Bisphosphonate가 치아 발육에 미치는 영향
Bisphosphonate and the Eruption of Developing Teeth:Its Effects and Mechanism
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bisphosphonate는 수산화인회석과 결합하여 뼈파괴세포에 의한 뼈조직 흡수를 억제하는 작용을 갖는 것으로 알려져 있으나, 발생기 뼈조직, 치아조직 및 세포에 미치는 영향 및 분자적 기전은 확실하지 않다. 본 연구는 성장기 흰쥐에서 bisphosphonate계 2세대 약제인 alendronate가 치아 형성과 발육에 미치는 영향을 구명하고자 출생 1일 흰쥐에 10일간 매일 2.5 mg/kg 투여 후 3일, 12일, 40일에 희생한 후, 광학현미경적 관찰과 TUNEL 염색 및 alkaline phosphatase mRNA 발현 조사를 시행하여 다음과 같은 결과를 얻었다. alendronate는 발생중인 치아 형성을 억제하고 맹출을 지연시키는 작용을 였다. 투여 종료 후 3일 대조군에서 아래턱 첫째큰어금니와 둘째큰어금니는 각각 치아 단단조직 형성기에 있었으나, alendronate 투여군에서 첫째 및 둘째큰어금니의 경조직 형성은 불완전하였고 셋째큰어금니 치배는 관찰되지 않았다. 둘째큰어금니 치배 내로 뼈 잔기둥이 침입하여 치배 성장이 이루어지지 않고 있었으며, 앞니의 상아질은 뼈유사상아질(osteodentin) 소견을 보이기도 하였다. TUNEL 염색에서 때로 법랑질모세포의 세포자멸사가 관찰되었다. 또한 alendronate 투여군에서 뼈 모세포의 alkaline phosphatase 발현은 대조군에 비하여 현저히 저하되어 있었으며 뼈잔기둥의 방향과 성숙 정도는 대조군에 비하여 미약하였다. 투여 후 40일 경과 후에도 어금니 치배 맹출은 관찰되지 않았다. 이상의 결과는 과량의 bisphosphonate는 치아 단단조직 형성 세포에 직접 작용함으로써 성장기 치아 형성 및 발육 지연을 유발할 수 있음을 시사하였다.
Abstract
Bisphosphonates have similar chemical structures to endogenous inorganic pyrophosphate which inhibits mineral deposition in biological tissues. Even though their clinical applications have been attempted, their molecular mechanism and cellular effects on dental hard tissue development remain to be elucidated. The present study was performed to investigate their effects on the development of the tooth and their mode of action. Alendronate, a synthetic derivative of bisphosphonates was subcutaneously daily injected in postnatal day 1 Sprague Dawley rats for successive 10 days. Animals were sacrificed at 3, 12 and 40 days after the final administration and light microscopy, RT-PCR and TUNEL were used for the analyses. Alendronate inhibited the teeth development and retarded their eruption. In the alendronate group, the mandibular first and second molars were under-developed, compared with those in the control group at day 3. Ameloblasts in the mandibular 1st molar were discontinuous in several parts. The development of the mandibular 2nd molar was deterred by the woven bone growing into the dental papilla. The third molar tooth germ did not appear. The TUNEL positive cells were rarely seen in the normally developing hard tissue cells. But in the alendronate group, the positive cells appeared frequently in layers of ameloblasts. Furthermore, the expression of alkaline phosphatase mRNA was downregulated in the alendronate group, suggesting that osteoblastic activity was decreased. These results suggested that bisphosphonates may act on dental hard tissue cells, preventing tooth development and eruption.
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