57bl6 kalwrij mice and modulates mouse sensitivity to 5tgm1 myeloma cell line
Blood, 2015Co-Authors: Maurizio Zangari, H Yoo, Larry J Suva, D YoonAbstract:Abstract We have previously reported a significant correlation between serum PTH levels and myeloma responses to proteasome inhibition and have recently demonstrated a crucial role for the parathyroid hormone receptor 1 (PTHR1) in vitro and in vivo. In this study the effect of abrogation of parathyroid-derived PTH was tested in 5TGM1 myeloma transplanted C57BL6/KaLwRij mice. To interrogate PTH activity in vivo, Thyroparathyroidectomy (TX-PTX) was performed on the C57BL6/KaLwRij mice before or after the transplantation of 5TGM1 cells. Surgical success was confirmed by the rapid loss of measureable circulating PTH. In TX-PTX mice bearing transplanted 5TGM1 tumors, serum PTH levels was noted to recover 3-4 weeks after surgery and to achieve levels consistently higher than baseline levels pre TX-PTX. These data raised the compelling possibility of an alternative PTH source. To determine the potential source of the recovered PTH levels, multiple organs were examined. Whole tissue lysates were analyzed by Western blot and revealed a faint but specific band from thymic tissue, as expected with no obvious bands detected in 13 other tissues investigated including the liver, lung, kidney, ovary and testis. In addition, murine PTH mRNA transcripts from thymus RNA were measured by Real-Time PCR, using a specifically designed primer set that spans exons 1 and 2, since intron 1 is >1kb. These primers specifically discriminate mRNA transcripts from genomic DNA and improve the assay sensitivity for the detection of PTH transcripts. Using these custom-designed primers, control thymus expressed measureable PTH mRNA transcripts that was significantly elevated in TX-PTX mice. Since the thymus is considerably bigger than the parathyroid glands, PTH was immunoprecipitated before performing Western blot analysis. Following immunoprecipitation, a distinct PTH protein band was observed from the thymus in both TX-PTX and control mice. These data suggest that the thymus is the major source of serum PTH in TX-PTX mice and that the organ can compensate for the loss of serum PTH from the parathyroid gland. We propose that thymus-derived PTH in the TX-PTX mouse may contribute to the control of the 5TGM1 murine myeloma model. Disclosures Zangari: University of Arkansas for Medical Sciences: Employment; Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding.