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난소절제술을 시행한 백서에서 간헐적인 부갑상선호르몬 투여가 골절치유에 미치는 영향

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 Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rat 
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[한글] 부갑상선호르몬은 골의 흡수를 증가시키고 신장에서 칼슘의 재흡수를 증가시키며 동시에 근위 신세뇨관의 l-alpha hydroxylase를 활성화시킴으로써 혈중 칼슘의 항상성을 유지하는데 필수적인 전신성 호르몬이다. 그러나 최근 연구결과에 의하면, 이를 간헐적으로 피하주사할 경우 난소절제술을 시행한 백서 모델에서 골형성 자체를 촉진한다는 사실이 밝혀졌다. 즉, 부갑상선호르몬은 소주골의 두께 및 수를 증가시키므로써 전체적인 소주골의 골량을 증가시키며 골막표면에서도 골형성을 촉진시킨다는 사실을 알게 되었다. 한편 골절치유에는 여러 국소적 혹은 전신적 인자가 관여하며, 전신적 인자 중 일부 호르몬이 골절치유 과정에 도움을 준다는 가설이 제시된 바 있으나 이들의 대부분은 실험적 연구수준에 불과하여 더 많은 연구가 필요하다. 호르몬 이외의 다른 전신적 인자 중 노령이나, 폐경 후 골소실 혹은 골다공증의 경우 여러 호르몬의 부족 등으로 골절치유의 지연을 관찰할 수 있으나 아직까지 체계적인 연구가 진행된 바 없다. 본 연구의 목적은 폐경 후 골소실이 골절치유에 미치는 영향을 알아보고, 부갑상선호르몬 투여가 동반된 골절치유에도 유용한 지를 평가하고자 함에 있다. 본 연구에서는 난소절제술을 시행한 백서에서의 실험적 골소실 및 골절 모델을 이용하여 난소절제술이 골절치유에 미치는 영향을 알아보았으며, 골흡수 억제제인 에스트로겐과 골형성촉진제인 부갑상선호르몬을 간헐적으로 피하주사한 후 골절가골에 대한 조직학적 소견을 관찰하고 조직형태학적 및 생역학적 인자를 측정하여 다음과 같은 결과를 얻었다. 1. 조직학 및 조직형태학적 소견상,아무 약제도 투여하지 않은 난소절제술군과 에스트로겐을 투여한 난소절제술군의 경우 가장수술군과 부갑상선호르몬을 투여한 군에 비해 가골의 생성 저하를 보였으며 부갑상선호르몬을 투여한 군은 투여 용량에 비례하여 타 난소절제술군보다 높은 골밀도를 갖는 큰 형태의 가골형성을 보였다. 2. 생역학적 검사상, 부갑상선호르몬의 투여는 투여 용량에 비례하여 타 난소절계술군에 비해 생역학적인자의 전반적인 증가를 초래 하였으며 아무 약제도 투여하지 않은 난소절제술군과 에스트로겐을 투여한 난소절제술군의 경우 가장수술군에 비해 유의한 골절강도의 저하를 보였다. 이상의 결과로써, 난소기능이 감소내지 소실되는 폐경 후 골소실은 골절치유를 지연케하는 하나의 인자임을 확인할 수 있었으며 간헐적인 부갑상선호르몬의 투여는 폐경 후 골소실과, 이로 인한 골다공증성 골절에 있어서 임상적 응용의 가능성을 갖는 것으로 사료된다. 본 연구결과들의 임상적 적용을 위해 향후 전신적 혹은 장기적 효과 및 그 기전에 대한 연구와 함께 국소성장인자와의 관련성에 대한 연구가 필요할 것으로 사료된다.
[영문] Although little data is available, fracture healing is known to be delayed with aging and estrogen deficiency. Among bone-forming agents that have been studied, intermittent administration of parathyroid hormone has been proven to have an anabolic action on the cortical bone as well as the cancellous bone in an ovariectomized rat model. Parathyroid hormone has been known to act directly on the osteoblast, and mediate cyclic AMP-dependent protein kinases. This study was designed to compare fracture healing in normal and overiectomized rat, and to evaluate the effect of parathyroid hormone on fracture healing. Four months old 95 mature female Sprague-Dawley rats were randomized into 5 groups. 19 animals of Group I underwent a sham operation, and others were ovariectomized. At three months after the ovariectomy or sham operation, standardized bilateral transverse tibial fractlues using modified technique of Bak and Andreassen were created, and the intramedullary nailings with Kirschnerwire were performed. The rats were then injected with daily subcutaneous placebo in Groups Ⅰ(n= 13) and Group Ⅱ(n=14),17 β -estradiol(30μg/Kg)in Group Ⅲ(n=12), low doses of recombinant human PTH(1-84)(30μg/Kg) in Group Ⅳ(n=13), and high doses of recombinant human PTH(1-84)(300μg/Kg) in Group Ⅴ(n=11) for 4 weeks. At post-fracture 30th day, the animals were sacrificed, and left and right healing tibiae were harvested with soft tissue and the wire removed for histologic / histomorphometric analysis and biomechanical testing respectively. Microscopic images of the three mid-frontal sections of the decalcified specimen were transferred to computer image analysis system, and then hismorphometric measurements were done. Measurements included external callus length, diameter, per cent trabecular bone and total bone volume area of callus. The biomechanical properties were analyzed in a material testing machine using a standardized three-point bending procedure. The bones were placed on two supporting bars after removal of fibula and the Kirschner wire, and deflected by lowering a third bar on the healed fracture site with a constant speed of 1 mm/min until failure. Ultimate load, ultimate stiffness, deflection at ultimate load, energy absorption at ultimate load were calculated from a load-deflection curve. To normalize raw data and calculate ultimate stress, scanning electron microscopy was performed on the cross-sectional area of fracture, and internal and external diameters in the load direction and perpendicular to it were obtained. Differences between groups were evaluated using One-way ANOVA and Tukey's Studentized Range test at a cofidrnce level of p=0.05, and data is presented as mean±S.D. On histologic / histomorphometric evaluation of the sham operation group, the fracture calluses mainly consisted of dense trabecular bone. On the other hand, Group Ⅱ & Ⅲ seemed to have much looser cancellous network which is abundant in fibrous marrow. In parathyroid hormone-treated groups, external callus consisted of more dense trabecular, woven bone than that of Group Ⅱ or Ⅲ, and especially high doses of parathyroid hormone-treated group was comparable to the sham operation group concerning per cent trabecular bone volume(Group Ⅰ>Ⅴ>Ⅳ>Ⅲ=Ⅱ, p<0.05). Biomechanical testing indicated that ultimate load was reduced in Group Ⅱ & Ⅲ compared to sham operated or parathyroid hormone-treated groups(Group Ⅰ=Ⅴ>Ⅳ>Ⅲ=Ⅱ, p<0.05). Other significant differences are the increase in the absorbed energy at ultimate load of Group Ⅰ & Ⅴ(Group Ⅰ=Ⅴ>Ⅳ=Ⅲ=Ⅱ, p<0.05), and the increase in the ultimate stress of Group Ⅰ & Ⅴ(GroupⅠ=Ⅴ=Ⅱ=Ⅲ, p<0.05). On the basis of this study, it may be concluded that fracture healing is impaired in the ovariectomy-induced osteopenic rat model. Parathyroid hormone-treated rats have more trabecular bone in their callus resulting in the increase of callus diameter, but remained more porotic than the sham group. This fact explains no differences in ultimate load and ultimate stress between sham operated and parathyroid hormone-treated group despite differences in cross-sectional area. Our experiment showed dose-related stimulation of parathyroid hormone in the strength of fracture, and no effect of antiresorptive agent such as estrogen. Further study is needed in large animal models. and attention should be focused on systemic / long-term effects of parathyroid hormone and its relationship with local growth factors in fracture healing.
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1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 3. Dissertation
Yonsei Authors
Kim, Hyun Woo(김현우) ORCID logo https://orcid.org/0000-0001-8576-1877
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