Lotinun Sutada, Sibonga Jean D, Turner Russell T
Department of Orthopedics, Mayo Clinic, Rochester, Minnesota 55905, USA.
Endocrinology. 2003 May;144(5):2000-7. doi: 10.1210/en.2002-221000.
Parathyroid bone disease in humans is caused by chronic hyperparathyroidism (HPT). Continuous infusion of PTH into rats results in histological changes similar to parathyroid bone disease, including increased bone formation, focal bone resorption, and severe peritrabecular fibrosis, whereas pulsatile PTH increases bone formation without skeletal abnormalities. Using a cDNA microarray with over 5000 genes, we identified an association between increased platelet-derived growth factor-A (PDGF-A) signaling and PTH-induced bone disease in rats. Verification of PDGF-A overexpression was accomplished with a ribonuclease protection assay. Using immunohistochemistry, PDGF-A peptide was localized to mast cells in PTH-treated rats. We also report a novel strategy for prevention of parathyroid bone disease using triazolopyrimidine (trapidil). Trapidil, an inhibitor of PDGF signaling, did not have any effect on indexes of bone turnover in normal rats. However, dramatic reductions in marrow fibrosis and bone resorption, but not bone formation, were observed in PTH-treated rats given trapidil. Also, trapidil antagonized the PTH-induced increases in mRNA levels for PDGF-A. These results suggest that PDGF signaling is important for the detrimental skeletal effects of HPT, and drugs that target the cytokine or its receptor might be useful in reducing or preventing parathyroid bone disease.
人类甲状旁腺骨病由慢性甲状旁腺功能亢进症（HPT）引起。持续向大鼠输注甲状旁腺激素（PTH）会导致类似于甲状旁腺骨病的组织学变化，包括骨形成增加、局灶性骨吸收和严重的骨小梁周围纤维化，而脉冲式PTH增加骨形成但无骨骼异常。使用具有5000多个基因的cDNA微阵列，我们在大鼠中确定了血小板衍生生长因子-A（PDGF-A）信号增强与PTH诱导的骨病之间的关联。通过核糖核酸酶保护试验完成了PDGF-A过表达的验证。使用免疫组织化学方法，在PTH处理的大鼠中，PDGF-A肽定位于肥大细胞。我们还报告了一种使用三唑并嘧啶（曲匹地尔）预防甲状旁腺骨病的新策略。曲匹地尔是一种PDGF信号抑制剂，对正常大鼠的骨转换指标没有任何影响。然而，在给予曲匹地尔的PTH处理大鼠中，观察到骨髓纤维化和骨吸收显著减少，但骨形成未减少。此外，曲匹地尔拮抗了PTH诱导的PDGF-A mRNA水平升高。这些结果表明，PDGF信号对于HPT对骨骼的有害作用很重要，靶向该细胞因子或其受体的药物可能有助于减少或预防甲状旁腺骨病。
