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Pathogenesis of Bone Diseases in Chronic Renal Failure

Research Project

Project/Area Number 13671115
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Kidney internal medicine
Research InstitutionKobe University

Principal Investigator

FUKAGAWA Masafumi  Kobe University, Dialysis Center, Associate Professor, 医学部附属病院, 助教授 (00211516)

Co-Investigator(Kenkyū-buntansha) KAKUTA Takatoshi  Tokai University, Dept of Nephrology, Assistant Professor, 医学部, 講師 (50276854)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 2001: ¥2,800,000 (Direct Cost: ¥2,800,000)
Keywordsrenal failure / Bone metabolism / PTH / osteoprotegerin / uremic toxins / vitamin D / Osteoprotegerin / whole / ビタミンK2
Research Abstract

Due to the effective suppression of PTH by recently developed therapeutic modalities, this background abnormality has been uncovered and currently recognized as 'relative hypoparathyroidism' in terms of its relation to bone turnover. The purpose of this study was to elucidate the pathophysiological mechanisms underlying such a skeletal resistance to PTH in uremia.
Fist mechanism is the overestimation of PTH activity. As we demonstrated by a recently developed 'whole PTH assay', conventional intact PTH assay detects not only 1-84PTH, but also 7-84 PTH due to the recognition site of the antibody. Accumulation of 7-64PTH seemed to be due to the reduced clearance from the kidney.
Second mechanism is the possible suppressive effects of uremic toxins on osteoblastic function. In our model rats of ABD, decline of bone formation rate was dependent on the degree of renal dysfunction. Intermittent PTH treatment ameliorated the suppression of osteoblast function (mineral appositional rate), and bone formation (bone formation rate) in a dose dependent manner. Oral absorbent for uremic toxin partly reversed such abnormalities without affecting renal function. Thus, some of the accumulated uremic toxins may be responsible for such a suppression of osteobtastic function.
Third mechanism is the suppressed activation of osteoctasts. In uremic patients, serum level of osteoprotegerin (OPG) markedly increased, which molecule is a decoy receptor blocking a signal molecule expressed on osteoblasts by PTH. By bone histomorphometry, parameters of bone resorption negatively correlated with serum OPG levels. Thus, accumulated OPG may play a critical role in the attenuated osteoclastic function in uremia.
As a conclusion, correction of skeletal resistance to PTH is mandatory for the balanced control of bone metabolism and parathyroid function in renal failure.

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (40 results)

All Other

All Publications (40 results)

  • [Publications] Nakanishi et al.: "Comparison of intact PTH assay and whole PTH assay in long-term dialysis parients"Am J Kidney Dis. 38. S152-S155 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kazama JJ et al.: "Increased circulating levels of osteoclastgenesis inhibitory factor/osteoprotegerin in patients with chronic renal failure : Possible roles in skeletal resistance to PTH in uremia"Am J Kidney Dis. 39. 525-532 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwasaki Y et al.: "Maintenance of trabecular structure and bone volume by vitamin K2 in mature rats with long-term tail suspension"J Bone Mineral Metab. 20. 216-222 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamashita H et al.: "Role of cyclase activating parathyroid hormone (1-84PTH) measurements during parathyroid surgery : Potential improvement of intraoperative PTH assay"Ann Surg. 236. 105-111 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukagawa M et al.: "Management of the patients with advanced secondary Hyperparathyroidism : the Japanese approach"Nephrol Dial Transplant. 17. 1553-1557 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hirata M et al.: "22-Oxacalcitriol suppresses PTH with less risk of cardiovascular calcification and deterioration of residual renal function in subtotally nephrectomized rats"Nephrol Dial Transplant. 18(印刷中). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukagawa M, Kazama JJ, Shigematsu T: "Skeletal resistance to PTH as a basic abnormality underlying uremic bone diseases"Am J Kidney Dis. 38 (Suppl 1). S152-S155 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakanishi S, Kazama JJ, Shigematsu T, Iwasaki Y, Cantor TL, Kurosawa T, Fukagawa M: "Comparison of intact PTH assay and whole PTH assay in long-tern dialysis patients"Am J Kidney Dis. 38 (Suppl 1). S172-S174 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sato T, Tominaga Y, Iwasaki Y, Kazama JJ, Shigematsu T, Inagaki H, Watanabe I, Katayama A, Haba T, Uchida K, Fukagawa M: "Osteopritegerin levels befort and after renal transplantation"Am J Kidney Dis. 38 (Suppl 1). S175-S177 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Komuro H, Mori M, Hayashi Y, Fukagawa M, Makino S, Takahara K, Greenspan DS, Momoi M: "Lack of the BMP-1 gene mutation in patients with gastroschisis"J Pediat Surg. 36. 885-887 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tsuruta Y, Ito Y, harada KI, Narita Y, Ohbayashi T, Azekura H, Fukagawa M, Narita M, Maeda K: "Measurements of blood DMSO and DMSO2 in a healthy person and a hemodialysis patient"Clin Exp Nephrol. 5. 158-162 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kazama JJ, Shigematsu T, Tsuda E, Yano K, Miura M, Kawaguchi Y, Gejyo F, Kurokawa K, Fukagawa M: "Increased circulating levels of osteoclastogenesis inhibitory factor/osteoprotegerin in patients with chronic renal failure : Possible roles in skeletal resistance to FTH in uremia"Am J Kidney Dis. 39. 525-532 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hanafusa N, Yatomi Y, Yamada K, Hori Y, Nangaku H, Okuda T, Fujita T, Kurokawa K, Fukagawa M: "Sphingosine 1-phosphate stimulates DNA synthesis in rat mesangial cells from outside of the cell"Nephrol Dial Transplant. 17. 580-586 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwasaki Y, Yamato H, Murayama H, Sato M, Takahashi T, Ezawa I, Kurokawa K, Fukagawa M: "Maintenance of trabecular structure and bone volume by vitamin K2 in mature rats with long-term tail suspension"J Bone Mineral Metab. 20. 216-222 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamashita H, Gao P, Noguchi S, Cantor T, Uchino S, Watanabe S, Yamashita H, Kawamoto H, Fukagawa M: "Role of cyclase activating parathyroid hormone (1-84 PTH) measurements during parathyroid surgery : Potential improvement of intraoperative PTH assay"Ann Surg. 236. 105-111 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yokoyama K, Kagami S, Shigematsu T, Nakayama M, Fukagawa M, Kawaguchi Y, Hosoya T: "The negative Ca2+ balance is involved in the stimulation of PTH secretion"Nephron. 92. 86-90 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukagawa M, Kazama JJ, Shigematsu T: "Management of the patients with advanced secondary hyperparathyroidism : the Japanese approach"Nephrol Dial Transplant. 17. 1553-1557 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yano S, Tsukamoto T, Kobayashi A, Murata M, Nakanishi S, Nomura R, Sowa H, Fukagawa M, Sugimoto T, Chihara K: "Determination of parathyroid hormone levels in fine needle aspirates of ectopic parathyroid glands (letter)"Nephrol Dial Transplant. 17. 1707-1708 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwasaki Y, yamato H, Murayama H, Takahashi T, Ezawa I, Kurokawa K, Fukagawa M: "Menatetrenone prevents osteoblast dysfunction in unilateral sciatic neurectomized rats"Jpn J Pharmacol. 90. 88-93 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukagawa M, Kazama JJ, Kurokawa K: "Renal osteodystrophy and secondary Hyperparathyroidism"Nephrol Dial Transplant. 17 (Suppl 10). 2-5 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hirata M, Endo K, Ohkawa H, Kumaki K, Kubodera N, Slatopolsky E, Kurokawa K, Fukagawa M: "A comparison between daily and thrice-weekly i.v. administration of 1,25-dihydroxy-22-oxavitamin D3 regarding suppression of parathyroid hormone secretion and calcemic action in uraemic rats"Nephrol Dial Transplant. 17 (Suppl 10). 37-40 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hirata M, Endo K, Katsumata K, Ichikawa F, Kubodera N, Fukagawa M: "A comparison between 1,25-dihydroxy-22-oxavitamin D3 and 1,25-dihydroxyvitamin D3 regarding suppression of parathyroid hormone secretion and calcaemic action"Nephrol Dial Transplant. 17 (Suppl 10). 41-45 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Fukagawa M, Kurokawa K: "Calcium homeostasis and imbalance"Nephron. 92 (Suppl 1). 41-45 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kazama JJ, Kato H, Sato T, Shigematsu T, Fukagawa M, Iwasaki Y, Gejyo F: "Circulating osteoprotegerin is not removed through haemodialysis membrane (letter)"Nephrol Dial Transplant. 17. 1860-1861 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwasaki Y, Yamato H, Murayama H, Sato M, Takahashi T, Ezawa I, Kurokawa K, Fukagawa M: "Combination use of vitamin K2 further increases bone volume and ameriolates extremely low turnover bone induced by bisphosphonate therapy in tail-susupension rats"J Bone Miner Metab. 21. 154-160 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Hirata M, Katsumata K, Endo K, Fukushima N, Ohkawa H, Fukagawa M: "22-Oxacalcitriol suppresses PTH with less risk of cardiovascular calcification and deterioration of residual renal function in subtotally nephrectomized rats"Nephrol Dial Transplant. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Iwasaki Y, Kakuta T, Haruguchi H, Fukuda N, Kurokawa K, Fukagawa M: "Adenovirus mediated functional genes transfer into parathyroid cell in vivo and in vitro"Nephrol Dial Transplant. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tanno Y, Yokoyama K, Nakayama M, Katoh A, Yamamoto H, Iwasaki Y, cantor T, Fukagawa M, Shigematsu T, Hosoya T: "The new IRMA assay (whole PTH) is a more useful for PTH effect on bone than the Allegro "intact" PTH assay in CAPD patients with low bone turnover marker"Nephrol Dial Transplant. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kazama JJ, Gejyo F, Kurosawa T, Fukagawa M: "Role of osteoclastic dysfunction in the development of renal bone disease"Nephrol Dial Transplant. in press.

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kazama JJ et al.: "Increased circulating levels of osteoclastogenesis inhibitory factor/osteoprotegerin in patients with chronic renal failure"Am J Kidney Dis. 39. 525-532 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hanafusa et al.: "Sphingosine 1-phosphate stimulates DNA synthesis in rat mesangeal cells from outside of the cell"Nephrol Dial Transplant. 17. 580-586 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iwasaki Y et al.: "Maintenance of trabecular structure and bone volume by vitamin K2 in mature rats with long-term tail suspension"J Bone Mineral Metab. 20. 216-222 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yamashita H et al.: "Role of cyclase activating parathyroid hormone (1-84 PTH) measurements during parathyroid surgery"Ann Surgery. 236. 105-111 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Yokoyama K et al.: "The negative Ca2+ balance is involved in the stimulation of PTH secretion"Nephron. 92. 86-92 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Iwasaki Y et al.: "Adenovirus mediated functional gene transfer in to parathyroid cells in vivo and in vitro"Nephrol Dial Transplant. 18(in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kazama JJ et al.: "Increased circulating levels of osteoclastogenesis inhibitory factor/osteoporotegerin in Patients with chronic renal failure"Am J Kidney Dis. 39. 525-532 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Fukagawa M et al.: "Skeletal resistance to PTH as a basic abnormality underlying uremic bone diseases"Am J Kidney Dis. 38(Suppl 1). S152-S155 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Nakanishi S et al.: "Comparison of intact PTH assay and whole PTH assay in long-term dialysis Patients"Am J Kidney Dis. 38(Suppl 1). S172-S177 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Sato T et al.: "Osteoprotegerin levels before and after renal transplantation"Am J Kidney Dis. 38(Suppl 1). S175-S177 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hanafusa N et al.: "Sphingosine 1-phosphate stimulates DNA synthesis in rat mesangial cells from outside of the cell"Nephrol Dial Transplant. 17(印刷中). (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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